bluuebunny/crossref_metadata_2025 huggingface dataset:
The molecular determinants of CD8 co‐receptor function
Authors: Cole David K. , Laugel Bruno , Clement Mathew , Price David A. , Wooldridge Linda , Sewell Andrew K.
Published: July 2012

CD8+ T cells respond to signals mediated through a specific interaction between the T‐cell receptor (TCR) and a composite antigen in the form of an epitopic peptide bound between the polymorphic α1 and α2 helices of an MHC class I (MHCI) molecule. The CD8 glycoprotein ‘co‐receives’ antigen by binding to an invariant region of the MHCI molecule and can enhance ligand recognition by up to 1 million‐fold. In recent years, a number of structural and biophysical investigations have shed light on the role of the CD8 co‐receptor during T‐cell antigen recognition. Here, we provide a collated resource for these data, and discuss how the structural and biophysical parameters governing CD8 co‐receptor function further our understanding of T‐cell cross‐reactivity and the productive engagement of low‐affinity antigenic ligands.
Ruminant organotypic brain‐slice cultures as a model for the investigation of CNS listeriosis
Authors: Guldimann Claudia , Lejeune Beatrice , Hofer Sandra , Leib Stephen L. , Frey Joachim , Zurbriggen Andreas , Seuberlich Torsten , Oevermann Anna
Published: July 2012

Central nervous system (CNS) infections in ruminant livestock, such as listeriosis, are of major concern for veterinary and public health. To date, no host‐specific in vitro models for ruminant CNS infections are available. Here, we established and evaluated the suitability of organotypic brain‐slices of ruminant origin as in vitro model to study mechanisms of Listeria monocytogenes CNS infection. Ruminants are frequently affected by fatal listeric rhombencephalitis that closely resembles the same condition occurring in humans. Better insight into host–pathogen interactions in ruminants is therefore of interest, not only from a veterinary but also from a public health perspective. Brains were obtained at the slaughterhouse, and hippocampal and cerebellar brain‐slices were cultured up to 49 days. Viability as well as the composition of cell populations was assessed weekly. Viable neurons, astrocytes, microglia and oligodendrocytes were observed up to 49 days in vitro. Slice cultures were infected with L. monocytogenes, and infection kinetics were monitored. Infected brain cells were identified by double immunofluorescence, and results were compared to natural cases of listeric rhombencephalitis. Similar to the natural infection, infected brain‐slices showed focal replication of L. monocytogenes and bacteria were predominantly observed in microglia, but also in astrocytes, and associated with axons. These results demonstrate that organotypic brain‐slice cultures of bovine origin survive for extended periods and can be infected easily with L. monocytogenes. Therefore, they are a suitable model to study aspects of host–pathogen interaction in listeric encephalitis and potentially in other neuroinfectious diseases.
From middens to molecules: phylogeography of the piñon pine, Pinus edulis
Authors: Duran Kristy L. , Pardo Alicia , Mitton Jeffry B.
Published: July 2012

Aim  Data from packrat middens have established a hypothesized historical biogeography of piñon pine, Pinus edulis, including locations of glacial refugia in the south‐western USA and subsequent migration out of the refugia. In this study, we used molecular techniques to test the glacial refugial hypotheses inferred from packrat (Neotoma) midden data for P. edulis.

Location  South‐western USA.

Methods  Two fragments of chloroplast DNA (a portion of the matK gene and a portion of the rbcL gene) for a total of 1045 base pairs were amplified and sequenced for 100 individuals. Thirty‐one populations were sampled throughout the range of P. edulis. Phylogenetic analyses included maximum parsimony and maximum likelihood.

Results  Very little variation existed among the individuals sampled. Four haplotypes were identified. The inferred ancestral haplotype was the most widespread; it was most common in Texas and New Mexico where, with the exception of one individual, it was the only haplotype found. Arizona and Utah populations were more diverse, with almost half of the populations containing two or more haplotypes. The most derived haplotype was most abundant in Arizona.

Main conclusions  The distribution of haplotypes is geographically informative. Only one haplotype exists in the south‐eastern portion of the range of P. edulis whereas up to four haplotypes are found in other populations, suggesting one of two hypotheses: either all modern populations are descended from a refugial population in central Arizona, or modern populations are descended from two refugial populations, one in central Arizona and another in Texas–southern New Mexico. Interpreting these data in the light of packrat midden data gives more support for the latter hypothesis.
Diagnosis of pheochromocytoma: a clinical practice guideline appraisal using AGREE II instrument
Authors: Yan Juping , Min Jie , Zhou Bo
Published: July 2012

Objective

The objective of this study was to assess the quality of clinical practice guidelines providing diagnostic recommendations on pheochromocytoma (PHEO) using the new Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and to promote the development of clinical guidelines.

Research design and methods

We searched MEDLINE and electronic databases for guidelines published between 2001 and 2010 regarding the diagnosis of PHEO. The methodological quality of guidelines for three fields for the diagnosis of PHEO was evaluated using the new AGREE II instrument by two independent appraisers. We also compared two different types of guidelines to determine the superior guideline.

Results

Four special guidelines and six general guidelines related to the diagnosis of PHEO were included in the study. According to AGREE II, two guidelines performed well in recommending biochemical evaluations. One guideline was good for radiodiagnosis, but no guideline was good for recommending genetic testing. The best‐performing domain of the AGREE II instrument was domain 1 (D1) (scope and purpose), while the worst performing domain was D5 (applicability) in both types of guidelines. The special guideline was significantly better than the general guideline in D4 (P < 0.01), while the general guideline performed better in D6. There were no differences in the other four domains.

Conclusions

The quality and rigour of guidelines for the diagnosis of PHEO vary. It is difficult to identify one guideline that performed well in all three fields for the diagnosis of PHEO based on the AGREE II instrument. Therefore, additional studies and greater efforts should be taken to provide high‐quality guidelines that serve as a useful and reliable tool for clinical decision making in diagnosing PHEO according to the AGREE II instrument.
The conserved lysine 151 of HCV NS5B modulates viral genome replication and infectious virus production
Authors: Haqshenas G.
Published: July 2012

Summary.  Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA‐dependent RNA polymerase (RdRp) that is involved in genome replication and virus assembly. NS5B contains a distinct loop (loop Λ2) at the beginning of the nucleoside triphosphate tunnel with a highly conserved lysine (K151). In this study, reverse genetic analysis revealed that substitution of Jc1 NS5B K151 for alanine (K151A) and aspartic acid (K151D) affected genome replication and infectious virus production. However, genome replication and virus production by Jc1 containing NS5B K151R remained unaltered. A major deletion in loop Λ2 abolished RNA replication, suggesting a role for this structural domain in NS5B polymerase activity. In conclusion, this study demonstrated that the conserved K151 modulates infectious virus production; and loop Λ2 is essential for the polymerase activity of NS5B.
Disassortative mating and the maintenance of sexual polymorphism in painted maple
Authors: FIELD DAVID L. , BARRETT SPENCER C. H.
Published: July 2012

Since Darwin’s pioneering research on plant reproductive biology (e.g. Darwin 1877), understanding the mechanisms maintaining the diverse sexual strategies of plants has remained an important challenge for evolutionary biologists. In some species, populations are sexually polymorphic and contain two or more mating morphs (sex phenotypes). Differences in morphology or phenology among the morphs influence patterns of non‐random mating. In these populations, negative frequency‐dependent selection arising from disassortative (intermorph) mating is usually required for the evolutionary maintenance of sexual polymorphism, but few studies have demonstrated the required patterns of non‐random mating. In the current issue of Molecular Ecology, Shang et al. (2012) make an important contribution to our understanding of how disassortative mating influences sex phenotype ratios in Acer pictum subsp. mono (painted maple), a heterodichogamous, deciduous tree of eastern China. They monitored sex expression in 97 adults and used paternity analysis of open‐pollinated seed to examine disassortative mating among three sex phenotypes. Using a deterministic ‘pollen transfer’ model, Shang et al. present convincing evidence that differences in the degree of disassortative mating in progeny arrays of the sex phenotypes can explain their uneven frequencies in the adult population. This study provides a useful example of how the deployment of genetic markers, demographic monitoring and modelling can be integrated to investigate the maintenance of sexual diversity in plants.
Tales of the unexpected: Phylogeography of the arctic‐alpine model plant Saxifraga oppositifolia (Saxifragaceae) revisited
Authors: WINKLER MANUELA , TRIBSCH ANDREAS , SCHNEEWEISS GERALD M. , BRODBECK SABINE , GUGERLI FELIX , HOLDEREGGER ROLF , ABBOTT RICHARD J. , SCHÖNSWETTER PETER
Published: July 2012

Arctic‐alpine biota occupy enormous areas in the Arctic and the northern hemisphere mountain ranges and have undergone major range shifts during their comparatively short history. The origins of individual arctic‐alpine species remain largely unknown. In the case of the Purple saxifrage, Saxifraga oppositifolia, an important model for arctic‐alpine plants, phylogeographic studies have remained inconclusive about early stages of the species’ spatiotemporal diversification but have provided evidence for long‐range colonization out of a presumed Beringian origin to cover today’s circumpolar range. We re‐evaluated the species’ large‐scale range dynamics based on a geographically extended sampling including crucial areas such as Central Asia and the (south‐)eastern European mountain ranges and employing up‐to‐date phylogeographic analyses of a plastid sequence data set and a more restricted AFLP data set. In accordance with previous studies, we detected two major plastid DNA lineages also reflected in AFLP divergence, suggesting a long and independent vicariant history. Although we were unable to determine the species’ area of origin, our results point to Europe (probably the Alps) and Central Asia, respectively, as the likely ancestral areas of the two main lineages. AFLP data suggested that contact areas between the two clades in the Carpathians, Northern Siberia and western Greenland were secondary. In marked contrast to high levels of diversity revealed in previous studies, populations from the major arctic refugium Beringia did not exhibit any plastid sequence polymorphism. Our study shows that adequate sampling of the southern, refugial populations is crucial for understanding the range dynamics of arctic‐alpine species.
Cross‐allergic Reactions to Legumes in Lupin and Fenugreek‐Sensitized Mice
Authors: Vinje N. E. , Namork E. , Løvik M.
Published: July 2012

Several legumes may induce allergy, and there is extensive serological cross‐reactivity among legumes. This cross‐reactivity has traditionally been regarded to have limited clinical relevance. However, the introduction of novel legumes to Western countries may have changed this pattern, and in some studies cross‐allergy to lupin has been reported in more than 60% of peanut‐allergic patients. We wanted to explore cross‐reactions among legumes using two newly established mouse models of food allergy. Mice were immunized perorally with fenugreek or lupin with cholera toxin as adjuvant. The mice were challenged with high doses of fenugreek, lupin, peanut or soy, and signs of anaphylactic reactions were observed. Cross‐allergic mechanisms were investigated using serum mouse mast cell protease‐1 (MMCP‐1), antibody responses, immunoblotting and ex vivo production of cytokines by spleen cells. Signs of cross‐allergy were observed for all the tested legumes in both models. The cross‐allergic symptoms were milder and affected fewer mice than the primary allergic responses. The cross‐allergy was reflected to a certain extent in the antibody and T‐cell responses, but not in serum MMCP‐1 levels. Cross‐allergy to peanut, soy, fenugreek and lupin was observed in lupin‐sensitized and fenugreek‐sensitized mice. Differences in serological responses between primary allergy and cross‐allergy might be due to mediation through different immune mechanisms or reflect different epitope affinity to IgE. These differences need to be further investigated.
Blood and bombs: the demand and use of blood following the London Bombings of 7 July 2005 – a retrospective review
Authors: Glasgow S. M. , Allard S. , Doughty H. , Spreadborough P. , Watkins E.
Published: July 2012

Mass casualty events (MCE) present health systems with a sudden demand on key services. The overall objective of this study was to describe the experience of the National Blood Service (NBS) following the largest UK MCE in recent times. Data was collated from the NBS database and directly from the hospitals involved. All data was collected immediately following the event and included: all blood components requested, issued and transfused in relation to the bombings, blood stock levels at the time and the injury profiles of the casualties transfused. The total NBS order from hospitals for the event was 1455 units of blood components. All requests were fulfilled, this included: 978 units of red cells (RC), 36 doses of platelets, 141 units of fresh frozen plasma (FFP) and 300 doses of cryoprecipitate. The amount of blood ordered was three times that initially used and the total number of RC transfused in treating all victims from admission to discharge was approximately 440 units. The greatest use of blood components was for those casualties who had sustained traumatic amputations amongst their injury profile. Published data with which to compare these results is lacking, although the RC use was similar to the initial mean individual usage described in previous military and civilian bombings. The overall implication for any blood service remains, there is now likely to be a far greater demand for plasma, platelets and cryoprecipitate in any future incidents involving victims suffering major haemorrhage.
Procalcitonin and C‐reactive protein as predictors of blood culture positivity among hospitalised children with severe pneumonia in Mozambique
Authors: Díez‐Padrisa N. , Bassat Q. , Morais L. , O’Callaghan‐Gordo C. , Machevo S. , Nhampossa T. , Ibarz‐Pavón A. B. , Quintó L. , Alonso P. L. , Roca A.
Published: July 2012

Objectives  To evaluate the benefits of using procalcitonin (PCT) and C‐reactive protein (CRP) as pre‐screening tools to predict blood culture positivity among Mozambican children with clinical severe pneumonia (CSP).

Methods  586 children <5 years with CSP and no concurrent malaria fulfilled criteria to be included in the study groups. We determined PCT and CRP for all children with positive bacterial culture (BC+ group, n = 84) and of a random selection of children with negative bacterial culture (BC− group, n = 246).

Results  PCT and CRP levels were higher in the BC+ group than the BC− one (PCT: median 7.73 versus 0.48 ng/ml, P < 0.001; CRP: 177.65 mg/l vs. 26.5 mg/l, P < 0.001). In multivariate analysis, PCT was the only independent predictor of the group. To be used as pre‐screening tool, PCT presented higher specificities for predetermined sensitivities (≥85%) than CRP. Pursuing a sensitivity of 95%, PCT could reduce the need for bacterial culture by 49% and overall diagnosis costs by 7–35% [assuming variable costs for PCT measurement (ranging from 10 to 30 USD) and a fixed cost of 72.5 USD per blood culture].

Conclusions  Among hospitalised children with CSP and absence of concurrent malaria, PCT pre‐screening could help reduce the number of blood cultures and diagnosis costs by specifically targeting patients more likely to yield positive results.
Neurocysticercosis: is serology useful in the absence of brain imaging?
Authors: Garcia Hector H. , Rodriguez Silvia , Gilman Robert H. , Gonzalez Armando E. , Tsang Victor C. W. ,   for the Cysticercosis Working Group in Peru
Published: July 2012

Neurocysticercosis (NCC) is endemic in most parts of the world and is now recognised as an important contributor to neurological disease. Serological diagnosis of NCC improved greatly in the past two decades and contributed to demonstrating previously unsuspected regions of endemicity. Claims for an accurate serological screening tool for human cysticercosis are frequently raised. However, after symptomatic therapeutics are applied, management of NCC is driven by the characteristics of the central nervous system infection in terms of viability, number, location size and evolutionary stage of parasites, as well as by the resulting inflammation. It is unclear whether, in the absence of neuroimaging, serological confirmation of aetiology of suspected cases (neurologically symptomatic) or detection of asymptomatic cases in population screening would affect their management or prognosis.
Space‐time clusters of dengue fever in Bangladesh
Authors: Banu Shahera , Hu Wenbiao , Hurst Cameron , Guo Yuming , Islam Mohammad Zahirul , Tong Shilu
Published: July 2012

Objective  To examine the space‐time clustering of dengue fever (DF) transmission in Bangladesh using geographical information system and spatial scan statistics (SaTScan).

Methods  We obtained data on monthly suspected DF cases and deaths by district in Bangladesh for the period of 2000–2009 from Directorate General of Health Services. Population and district boundary data of each district were collected from national census managed by Bangladesh Bureau of Statistics. To identify the space‐time clusters of DF transmission a discrete Poisson model was performed using SaTScan software.

Results  Space‐time distribution of DF transmission was clustered during three periods 2000–2002, 2003–2005 and 2006–2009. Dhaka was the most likely cluster for DF in all three periods. Several other districts were significant secondary clusters. However, the geographical range of DF transmission appears to have declined in Bangladesh over the last decade.

Conclusion  There were significant space‐time clusters of DF in Bangladesh over the last decade. Our results would prompt future studies to explore how social and ecological factors may affect DF transmission and would also be useful for improving DF control and prevention programs in Bangladesh.
Characteristics of adults and children diagnosed with tuberculosis in Lilongwe, Malawi: findings from an integrated HIV/TB clinic
Authors: Feldacker C. , Tweya H. , Keiser O. , Weigel R. , Kalulu M. , Fenner L. , Egger M. , Manda E. , Mwafilaso J. B. , Kamba C. , Phiri S.
Published: July 2012

Objectives  To describe initial registration characteristics of adult and paediatric TB patients at a large, public, integrated TB and HIV clinic in Lilongwe, Malawi, between January 2008 and December 2010.

Methods  Routine data on patient with TB category and TB type, stratified by HIV and ART status, were used to explore differences in proportions among TB only, TB/HIV co‐infected patients not on ART and TB/HIV co‐infected patients on ART using chi‐square tests. Trends over time illustrate strengths and weaknesses of integrated service provision.

Results  Among 10 143 adults, HIV ascertainment and ART uptake were high and increased over time. The proportion of relapse was highest among those on ART (5%). The proportion of smear‐positive pulmonary TB (PTB) was highest among HIV‐negative patients with TB (34.9%); extra‐pulmonary TB (EPTB) was lowest among TB only (16.2%). Among 338 children <15 years, EPTB and smear‐positive PTB were more common among TB‐only patients. Time trends showed significant increases in the proportion of adults with smear‐positive PTB and the proportion of adults already on ART before starting TB treatment. However, some co‐infected patients still delay ART initiation.

Conclusions  HIV ascertainment and ART uptake among co‐infected patients are successful and improving over time. However, delays in ART initiation indicate some weakness linking TB/HIV patients into ART during TB follow‐up care. Improved TB diagnostics and screening efforts, especially for paediatric patients, may help improve quality care for co‐infected patients. These results may aid efforts to prioritise TB and HIV prevention, education and treatment campaigns for specific populations.
Response to hepatitis A and B vaccination after pediatric heart transplant
Authors: Martin Kathy , Drabble Alison , Manlhiot Cedric , Dipchand Anne I.
Published: July 2012

Martin K, Drabble A, Manlhiot C, Dipchand AI. Response to hepatitis A and B vaccination after pediatric heart transplant.

Abstract:  The determination of optimal immunization protocols for immunocompromised patients is important given limited data, the potential for decreased vaccine response, and the increased threat of infection. This retrospective study assessed the response to HA and/or HB vaccination in a cohort of 13 PHTx recipients. Descriptive statistics were applied to the data, and univariate analysis was utilized to identify possible factors associated with vaccine response. HA vaccination occurred in 12 (92%) patients of whom three (25%) became HA IgG positive post‐vaccination. Eight (62%) patients had previously received HB vaccination. HB vaccination occurred in 10 (77%) patients of whom five (50%) were anti‐HBS IgG positive post‐vaccination. Median age at HA and HB vaccination was 10.0 yr, and median time post‐PHTx was 8.2 yr. Looking at the entire patient cohort, a previous history of HB vaccination was associated with increased probability of HB vaccine success (7/8 [88%] vs. 1/5 [20%], p = 0.03). Vaccine response in this cohort of PHTx recipients was well below the rates of healthy children. Only a previous history of HB vaccination was significant for increased likelihood of vaccine response. Further study is needed to identify the optimal approach to vaccination for PHTx recipients.
A case of pulmonary papillary adenoma: Possible relationship between tumor histogenesis/tumorigenesis and fibroblast growth factor receptor 2 IIIb
Authors: Masunaga Atsuko , Nagashio Ryo , Iwamoto Sanju , Takeyama Nobuyuki , Sato Yuichi , Miyazaki Akira , Mitsuya Toshiyuki
Published: July 2012

Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16‐year‐old Japanese woman. The tumor histologically showed papillary proliferation of one‐layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type‐II pneumocytes with electron‐microscope. In this study, using immunohistochemistry, in situ hybridization and real‐time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated.
Desquamative interstitial pneumonia may progress to lung fibrosis as characterized radiologically
Authors: KAWABATA YOSHINORI , TAKEMURA TAMIKO , HEBISAWA AKIRA , SUGITA YUTAKA , OGURA TAKASHI , NAGAI SONOKO , SAKAI FUMIKAZU , KANAUCHI TETSU , COLBY THOMAS V. ,   THE DESQUAMATIVE INTERSTITIAL PNEUMONIA STUDY GROUP
Published: July 2012

Background and objective:  In some patients, desquamative interstitial pneumonia may progress to lung fibrosis. The aim of this study was to assess the long‐term radiological follow‐up results in patients with desquamative interstitial pneumonia.

Methods:  Among 75 patients suspected of having desquamative interstitial pneumonia, 31 who fulfilled the criteria were included in this study. Clinical characteristics at presentation, responses to treatment and long‐term follow‐up were evaluated.

Results:  The 31 patients were predominantly males (94%), and the mean age was 55 years; 93% (28/30) had a history of smoking. The clinical findings included high serum levels of lactate dehydrogenase and immunoglobulin G. Bronchoalveolar lavage (26 patients, 84% of cases) frequently showed an increased percentage of eosinophils (mean 17%). Computed tomography (CT) or high resolution (HR) CT at presentation showed ground glass opacities and/or consolidation in all patients, with one third of patients also showing thin‐walled cysts within the ground glass opacities. There was no honeycombing on CT or HRCT scans at presentation. Corticosteroid therapy was effective early in the course of the disease; long‐term follow‐up (mean 99 months) of 31 patients showed only one death due to progression of the disease, but long‐term follow‐up of 14 patients (mean 125 months) by HRCT showed the development of new thin‐walled cysts and honeycombing in five and lung cancer in four patients, respectively.

Conclusions:  In a proportion of patients, desquamative interstitial pneumonia may progress to lung fibrosis with honeycombing on HRCT, despite therapy.
Dietary treatment of hypoglycaemia: should the Australian recommendation be increased?
Authors: Vindedzis S. , Marsh B. , Sherriff J. , Dhaliwal S. , Stanton K.
Published: July 2012

Australian recommendations for treatment of hypoglycaemia are 15 g of carbohydrate repeated at 10–15 min if hypoglycaemia persists. Cited evidence is expert opinion or older studies not pertinent to current insulin regimens. This study aimed to determine the effect of increasing initial treating carbohydrate and decreasing wait‐time to retreatment on resolution of hypoglycaemia in 92 free‐living adults on current insulin regimens. The results support an initial treatment of 20‐g carbohydrate, with a 10‐min wait to repeat treatment as an optimal recommendation for the insulin‐treated individual self‐treating hypoglycaemia.
Using computational models to relate structural and functional brain connectivity
Authors: Hlinka Jaroslav , Coombes Stephen
Published: July 2012

Modern imaging methods allow a non‐invasive assessment of both structural and functional brain connectivity. This has lead to the identification of disease‐related alterations affecting functional connectivity. The mechanism of how such alterations in functional connectivity arise in a structured network of interacting neural populations is as yet poorly understood. Here we use a modeling approach to explore the way in which this can arise and to highlight the important role that local population dynamics can have in shaping emergent spatial functional connectivity patterns. The local dynamics for a neural population is taken to be of the Wilson–Cowan type, whilst the structural connectivity patterns used, describing long‐range anatomical connections, cover both realistic scenarios (from the CoComac database) and idealized ones that allow for more detailed theoretical study. We have calculated graph–theoretic measures of functional network topology from numerical simulations of model networks. The effect of the form of local dynamics on the observed network state is quantified by examining the correlation between structural and functional connectivity. We document a profound and systematic dependence of the simulated functional connectivity patterns on the parameters controlling the dynamics. Importantly, we show that a weakly coupled oscillator theory explaining these correlations and their variation across parameter space can be developed. This theoretical development provides a novel way to characterize the mechanisms for the breakdown of functional connectivity in diseases through changes in local dynamics.
Network effects of subthalamic deep brain stimulation drive a unique mixture of responses in basal ganglia output
Authors: Humphries Mark D. , Gurney Kevin
Published: July 2012

Deep brain stimulation (DBS) is a remarkably successful treatment for the motor symptoms of Parkinson’s disease. High‐frequency stimulation of the subthalamic nucleus (STN) within the basal ganglia is a main clinical target, but the physiological mechanisms of therapeutic STN DBS at the cellular and network level are unclear. We set out to begin to address the hypothesis that a mixture of responses in the basal ganglia output nuclei, combining regularized firing and inhibition, is a key contributor to the effectiveness of STN DBS. We used our computational model of the complete basal ganglia circuit to show how such a mixture of responses in basal ganglia output naturally arises from the network effects of STN DBS. We replicated the diversification of responses recorded in a primate STN DBS study to show that the model’s predicted mixture of responses is consistent with therapeutic STN DBS. We then showed how this ‘mixture of response’ perspective suggests new ideas for DBS mechanisms: first, that the therapeutic frequency of STN DBS is above 100 Hz because the diversification of responses exhibits a step change above this frequency; and second, that optogenetic models of direct STN stimulation during DBS have proven therapeutically ineffective because they do not replicate the mixture of basal ganglia output responses evoked by electrical DBS.
Neuronal avalanches, epileptic quakes and other transient forms of neurodynamics
Authors: Milton John G.
Published: July 2012

Power‐law behaviors in brain activity in healthy animals, in the form of neuronal avalanches, potentially benefit the computational activities of the brain, including information storage, transmission and processing. In contrast, power‐law behaviors associated with seizures, in the form of epileptic quakes, potentially interfere with the brain’s computational activities. This review draws attention to the potential roles played by homeostatic mechanisms and multistable time‐delayed recurrent inhibitory loops in the generation of power‐law phenomena. Moreover, it is suggested that distinctions between health and disease are scale‐dependent. In other words, what is abnormal and defines disease it is not the propagation of neural activity but the propagation of activity in a neural population that is large enough to interfere with the normal activities of the brain. From this point of view, epilepsy is a disease that results from a failure of mechanisms, possibly located in part in the cortex itself or in the deep brain nuclei and brainstem, which truncate or otherwise confine the spatiotemporal scales of these power‐law phenomena.
The dynamics of neurological disease: integrating computational, experimental and clinical neuroscience
Authors: Coombes Stephen , Terry John R.
Published: July 2012

There is a vast (and rapidly growing) amount of experimental and clinical data of the nervous system at very diverse spatial scales of activity (e.g. from sub‐cellular through to whole organ), with many neurological disorders characterized by oscillations in neural activity across these disparate scales. Computer modelling and the development of associated mathematical theories provide us with a unique opportunity to integrate information from across these diverse scales of activity; leading to explanations of the potential mechanisms underlying the time‐evolving dynamics and, more importantly, allowing the development of new hypotheses regarding neural function that may be tested experimentally and ultimately translated into the clinic. The purpose of this special issue is to present an overview of current integrative research in the areas of epilepsy, Parkinson’s disease and schizophrenia, where multidisciplinary relationships involving theory, experimental and clinical research are becoming increasingly established.
Motifs in health and disease: the promise of circuit interrogation by optogenetics
Authors: Tiesinga Paul H. E.
Published: July 2012

Identifying the dominant dynamical motifs in cortical circuits and determining their functional relevance is of the utmost importance to understand the underlying mechanisms of psychiatric diseases and to develop effective therapies. Optogenetics can be used to interrogate cortical circuits to determine the dominant motif and thereby identify the relevant biophysical time scales that set the oscillation frequency. We review how computational models of cortical networks can help guide optogenetics experiments. We focus our attention on the pyramidal interneuron gamma motif, which is comprised of reciprocally connected excitatory and inhibitory neurons, and determine how the different biophysical time scales of the circuit components are reflected in the resonance of the power in the local field potential at the frequency of stimulation as a function of that frequency. Cardin et al. [J.A. Cardin et al. (2009)Nature, 459, 663–667] find that periodic stimulation of inhibitory cells leads to a resonance at gamma frequencies (30–80 Hz), but that stimulation of excitatory cells does not lead to a resonance. We can account for these results when the pyramidal cells are endowed with an intrinsic frequency preference due to a slow hyperpolarizing current. Furthermore, when fast α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐mediated excitatory currents are replaced by slow N‐methyl‐d‐aspartate (NMDA)‐mediated ones in inhibitory cells, the gamma frequency resonance is reduced; however, when the same replacement is made in excitatory cells, gamma oscillations are enhanced. The results are relevant to schizophrenia, because there is evidence that NMDA receptors on parvalbumin‐positive cells are primarily affected and that the regulation of gamma oscillations is impaired.
Changes in acetylcholinesterase in experimental autoimmune myasthenia gravis and in response to treatment with a specific antisense
Authors: Blotnick Edna , Hamra‐Amitai Yasmine , Wald Chen , Brenner Talma , Anglister Lili
Published: July 2012

Controlled regulation of synaptic nicotinic acetylcholine receptors (AChRs) and acetylcholinesterase (AChE), together with maintenance of a dynamic balance between them, is a requirement for proper function of cholinergic synapses. In the present study we assessed whether pathological changes in AChR perturb this balance, and whether such changes can be corrected. We studied the influence of AChR loss, caused by experimental autoimmune myasthenia gravis (EAMG), on muscle AChE, as well as the reciprocal effect of an antisense targeted towards AChE on both AChR and AChE at the neuromuscular synapse. The extensor digitorum longus (EDL) muscles of EAMG Lewis rats were isolated, and AChE levels and isoform compositions were examined. Although AChE levels in the muscles of healthy and EAMG rats were similar, marked changes were observed in isoform composition. Healthy EDL muscles contained globular (G1,2, G4) and asymmetric (primarily A12) isoforms. G1,2‐AChE was significantly reduced in EAMG muscles, whereas both G4‐ and A12‐AChE remained unchanged. Treatment of EAMG rats with the antisense EN101 resulted in decreased total muscle AChE, with recovery in G1,2 and reduction in A12‐AChE. AChE/AChR ratios were determined at the neuromuscular junctions (NMJ). The decrease in AChR levels that occurred as the disease progressed resulted in a dramatic increase in this ratio, and a significant recovery towards normal ratios occurred after EN101 treatment. This improvement was primarily due to increased synaptic AChR content. Our findings emphasise the tight connection between AChR and AChE at the myasthenic NMJ, and the importance of the AChE/AChR ratio in maintaining the required cholinergic balance.
Distinctive patterns of alterations in proton efflux from goldfish retinal horizontal cells monitored with self‐referencing H+‐selective electrodes
Authors: Kreitzer Matthew A. , Jacoby Jason , Naylor Ethan , Baker Adam , Grable Trent , Tran Emma , Booth Sophie Erwin , Qian Haohua , Malchow Robert Paul
Published: July 2012

The H+ hypothesis of lateral feedback inhibition in the outer retina predicts that depolarizing agents should increase H+ release from horizontal cells. To test this hypothesis, self‐referencing H+‐selective microelectrodes were used to measure extracellular H+ fluxes from isolated goldfish horizontal cells. We found a more complex pattern of cellular responses than previously observed from horizontal cells of other species examined using this technique. One class of cells had an initial standing signal indicative of high extracellular H+ adjacent to the cell membrane; challenge with glutamate, kainate or high extracellular potassium induced an extracellular alkalinization. This alkalinization was reduced by the calcium channel blockers nifedipine and cobalt. A second class of cells displayed spontaneous oscillations in extracellular H+ that were abolished by cobalt, nifedipine and low extracellular calcium. A strong correlation between changes in intracellular calcium and extracellular proton flux was detected in experiments simultaneously monitoring intracellular calcium and extracellular H+. A third set of cells was characterized by a standing extracellular alkalinization which was turned into an acidic signal by cobalt. In this last set of cells, addition of glutamate or high extracellular potassium did not significantly alter the proton signal. Taken together, the response characteristics of all three sets of neurons are most parsimoniously explained by activation of a plasma membrane Ca2+ ATPase pump, with an extracellular alkalinization resulting from exchange of intracellular calcium for extracellular H+. These findings argue strongly against the hypothesis that H+ release from horizontal cells mediates lateral inhibition in the outer retina.
A complicated pregnancy in a patient with lipodystrophic diabetes attributable to a peroxisome proliferator‐activated receptor gamma (PPARG) mutation
Authors: Madhra M. , Noh R. M. , Zammitt N. N. , Patrick A. W. , Love C. D. B.
Published: July 2012

Diabet. Med. 29, e398–e401 (2012)

Background  We describe an unplanned pregnancy in a 19‐year‐old with lipodystrophic diabetes caused by a mutation in the peroxisome proliferator‐activated receptor gamma (PPARG) gene. The pregnancy was complicated by poor compliance with treatment, severe hypertriglyceridaemia and pancreatitis.

Case report  The patient presented at 6 weeks’ gestation with an HbA1c of 140 mmol/mol (15%), cholesterol 8.1 mmol/l and triglycerides 20.1 mmol/l. She wished to continue the pregnancy so lipid‐lowering therapy was discontinued. She was severely insulin resistant and poorly compliant with diet and medication. A continuous subcutaneous insulin infusion was required for efficient delivery of large doses of basal insulin, alongside injected mealtime boluses, (up to 300 units insulin per day). At 17 weeks’ gestation she developed acute pancreatitis secondary to hypertriglyceridaemia (triglycerides > 100 mmol/l) and required plasmapheresis. Lipid‐lowering therapy was reinstated in the third trimester and plasmapheresis was required repeatedly to maintain triglycerides < 10 mmol/l. Delivery was arranged at 32 weeks, because of deteriorating glycaemic and lipid control (blood pressure was normal). Following betamethasone for fetal lung maturation, 20 units/h of intravenous insulin were required to maintain glycaemic control. A baby boy with significant subsequent developmental delay was delivered.

Discussion  The features of PPARG mutations are discussed, with literature on lipodystrophy and pancreatitis in pregnancy reviewed. There are few documented cases of pregnancy in women with PPARG mutations. The notable features of this case include the consequences of non‐concordance with treatment, the use of continuous subcutaneous insulin infusion to treat insulin‐resistant diabetes and the need for repeated plasmapheresis during pregnancy to avert pancreatitis.
Assessing the impact of diabetes on the quality of life of older adults living in a care home: validation of the ADDQoL Senior
Authors: Speight J. , Sinclair A. J. , Browne J. L. , Woodcock A. , Bradley C.
Published: July 2012

Diabet. Med. 30, 74–80 (2013)

Aims  Around a quarter of UK care‐home residents have diabetes. Diabetes is known to impact quality of life but existing diabetes‐specific quality of life measures are unsuitable for elderly care‐home residents. We aimed to develop and evaluate a new measure for use with older adults, to be particularly suitable for use with care‐home residents: the Audit of Diabetes‐Dependent Quality of Life (ADDQoL) Senior*.

Methods  Content and format changes were made to the 19‐domain ADDQoL, informed by related measures for people with visual impairments (12 domain‐specific items were retained, four items were revised/added and three items were removed). This revision was modified further following cognitive debriefing interviews with three older adults living in a care home. Psychometric evaluation of the newly developed 17‐domain ADDQoL Senior was conducted using data from 90 care‐home residents with diabetes who took part in a broader intervention study.

Results  The life domains most impacted by diabetes were ‘independence’ and ‘freedom to eat as I wish’. The ADDQoL Senior demonstrated good factor structure and internal consistency (Cronbach’s alpha = 0.924). Domain scores were, as expected, significantly intercorrelated.

Conclusions  The ADDQoL Senior measures the perceived impact of diabetes on quality of life in older adults, and has been found to be suitable for those living in care homes if administered by interview. The scale has demonstrated acceptability and excellent psychometric properties. It is anticipated that the number of items may be reduced in the future if our current findings can be replicated.
Immersion research education: students as catalysts in international collaboration research
Authors: Anderson K.H. , Friedemann M.L. , Bűscher A. , Sansoni J. , Hodnicki D.
Published: July 2012

ANDERSON K.H., FRIEDEMANN M.L., BŰSCHER A., SANSONI J. & HODNICKI D. (2012) Immersion research education: students as catalysts in international collaboration research. International Nursing Review

Background:  This paper describes an international nursing and health research immersion program. Minority students from the USA work with an international faculty mentor in teams conducting collaborative research. The Minority Health International Research Training (MHIRT) program students become catalysts in the conduct of cross‐cultural research.

Aim:  To narrow the healthcare gap for disadvantaged families in the USA and partner countries.

Methods:  Faculty from the USA, Germany, Italy, Colombia, England, Austria and Thailand formed an international research and education team to explore and compare family health issues, disparities in chronic illness care, social inequities and healthcare solutions. USA students in the MHIRT program complete two introductory courses followed by a 3‐month research practicum in a partner country guided by faculty mentors abroad. The overall program development, student study abroad preparation, research project activities, cultural learning, and student and faculty team outcomes are explored.

Results:  Cross‐fertilization of research, cultural awareness and ideas about improving family health occur through education, international exchange and research immersion. Faculty research and international team collaboration provide opportunities for learning about research, health disparities, cultural influences and healthcare systems. The students are catalysts in the research effort, the dissemination of research findings and other educational endeavours. Five steps of the collaborative activities lead to programmatic success.

Conclusions:  MHIRT scholars bring creativity, enthusiasm, and gain a genuine desire to conduct health research about families with chronic illness. Their cultural learning stimulates career plans that include international research and attention to vulnerable populations.
In‐hospital paediatric accidents: an integrative review of the literature
Authors: Da Rin Della Mora R. , Bagnasco A. , Sasso L.
Published: July 2012

DA RIN DELLA MORA R., BAGNASCO A. & SASSO L. (2012) In‐hospital paediatric accidents: an integrative review of the literature. International Nursing Review

Background:  Paediatric hospitals can be perceived by children, parents, health professionals as ‘safe’ places, but accidents do occur.

Aim:  To review publications relating to in‐hospital paediatric accidents and highlight the state‐of‐the‐science concerning this issue especially in relation to falls, and the evolution of research addressing this issue.

Methods:  Integrative review of papers published before March 2011 on accidents and falls occurred in hospitalized children. Electronic databases (PubMed, Cumulative Index to Nursing and Allied Health Literature and Cochrane Library databases) and further hand searching through references were searched. The inclusion criteria were articles involving observational, quasi‐experimental or experimental studies in English or Italian. Exclusion criteria were articles addressing the outcomes of falls caused by suspect violence on children. Thirteen studies in English were included.

Results:  Of the 13 studies conducted between 1963 and 2010, 10 had been conducted in the last 5 years; 10 in the USA. The studies were divided into two categories: contextualization and prevention of the ‘accident’ or ‘fall’ phenomenon (10 studies), and fall risk assessment (three studies). The most frequent type of design was observational explorative/descriptive. Several areas of investigation were explored (hazardous environment, children's characteristics correlated to accidents/falls, characteristics of the accidents/falls and their outcomes, paediatric fall risk factors and risk assessment tools, fall risk prevention programmes, parents' perceptions of accident/fall risks, etc.).

Discussion:  No comparable methods were used to investigate the contextualization and prevention of the ‘accident’ and ‘fall’ phenomena; proposed fall risk assessment tools were not evaluated for their reliability and validity.

Conclusions:  Consensus would be needed around the approach to accidents in terms of: the definition of ‘accident’ and ‘fall’; ‘fall‐related injury’ and respective classifications; the frequency and rate calculation methods; the tools used to assess the risk of falls; and evidence‐based practice aimed at preventing them.