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1.  Altered spatial learning, cortical plasticity and hippocampal anatomy in a neurodevelopmental model of schizophrenia-related endophenotypes 
The European journal of neuroscience  2012;36(6):2773-2781.
Adult rats exposed to the DNA-methylating agent methylazoxymethanol on embryonic day 17 show a pattern of neurobiological deficits that model some of the neuropathological and behavioral changes observed in schizophrenia. Although it is generally assumed that these changes reflect targeted disruption of embryonic neurogenesis, it is unknown whether these effects generalize to other antimitotic agents administered at different stages of development. In the present study, neurochemical, behavioral and electrophysiological techniques were used to determine whether exposure to the antimitotic agent Ara-C later in development recapitulates some of the changes observed in methylazoxymethanol (MAM)-treated animals and in patients with schizophrenia. Male rats exposed to Ara-C (30 mg/kg/day) at embryonic days 19.5 and 20.5 show reduced cell numbers and heterotopias in hippocampal CA1 and CA2/3 regions, respectively, as well as cell loss in the superficial layers of the pre- and infralimbic cortex. Birth date labeling with bromodeoxyuridine reveals that the cytoarchitectural changes in CA2/3 are a consequence rather that a direct result of disrupted cortical neurogenesis. Ara-C-treated rats possess elevated levels of cortical dopamine and DOPAC (3,4-didyhydroxypheylacetic acid) but no change in norepinephrine or serotonin. Ara-C-treated rats are impaired in their ability to learn the Morris Water Maze task and showed diminished synaptic plasticity in the hippocampocortical pathway. These data indicate that disruption of neurogenesis at embryonic days 19.5 and 20.5 constitutes a useful model for the comparative study of deficits observed in other gestational models and their relationship to cognitive changes observed in schizophrenia.
doi:10.1111/j.1460-9568.2012.08204.x
PMCID: PMC3902091  PMID: 22762562
animal model; cytosine arabinoside; long-term potentiation; methylazoxymethanol; rat; spatial learning
2.  Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors 
Leukemia  2012;27(1):10.1038/leu.2012.191.
FMS-like tyrosine kinase 3 (FLT3) normally functions in the survival/proliferation of hematopoietic stem/progenitor cells, but its constitutive activation by internal tandem duplication (ITD) mutations correlates with a poor prognosis in AML. The development of FLT3 tyrosine kinase inhibitors (TKI) is a promising strategy, but resistance that arises during the course of treatment caused by secondary mutations within the mutated gene itself poses a significant challenge. In an effort to predict FLT3 resistance mutations that might develop in patients, we used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. We identified F621L, A627P, F691L and Y842C mutations in FLT3/ITD that confer varying levels of resistance to FLT3 TKI. Western blotting confirmed that some FLT3 TKI were ineffective at inhibiting FLT3 autophosphorylation and signaling through MAP kinase, STAT5 and AKT in some mutants. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. These results indicate a growing number of FLT3 mutations that are likely to be encountered in patients. Such knowledge, combined with known remaining sensitivity to other FLT3 TKI, will be important to establish as secondary drug treatments that can be substituted when these mutants are encountered.
doi:10.1038/leu.2012.191
PMCID: PMC3822911  PMID: 22858906
acute myeloid leukemia; mutant FLT3; drug resistance; tyrosine kinase inhibitors
3.  Socioeconomic position, treatment, and survival of non-Hodgkin lymphoma in Denmark – a nationwide study 
British Journal of Cancer  2012;106(5):988-995.
Background:
Not all patients have benefited equally from the advances in non-Hodgkin lymphoma (NHL) survival. This study investigates several individual-level markers of socioeconomic position (SEP) in relation to NHL survival, and explores whether any social differences could be attributed to comorbidity, disease and prognostic factors, or the treatment given.
Methods:
This registry-based cohort study links clinical data on prognostic factors and treatment from the national Danish lymphoma database to individual socioeconomic information in Statistics Denmark including 6234 patients diagnosed with NHL in 2000–2008.
Results:
All-cause mortality was 40% higher in NHL patients with short vs higher education diagnosed in the period 2000–2004 (hazard ratio (HR)=1.40 (1.27–1.54)), and 63% higher in the period 2005–2008 (HR=1.63 (1.40–1.90)). Further, mortality was increased in unemployed and disability pensioners, those with low income, and singles. Clinical prognostic factors attenuated, but did not eliminate the association between education and mortality. Radiotherapy was less frequently given to those with a short education (odds ratio (OR)= 0.84 (0.77–0.92)), low income (OR=0.80 (0.70–0.91)), and less frequent to singles (OR=0.79 (0.64–0.96)). Patients living alone were less likely to receive all treatment modalities.
Conclusion:
Patients with low SEP have an elevated mortality rate after a NHL diagnosis, and more advanced disease at the time of diagnosis explained a part of this disparity. Thus, socioeconomic disparities in NHL survival might be reduced by improving early detection among patients of low SEP.
doi:10.1038/bjc.2012.3
PMCID: PMC3305955  PMID: 22315055
non-Hodgkin lymphoma; socioeconomic position; survival; radiotherapy; chemotherapy; immunotherapy
4.  Molecular Mechanisms of Cerebrospinal Fluid Production 
Neuroscience  2004;129(4):957-970.
The epithelial cells of the choroid plexuses secrete cerebrospinal fluid (CSF), by a process which involves the transport of Na+, Cl- and HCO3- from the blood to the ventricles of the brain. The unidirectional transport of ions is achieved due to the polarity of the epithelium, i.e. the ion transport proteins in the blood-facing (basolateral) membrane are different to those in the ventricular (apical) membrane. The movement of ions creates an osmotic gradient which drives the secretion of H2 O. A variety of methods (e.g. isotope flux studies, electrophysiological, RT-PCR, in situ hybridization and immunocytochemistry) have been used to determine the expression of ion transporters and channels in the choroid plexus epithelium. Most of these transporters have now been localized to specific membranes. For example, Na+-K+ ATPase, K+ channels and Na+-2Cl--K+ cotransporters are expressed in the apical membrane. By contrast the basolateral membrane contains Cl--HCO3 exchangers, a variety of Na+ coupled HCO3- transporters and K+-Cl- cotransporters. Aquaporin 1 mediates water transport at the apical membrane, but the route across the basolateral membrane is unknown. A model of CSF secretion by the mammalian choroid plexus is proposed which accommodates these proteins. The model also explains the mechanisms by which K+ is transported from the CSF to the blood.
doi:10.1016/j.neuroscience.2004.07.003
PMCID: PMC1890044  PMID: 15561411
choroid plexus; blood-cerebrospinal fluid barrier; epithelial cells; ion transport; ion channels; Na+-K+ ATPase
6.  Further Clinical Validation of the Walking Impairment Questionnaire for Classification of Walking Performance in Patients with Peripheral Artery Disease 
The purpose of this study was to further validate the Walking Impairment Questionnaire (WIQ) as a self-report tool to aid in the clinical identification of walking ability of patients with peripheral artery disease (PAD). 132 patients with PAD and an ankle brachial index (ABI) ≤0.90 were enrolled; 123 provided complete data for the WIQ and standardized graded treadmill test. The WIQ scores were consistent with reported scores in other studies. The absolute claudication distance (ACD) ranged from 42.3 to 1589.2 meters; the peak walking time (PWT) ranged from 68 to 1800 seconds. Adjusted WIQ scores were positively and moderately associated with the log transformed ACD and PWT (r > .53, P < .001). Based on the area under the curve analysis, an overall WIQ score of 42.5 or less identified low performers (sensitivity 0.90, specificity 0.73); the combined subscale score of distance and stair of 75.5 or more identified high performers (sensitivity 0.41, specificity 0.90). We conclude that WIQ cut-offs appropriately classify walking performance in PAD patients, making this a potentially useful clinical tool. Consideration needs to be given to incorporating a standardized WIQ version into practice guidelines and the use of innovative strategies to facilitate clinical uptake.
doi:10.1155/2012/190641
PMCID: PMC3419442  PMID: 22919494
7.  LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo-Controlled Trial 
Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA1c; and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.
doi:10.1038/clpt.2012.58
PMCID: PMC3400893  PMID: 22739142
8.  Beta band stability over time correlates with Parkinsonian rigidity and bradykinesia 
Experimental Neurology  2012;236(2):383-388.
Abnormal oscillatory activity in the basal ganglia is increasingly implicated in the pathophysiology of Parkinson's disease. Such activity is recorded in patients in the form of oscillations in the local field potential (LFP) picked up in the subthalamic nucleus. Previous studies have focused on correlations between features of the time averaged power or amplitude spectrum of the LFP and the clinical state, either off medication or in response to levodopa. However, average spectral densities do not take account of time variant spectral properties and we hypothesised that these dynamic properties of the spectrum of the LFP would contain additional information about clinical state. Here we assess the variability in LFP amplitude over time using the coefficient of variation (CV), evaluating this with regard to clinical state off medication and in response to levodopa in two datasets. The CV of activity in the high beta frequency band was found to be correlated with clinical state off levodopa (rho = − 0.59, p < 0.001) and this was shown to be complementary, rather than redundant, to spectral amplitude in a multiple regression analysis, selective for rigidity–bradykinesia and highly focal. Similarly, a strong correlation was found between change in clinical scores and change in high beta CV following levodopa (rho = − 0.66, p = 0.004). This too was selective for rigidity–bradykinesia and non-redundant to spectral power in a multiple regression model. Our results indicate that temporal stability in the beta band is correlated with rigidity–bradykinesia. It is suggested that loss of beta reactivity is deleterious to basal ganglia function over and above any concomitant change in absolute level of beta synchrony. The CV of LFP beta band amplitude may potentially provide an additional index of clinical state suitable for feedback control in closed loop stimulation therapy.
Highlights
► Variability in beta band amplitude correlates with rigidity–bradykinesia in Parkinson's. ► Correlations occur with motor impairment off medication. ► Correlations also occur with change in motor impairment upon treatment. ► Correlations are frequency and symptom specific, as well as spatially focal.
doi:10.1016/j.expneurol.2012.04.024
PMCID: PMC3400051  PMID: 22572590
CV, Coefficient of variation; DBS, Deep brain stimulation; KS, Kolmogorov–Smirnov test; LFP, Local field potential; LZC, Lempel–Ziv complexity; STN, Subthalamic nucleus; UPDRS, Unified Parkinson's disease rating scale; Parkinson's disease; Deep brain stimulation; Beta; Oscillations; Biomarker
9.  Psychosocial care for cancer: a framework to guide practice, and actionable recommendations for Ontario 
Current Oncology  2012;19(4):209-216.
Objectives
We set out to create a psychosocial oncology care framework and a set of relevant recommendations that can be used to improve the quality of comprehensive cancer care for Ontario patients and their families.meet the psychosocial health care needs of cancer patients and their families at both the provider and system levels.
Data Sources and Methods
The adapte process and the practice guideline development cycle were used to adapt the 10 recommendations from the 2008 U.S. Institute of Medicine standard Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs into the psychosocial oncology care framework. In addition, the evidence contained in the original document was used, in combination with the expertise of the working group, to create a set of actionable recommendations. Refinement after formal external review was conducted.
Data Extraction and Synthesis
The new framework consists of 8 defining domains. Of those 8 domains, 7 were adapted from recommendations in the source document; 1 new domain, to raise awareness about the need for psychosocial support of cancer patients and their families, was added. To ensure high-quality psychosocial care and services, 31 actionable recommendations were created. The document was submitted to an external review process. More than 70% of practitioners rated the quality of the advice document as high and reported that they would recommend its use.
Conclusions
This advice document advocates for a multidisciplinary approach to cancer care in response to the distress experienced by cancer patients and their families. The recommendations will be useful in future to measure performance, quality of practice, and access to psychosocial services.
doi:10.3747/co.19.981
PMCID: PMC3410830  PMID: 22876147
Guideline; framework; cancer; psychosocial oncology; patient-centred care
10.  Reproducibility of sodium MRI measures of articular cartilage of the knee in osteoarthritis 
Osteoarthritis and Cartilage  2011;20(1):29-35.
SUMMARY
Objective
To determine the stability and reproducibility of the sodium magnetic resonance imaging (MRI) signal measured in the articular cartilage of the knee in both healthy volunteers and osteoarthritis (OA) patients.
Design
This was a prospective Research Ethics Committee approved study that acquired sodium and proton MRI data from 15 subjects with OA (three males, age 64 ± 10) and five healthy controls age and sex matched over the group. Each subject underwent standing planar radiographs of their knees for radiological scoring as well as symptomatological assessment questionnaires. In two MRI sessions on the same day, high resolution double-echo steady state (DESS) and 3D short echo time sodium MRI images of the most diseased knee were acquired and co-registered in each session. A blinded reader (LT) manually delineated the articular cartilage into four discrete regions, and two combined regions, on the DESS images. These regions were applied to the sodium images, and a median sodium signal from each reported. Within-subject and between-subject coefficients of variation were estimated and intraclass correlation coefficients for the healthy control group, OA subject group, and all pooled subjects group were calculated.
Results
Within-subject variability of sodium MRI at 3 T was 3.2% overall, and 2.0% in healthy age-matched volunteers compared to a reproducibility of 3.6% on OA subjects.
Conclusions
The reproducibility of sodium MRI was similar in both healthy controls and OA subjects. Researchers piloting techniques in healthy controls thus may expect a similar reproducibility in a controlled trial involving subjects with American College of Rheumatology (ACR)-defined OA of the knee.
doi:10.1016/j.joca.2011.10.007
PMCID: PMC3270258  PMID: 22040861
Sodium; Magnetic resonance imaging; Osteoarthritis; Knee cartilage; Repeatability
11.  What traits are carried on mobile genetic elements, and why? 
Heredity  2010;106(1):1-10.
Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes.
doi:10.1038/hdy.2010.24
PMCID: PMC3183850  PMID: 20332804
mobile genetic elements; toxin–antitoxin; plasmid addiction; mutualisms; social evolution; microbial ecology
12.  Entourage: the immune microenvironment following follicular lymphoma 
Blood Cancer Journal  2012;2(1):e52-.
In follicular lymphoma, nonmalignant immune cells are important. Follicular lymphoma depends on CD4+ cells, but CD8+ cells counteract it. We hypothesized that the presence of follicular lymphoma is associated with higher CD4+ than CD8+ cell numbers in the tumor microenvironment but not in the immune system. Using flow cytometry, pre-treatment and follow-up CD4/CD8 ratios were estimated in the bone marrow, blood and lymph nodes of untreated follicular lymphoma patients in two independent data sets (N1=121; N2=166). The ratios were analyzed for their relation with bone marrow lymphoma involvement. Bone marrows were also investigated with immunohistochemistry. In either data set, the bone marrow CD4/CD8 ratios were higher in bone marrows involved with lymphoma (P=0.043 and 0.0002, respectively). The mean CD4/CD8 ratio was 1.0 in uninvolved and 1.4 in involved bone marrows. Also higher in involved bone marrows were CD4/CD56 and CD3CD25/CD3 ratios. No blood or lymph node ratios differed between bone marrow-negative and -positive patients. Sequential samples showed increased bone marrow CD4/CD8 ratios in all cases of progression to bone marrow involvement. Immunohistochemistry showed CD4+, CD57+, programmed death-1+, forkhead box protein 3+ and CD21+ cells accumulated inside the lymphoma infiltrates, whereas CD8+, CD56+ and CD68+ cells were outside the infiltrates. This study provides evidence in vivo that the microenvironment changes upon follicular lymphoma involvement.
doi:10.1038/bcj.2011.53
PMCID: PMC3270257  PMID: 22829236
follicular lymphoma; microenvironment; bone marrow; CD4/CD8 ratio
13.  Plant nutrition for sustainable development and global health 
Annals of Botany  2010;105(7):1073-1080.
Background
Plants require at least 14 mineral elements for their nutrition. These include the macronutrients nitrogen (N), phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg) and sulphur (S) and the micronutrients chlorine (Cl), boron (B), iron (Fe), manganese (Mn), copper (Cu), zinc (Zn), nickel (Ni) and molybdenum (Mo). These are generally obtained from the soil. Crop production is often limited by low phytoavailability of essential mineral elements and/or the presence of excessive concentrations of potentially toxic mineral elements, such as sodium (Na), Cl, B, Fe, Mn and aluminium (Al), in the soil solution.
Scope
This article provides the context for a Special Issue of the Annals of Botany on ‘Plant Nutrition for Sustainable Development and Global Health’. It provides an introduction to plant mineral nutrition and explains how mineral elements are taken up by roots and distributed within plants. It introduces the concept of the ionome (the elemental composition of a subcellular structure, cell, tissue or organism), and observes that the activities of key transport proteins determine species-specific, tissue and cellular ionomes. It then describes how current research is addressing the problems of mineral toxicities in agricultural soils to provide food security and the optimization of fertilizer applications for economic and environmental sustainability. It concludes with a perspective on how agriculture can produce edible crops that contribute sufficient mineral elements for adequate animal and human nutrition.
doi:10.1093/aob/mcq085
PMCID: PMC2887071  PMID: 20430785
Biofortification; fertilizer use efficiency; mineral nutrition; pollution; toxicity; transport protein
14.  Occupation and cancer in Britain 
British Journal of Cancer  2010;102(9):1428-1437.
Background:
Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens.
Methods:
We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed.
Results:
5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer).
Conclusion:
This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.
doi:10.1038/sj.bjc.6605637
PMCID: PMC2865752  PMID: 20424618
occupation; cancer burden; attributable fraction; industry sector; carcinogen
15.  SPINAL CORD STIMULATION FAILED TO RELIEVE AKINESIA OR RESTORE LOCOMOTION IN PARKINSON DISEASE 
Neurology  2010;74(16):1325-1327.
doi:10.1212/WNL.0b013e3181d9ed58
PMCID: PMC2860483  PMID: 20404313
16.  Prevention of tumorigenesis in p53 null mammary epithelium by rexinoid bexarotene, tyrosine kinase inhibitor gefitinib and celecoxib 
The chemopreventive effects of three agents, rexinoid bexarotene, tyrosine kinase inhibitor gefitinib and celecoxib, were tested on mammary tumor development arising in p53 null mammary epithelium. The rexinoid bexarotene was the most efficacious inhibitor as it reduced mammary tumor development by 75% in virgin mice and significantly delayed mean tumor development by 98 days in hormone stimulated mice. The tyrosine kinase inhibitor gefitinib reduced mammary tumor incidence by 50% in virgin mice but did not significantly delay mean tumor latency in hormone stimulated mice. Celecoxib did not reduce tumor incidence or mean tumor latency in either of the two models. The high doses of the rexinoid and the tyrosine kinase inhibitor did not affect the progression of tumors arising from the premalignant mammary outgrowth line, PN8a. A comparison of these agents with tamoxifen shows the superiority of tamoxifen in preventing tumor development in p53 null mammary cells. Similarly, a comparison of the results of the p53 model with other transgenic models to the chemopreventive agents demonstrated that mammary tumors arising from different oncogenic events will respond differently to the different agents.
doi:10.1158/1940-6207.CAPR-08-0107
PMCID: PMC2995265  PMID: 19174577
Research; prevention; mammary
17.  Orbitofrontal inactivation impairs reversal of Pavlovian learning by interfering with disinhibition of responding for previously unrewarded cues 
The European journal of neuroscience  2009;30(10):1941-1946.
Orbitofrontal cortex (OFC) is critical for reversal learning. Reversal deficits are typically demonstrated in complex settings that combine Pavlovian and instrumental learning. Yet recent work has implicated the OFC specifically in behaviors guided by cues and the features of the specific outcomes they predict. To test whether the OFC is important for reversing such Pavlovian associations in the absence of confounding instrumental requirements, we trained rats on a simple Pavlovian task in which two auditory cues were presented, one paired with a food pellet reward and the other presented without reward. After learning, we reversed the cue-outcome associations. For half the rats, OFC was inactivated prior to each reversal session. Inactivation of OFC impaired the ability of the rats to reverse conditioned responding. This deficit reflected the inability of inactivated rats to develop normal responding for the previously unrewarded cue; inactivation of OFC had no impact on the ability of the rats to inhibit responding to the previously rewarded cue. These data show that OFC is critical to reversal of Pavlovian responding, and that the role of OFC in this behavior cannot be explained as a simple deficit in response inhibition. Furthermore, the contrast between the normal inhibition of responding, reported here, and impaired inhibition of responding during Pavlovian over-expectation, reported previously, suggest the novel hypothesis that OFC may be particularly critical for learning (or behavior) when it requires the subject to generate predictions about outcomes by bringing together or integrating disparate pieces of associative information.
doi:10.1111/j.1460-9568.2009.06992.x
PMCID: PMC2810348  PMID: 19912335
orbitofrontal; pavlovian; reversal; associative learning; rat; expectancies
18.  Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients 
Background
Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity.
Methods
To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 μs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides.
Results
The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V.
Conclusion
The findings suggest that DBS can suppress pathological 11–30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.
doi:10.1136/jnnp.2010.217489
PMCID: PMC3072048  PMID: 20935326
Parkinson's disease; basal ganglia; deep brain stimulation; oscillations; neurophysiology; electrical stimulation; motor physiology; movement disorders; motor
19.  Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers 
Journal of Medical Genetics  2010;48(1):64-68.
Background
Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition.
Method
To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions.
Results
No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis.
Conclusion
Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.
doi:10.1136/jmg.2010.079814
PMCID: PMC3003879  PMID: 20921021
Hereditary lobular breast cancer; CDH1; E-cadherin; hereditary breast cancer; hereditary diffuse gastric cancer; genetic screening/counselling; oncology; cancer: breast
20.  Ventral striatal neurons encode the value of the chosen action in rats deciding between differently delayed or sized rewards 
SUMMARY
The ventral striatum (VS) is thought to serve as a gateway whereby associative information from the amygdala and prefrontal regions can influence motor output to guide behavior. If VS mediates this ‘limbic-motor’ interface, then one might expect neural correlates in VS to reflect this information. Specifically neural activity should reflect the integration of motivational value with subsequent behavior. To test this prediction, we recorded from single units in VS while rats performed a choice task in which different odor cues indicated that reward was available on the left or on the right. The value of reward associated with a left or rightward movement was manipulated in separate blocks of trials by either varying the delay preceding reward delivery or by changing reward size. Rats’ behavior was influenced by the value of the expected reward and the response required to obtain it, and activity in the majority of cue-responsive VS neurons reflected the integration of these two variables. Unlike similar cue-evoked activity reported previously in dopamine neurons, these correlates were only observed if the directional response was subsequently executed. Further, activity was correlated with the speed at which the rats’ executed the response. These results are consistent with the notion that VS serves to integrate information about the value of an expected reward with motor output during decision-making.
doi:10.1523/JNEUROSCI.2572-09.2009
PMCID: PMC2788608  PMID: 19846724
ventral striatum; decision-making; associative learning; single unit; rat; odor
21.  Quantifying within- and between-animal variation and uncertainty associated with counts of Escherichia coli O157 occurring in naturally infected cattle faeces 
Cattle faeces are considered the most important reservoir for human infection with Escherichia coli O157. We have previously described shedding of E. coli O157 in the faeces of naturally infected cattle cohorts. However, the data require further investigation to quantify the uncertainty and variability in the estimates previously presented. This paper proposes a method for analysing both the presence and the quantity of E. coli O157 in cattle faecal samples, using two isolation procedures, one of which enumerates E. coli O157. The combination of these two measurements, which are fundamentally different in nature and yet measuring a common outcome, has necessitated the development of a novel statistical model for ascertaining the contribution of the various components of variation (both natural and observation induced) and for judging the influence of explanatory variables. Most of the variation within the sampling hierarchy was attributable to multiple samples from the same animal. The contribution of laboratory-level variation was found to be low. After adjusting for fixed and random effects, short periods of increased intensity of shedding were identified in individual animals. We conclude that within-animal variation is greater than between animals over time, and studies aiming to elucidate the dynamics of shedding should focus resources, sampling more within than between animals. These findings have implications for the identification of persistent high shedders and for assessing their role in the epidemiology of E. coli O157 in cattle populations. The development of this non-standard statistical model may have many applications to other microbial count data.
doi:10.1098/rsif.2008.0183
PMCID: PMC2658787  PMID: 18647739
Escherichia coli O157; variation; epidemiology; concentration; cattle
22.  The prevalence of sight‐threatening uveitis in Scotland 
Aim
To identify and quantify the prevalence of patients with uveitis receiving systemic immunosuppression in Scotland.
Methods
Anonymised data were prospectively collected on all patients with uveitis requiring systemic immunosuppression. Seven health boards participated over a 4‐month period between 1 August 2005 and 30 November 2005.
Results
373 patients were identified, of whom 205 (55%) were female. The mean age was 46.4 (range 7–97 years). Using the data from the seven participating health boards, an estimated Scottish prevalence of 9 per 100 000 was calculated. Prevalence varied between 2 and 59 per 100 000. In National Health Service Grampian, all patients with uveitis, whether sight‐threatening or not, are followed up at a specialist clinic. Extrapolating this figure to Scotland gives a prevalence of 25 per 100 000.
Discussion
The data from National Health Service Grampian suggest that there is a significant shortfall in the number of patients identified by survey. If the “missing population” exists, then where are they? Some might be receiving appropriate treatment at non‐specialist clinics, although simple under‐reporting may play a part. Greater concern is for those patients receiving inappropriate treatment for their uveitis, or for those within the community who are either oblivious to or in self denial of their condition.
doi:10.1136/bjo.2006.101386
PMCID: PMC1857573  PMID: 16916876
23.  Collaborative annotation of genes and proteins between UniProtKB/Swiss-Prot and dictyBase 
UniProtKB/Swiss-Prot, a curated protein database, and dictyBase, the Model Organism Database for Dictyostelium discoideum, have established a collaboration to improve data sharing. One of the major steps in this effort was the ‘Dicty annotation marathon’, a week-long exercise with 30 annotators aimed at achieving a major increase in the number of D. discoideum proteins represented in UniProtKB/Swiss-Prot. The marathon led to the annotation of over 1000 D. discoideum proteins in UniProtKB/Swiss-Prot. Concomitantly, there were a large number of updates in dictyBase concerning gene symbols, protein names and gene models. This exercise demonstrates how UniProtKB/Swiss-Prot can work in very close cooperation with model organism databases and how the annotation of proteins can be accelerated through those collaborations.
doi:10.1093/database/bap016
PMCID: PMC2790310  PMID: 20157489
24.  Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons 
Psychopharmacology  2009;204(3):465-476.
Rationale
Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are prodrugs for gamma-hydroxybutyrate (GHB). Like GHB, GBL and 1,4-BD are drugs of abuse, but their behavioral effects may differ from GHB under some conditions.
Objectives
The first study compared the behavioral effects of GBL (32−240 mg/kg) and 1,4-BD (32−240 mg/kg) with each other and to effects previously reported for GHB (32−420 mg/kg). A second study determined GHB pharmacokinetics following intragastric administration of GHB, GBL, and 1,4-BD.
Methods
Operant responding for food, observed behavioral effects, and a fine-motor task occurred at multiple time intervals after administration of drug or vehicle. In a separate pharmacokinetics study, blood samples were collected across multiple time points after administration of GHB, GBL, and 1,4-BD.
Results
Like GHB, GBL, and 1,4-BD impaired performance on the fine-motor task, but the onset of motor impairment differed across drugs. GBL and 1,4-BD dose dependently decreased the number of food pellets earned, but at lower doses than previously observed for GHB. Similar to GHB, both GBL and 1,4-BD produced sedation, muscle relaxation, gastrointestinal symptoms, and tremors/jerks. Administration of GBL and 1,4-BD produced higher maximum concentrations of GHB with shorter times to maximum concentrations of GHB in plasma when compared to GHB administration.
Conclusions
GBL and 1,4-BD produced behavioral effects similar to those previously reported with GHB and the time course of effects were related to blood levels of GHB. Given their higher potency and faster onset of effects, the abuse liability of GBL and 1,4-BD may be greater than GHB.
doi:10.1007/s00213-009-1477-8
PMCID: PMC2682635  PMID: 19198808
GABA; Behavior; Drug abuse; Operant
25.  Intra-testicular injection of adenoviral constructs results in Sertoli cell-specific gene expression and disruption of the seminiferous epithelium 
Reproduction (Cambridge, England)  2008;137(2):361-370.
Spermatogenesis is a complex process that cannot be modelled in vitro. The somatic Sertoli cells (SCs) within the seminiferous tubules perform a key role in supporting maturation of germ cells (GCs). Progress has been made in determining what aspects of SC function are critical to maintenance of fertility by developing rodent models based on the Cre/LoxP system; however, this is time-consuming and is only applicable to mice. The aim of the present study was to establish methods for direct injection of adenoviral vectors containing shRNA constructs into the testis as a way of inducing target-selective knock-down in vivo. This paper describes a series of experiments using adenovirus expressing a green fluorescent protein (GFP) transgene. Injection via the efferent ductules resulted in SC-specific expression of GFP; expression levels paralleled the amount of infective viral particles injected. At the highest doses of virus seminiferous tubule architecture were grossly disturbed and immune cell invasion noted. At lower concentrations, the expression of GFP was variable/negligible, the seminiferous tubule lumen was maintained but stage-dependent GC loss and development of numerous basal vacuoles was observed. These resembled intercellular dilations of SC junctional complexes previously described in rats and may be a consequence of disturbances in SC function due to interaction of the viral particles with the coxsackie/adenovirus receptor that is a component of the junctional complexes within the blood testis barrier. In conclusion, intra-testicular injection of adenoviral vectors disturbs SC function in vivo and future work will therefore focus on the use of lentiviral delivery systems.
doi:10.1530/REP-08-0247
PMCID: PMC2709205  PMID: 18955374

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