bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis B, hepatitis C and HIV co-infection at an antiretroviral centre in Delhi
Authors: Raizada A , Dwivedi S , Bhattacharya S
Published: May 2011

With an estimated 5.7 million people living with HIV/AIDS, India has the highest HIV/AIDS prevalence in the world, according to UNAIDS. Due to similar routes of transmission, co-infection of HIV with hepatitis B and hepatitis C viruses is a common event with significant clinical implications. The present study was undertaken to highlight the profile of patients of HIV with HBV/HCV co-infection, as literature from India on this topic is sparse. Out of 1953 patients suffering from HIV registered at our centre during the study period, 80 patients were co-infected with HBV/HCV. HBV co-infection was detected in 2.61% of patients and HCV co-infection in 1.69% of subjects. Our study demonstrates low HIV /HCV/HBV co-infection rates in Delhi as compared to most other studies from India, which is partly attributable to low incidence of intravenous drug use and infrequent transfusion-related infections in our study group.
Childhood leprosy: lest we forget
Authors: Sachdeva Sandeep , Amin Syed Suhail , Khan Zulfia , Sharma Pranav Kumar , Bansal Saraansh
Published: May 2011

Leprosy remains an important public health and social issue in South Asia, particularly in India. Its presence in childhood is an immense social burden because of the associated disabilities and widely prevalent misconceptions regarding communicability and treatment potential. The prevalence of leprosy among children suggests a possible gap in the national programmes aimed at leprosy elimination. This article reports a 10-year retrospective study of childhood leprosy in a tertiary care hospital setting (2000–2009) along with an analysis of selected socio-epidemiologic correlates. We stress the importance of early detection and the application of appropriate prophylactic measures in susceptible children.
X-ray view box: on-site manufacture
Authors: Iserson Kenneth V , Tiimob Jeremiah M
Published: May 2011

Radiographic films remain the norm in developing countries. Interpreting them is easier and more reliable, using a view box, than holding them up to a light. Commercial view boxes are expensive and difficult to repair. We designed and built an inexpensive radiographic view box using commonly available materials and local craftsmen. If they break, they can be easily repaired by hospital staff. This design can be replicated anywhere in the world.
C-NORTA: A Rejection Procedure for Sampling from the Tail of Bivariate NORTA Distributions
Authors: Ghosh Soumyadip , Pasupathy Raghu
Published: May 2011

We propose C-NORTA, an exact algorithm to generate random variates from the tail of a bivariate NORTA random vector. (A NORTA random vector is specified by a pair of marginals and a rank or product–moment correlation, and it is sampled using the popular NORmal-To-Anything procedure.) We first demonstrate that a rejection-based adaptation of NORTA on such constrained random vector generation problems may often be fundamentally intractable. We then develop the C-NORTA algorithm, relying on strategic conditioning of the NORTA vector, followed by efficient approximation and acceptance/rejection steps. We show that, in a certain precise asymptotic sense, the sampling efficiency of C-NORTA is exponentially larger than what is achievable through a naïve application of NORTA. Furthermore, for at least a certain class of problems, we show that the acceptance probability within C-NORTA decays only linearly with respect to a defined rarity parameter. The corresponding decay rate achievable through a naïve adaptation of NORTA is exponential. We provide directives for efficient implementation.
New State-Space Relaxations for Solving the Traveling Salesman Problem with Time Windows
Authors: Baldacci Roberto , Mingozzi Aristide , Roberti Roberto
Published: May 2011

The traveling salesman problem with time windows (TSPTW) is the problem of finding in a weighted digraph a least-cost tour starting from a selected vertex, visiting each vertex of the graph exactly once according to a given time window, and returning to the starting vertex. This n𝒫-hard problem arises in routing and scheduling applications. This paper introduces a new tour relaxation, called ngL-tour, to compute a valid lower bound on the TSPTW obtained as the cost of a near-optimal dual solution of a problem that seeks a minimum-weight convex combination of nonnecessarily elementary tours. This problem is solved by column generation. The optimal integer TSPTW solution is computed with a dynamic programming algorithm that uses bounding functions based on different tour relaxations and the dual solution obtained. An extensive computational analysis on basically all TSPTW instances (involving up to 233 vertices) from the literature is reported. The results show that the proposed algorithm solves all but one instance and outperforms all exact methods published in the literature so far.
Discovery of Periodic Patterns in Sequence Data: A Variance-Based Approach
Authors: Yang Yinghui (Catherine) , Padmanabhan Balaji , Liu Hongyan , Wang Xiaoyu
Published: May 2011

We address the discovery of periodic patterns in sequence data. Building on prior work in this area, we present definitions and new methods for characterizing and identifying four types of periodic patterns. A unifying concept across the different types of periodic patterns we consider is the use of statistical variance to define periodicity. This lends itself to efficient variance-reduction algorithms for identifying periodic patterns. We motivate and test our approach using both extensive simulated sequences and real sequence data from online clickstream data.
Overcoming Network Overload and Redundancy in Interorganizational Networks: The Roles of Potential and Latent Ties
Authors: Mariotti Francesca , Delbridge Rick
Published: May 2011

This paper builds on Granovetter's distinction between strong and weak ties [ Granovetter, M. S. 1973 . The strength of weak ties. Amer. J. Sociol. 78(6) 1360–1380] in order to respond to recent calls for a more dynamic and processual understanding of networks. The concepts of potential and latent tie are deductively identified, and their implications for understanding how and why networks emerge, evolve, and change are explored. A longitudinal empirical study conducted with companies operating in the European motorsport industry reveals that firms take strategic actions to search for potential ties and reactivate latent ties in order to solve problems of network redundancy and overload. Examples are given, and their characteristics are examined to provide theoretical elaboration of the relationship between the types of tie and network evolution. These conceptual and empirical insights move understanding of the managerial challenge of building effective networks beyond static structural contingency models of optimal network forms to highlight the processes and capabilities of dynamic relationship building and network development. In so doing, this paper highlights the interrelationship between search and redundancy and the scope for strategic action alongside path dependence and structural influences on network processes.
Not All Identifications Are Created Equal: Exploring Employee Accounts for Workgroup, Organizational, and Professional Identification
Authors: Vough Heather
Published: May 2011

Scholars are increasingly interested in understanding the content and process of employee identification. In this paper, I contribute to this discussion by performing a qualitative case study investigating the accounts employees provide as they make sense of their identification with their workgroup, organization, and profession. Analyses of accounts from 31 members of an architecture firm reveal nine explanations individuals use to make sense of their identifications, which can be categorized using four sensemaking logics: similarity, familiarity, benefits, and investment. The explanations that informants provided differed markedly across targets. Whereas individuals relied heavily on personal relationships, and that their work actually happens in their workgroup in their accounts of workgroup identification, organizational identification was often explained based on the ideology of the organization, the support provided by the organization, the prestige of the organization, and the input the individual had into the organization. In further contrast, accounts of professional identification rested on explanations based in professional archetypes, the enjoyment informants found in their work, and professional norms about the work/life interface. These findings suggest that individuals may construct their identifications differently across targets. I theorize that these patterns are a function of target proximity and the characteristics that distinguish between targets. These findings open up the black box of identification by providing insight into how individuals interpret information about workplace targets. In doing so, the findings illustrate how sensemaking about identification is the result of firsthand experiences with a target in addition to sensegiving.
Resisters at Work: Generating Productive Resistance in the Workplace
Authors: Courpasson David , Dany Françoise , Clegg Stewart
Published: May 2011

Research has recognized the transformative dimension of resistance in the workplace. Yet resistance is still seen as an adversarial and antagonistic process that management can accept or reject; thus, understanding how resistance can actually influence workplace change remains a challenge for research. In this paper, we offer an analysis of two situations of resistance wherein resisters, organized in temporary enclaves, are able to influence top management's decisions and produce eventual change. Whether or not resistance becomes productive depends on the skillful work of resisters and the creation of powerful “objects of resistance” that enable resisters to modify temporarily the power configuration of a situation and oblige top management to listen to their claims and accommodate to the new configuration. This paper shows that resistance can be better explained by what resisters do to achieve their ends rather than by seeing resistance as a fixed opposition between irreconcilable adversaries.
Evaluation of a Simplified N-Acetylcysteine Dosing Regimen for the Treatment of Acetaminophen Toxicity
Authors: Johnson Michael T , McCammon Craig A , Mullins Michael E , Halcomb S Eliza
Published: May 2011

BACKGROUND:

Acetaminophen overdose is the most common pharmaceutical poisoning in the US. The labeled dosing regimen for Acetadote, the only intravenous N-acetylcysteine (IV-NAC) product approved by the Food and Drug Administration (FDA) for treatment of acetaminophen toxicity, is a complex 3-step process that produces frequent medication errors. We have been using an off-label, uncomplicated dosing regimen consisting of a standard preparation of IV-NAC 30 g in 1 L of 5% dextrose in water, with a 150-mg/kg loading dose administered over 1 hour followed by an infusion of 14 mg/kg/h for 20 hours.

OBJECTIVE:

To evaluate the frequency of medication errors, resolution of hepatotoxicity, and tolerability of the protocol used in our institution for treatment of acetaminophen toxicity.

METHODS:

This single-center, retrospective chart review evaluated patients receiving IV-NAC for acetaminophen toxicity from August 2006 to August 2008. Charts were reviewed for prescribing practices, dosing errors, and clinical outcomes.

RESULTS:

Among 70 patients who met inclusion criteria, 35 medication errors occurred, including 22 administration errors and 13 protocol initiation errors. The frequency of administration errors was 13.5 errors per 100 administration interventions. Loading dose errors were most common with 11 rate-related and 8 dose-related errors. Interruptions longer than 60 minutes occurred in only 3 patients. No adverse outcomes were associated with medication errors. The mean (SD) duration of therapy was 25.6 hours (n = 60 pts. [17.8], range 1-76.5), and mean length of stay was 2.99 days ([3.82], range 0.1-25.7). All patients with hepatotoxicity (aspartate aminotransferase >1000 units/L) due to acute acetaminophen toxicity had resolution of the toxicity and were successfully discharged.

CONCLUSIONS:

This single intravenous bag protocol is effective and well tolerated, and there is infrequent interruption of therapy. The overall rate of administration errors is similar to that in reports on the FDA regimen; thus, our protocol may be an acceptable alternative.
Morphine-Induced Cardiogenic Shock
Authors: Feeney Colin , Ani Chizobam , Sharma Naini , Frohlich Tom
Published: May 2011

OBJECTIVE:

Although animal and human models suggest that direct suppression of myocardial contractility may occur with morphine administration, to our knowledge, clinical observation of this potentially important effect has not been reported. This case report presents a unique case of morphine-induced transient reversible cardiogenic shock.

CASE SUMMARY:

A 44-year-old woman with a history of hypertension, diabetes, and asthma presented with a 3-day history of epigastric pain. Initial investigation results revealed elevated serum lipase level and computed tomography imaging that was consistent with a diagnosis of mild acute pancreatitis. Intravenous fluids and morphine, via patient-controlled analgesia, were started and the patient was admitted. The next day, she developed cardiogenic shock with a globally reduced left ventricular ejection fraction (LVEF) of 26% and was admitted to the intensive care unit. Morphine was discontinued and norepinephrine and naloxone were concurrently administered. Over the next 24 hours her clinical status improved, and an echocardiogram 29 hours after the initial echocardiogram showed normal LV function (LVEF 62%).

DISCUSSION:

To our knowledge, this represents the first reported case of clinically significant morphine-induced cardiogenic shock. An objective causality assessment using the Naranjo probability scale suggests that the cardiogenic shock was probably related to morphine. Other causes of shock were ruled out. Additionally, the fact that the transient nature of the observed LV dysfunction reversed with discontinuation of morphine and administration of naloxone provides further support, particularly with the evidence that opiates may depress cardiac myocytes and cardiac output in animal and human models.

CONCLUSIONS:

Opiates can cause severe LV dysfunction. Physicians should consider emergent evaluation for myocardial depression in patients who are receiving opioids and present with persistent hypotension or pulmonary edema without other known etiology.
Sexual Understanding and Development of Young People With Intellectual Disabilities: Mothers' Perspectives of Within-Family Context
Authors: Pownall Jaycee D. , Jahoda Andrew , Hastings Richard , Kerr Linda
Published: May 2011

The sexual development of young people with intellectual disabilities is a marker of their transition to adulthood and affects their sense of well being and identity. Cognitive impairments and a socially marginalized position increase dependence on their families to assist with sexual matters. In this study, the authors adopted a novel interpretive phenomenological analysis approach, asking 8 mothers to contrast their experience of supporting similarly aged siblings with and without intellectual disabilities. Acknowledgment of their nondisabled offspring's sexuality was demanded by increasing autonomy, whereas continuing dependence of the offspring with intellectual disabilities hindered mothers who were addressing this intensely private and sensitive issue with them. The topic of sexuality brought to the forefront mothers' fears about their offspring's ability to cope with the challenges of adulthood.
Subsequent Births in Families of Children With Disabilities: Using Demographic Data to Examine Parents' Reproductive Patterns
Authors: Burke Meghan M. , Urbano Richard C. , Hodapp Robert M.
Published: May 2011

The authors determined family reproductive patterns after the birth of a child with (vs. without) a disability. Using Tennessee birth records, the authors examined families of children with Down syndrome (N  =  1,123), spina bifida (N  =  368), and population group (N  =  734,189). Families of children with Down syndrome and with spina bifida were more likely to have subsequent children and larger family sizes than the population group. When a 1st-born target child was born, 28.8% of families had a 2nd child in the population group compared with 37.1% and 45.7% when the child had spina bifida or Down syndrome, respectively. Families of children with disabilities were more likely to have subsequent children regardless of maternal race, marital status, and educational level.
Modeling the Social Determinants of Caregiver Burden Among Families of Children With Developmental Disabilities
Authors: McManus Beth M. , Carle Adam , Acevedo-Garcia Dolores , Ganz Michael , Hauser-Cram Penny , McCormick Marie
Published: May 2011

This study described predictors of caregiver burden among parents of children with developmental disabilities. The sample, obtained from the 2005–2006 National Survey of Children With Special Health Care Needs, included 12,225 children, aged 5 to 17 years, with a developmental disability. Structural equation modeling assessed the relationships between the factors of Caregiver Burden, Ease of Accessing and Navigating the Health Care System, and Unmet Health Care Needs. Caregiver burden was inversely associated with ease of accessing and navigating the health care system (β  =  −0.094, SE (β)  =  0.045) and positively associated with unmet health care needs (β  =  0.428, SE (β)  =  0.036). Parents of poor, minority, and uninsured children experienced significantly greater caregiver burden. Bolstering services, particularly for vulnerable families, may ameliorate caregiver burden.
Type V collagen-induced upregulation of capn2 (large subunit of m-calpain) gene expression and DNA fragmentation in 8701-BC breast cancer cells
Authors: Luparello Claudio , Sirchia Rosalia
Published: May 2011

Type V collagen is known to be over-deposited in the stroma of ductal infiltrating carcinomas of the breast. When used as a substrate, type V collagen restrains growth and invasion, and affects gene expression of 8701-BC ductal infiltrating carcinomas cells. Here we supplement existing data by demonstrating type V collagen dependent upregulation of capn2 gene expression in 8701-BC cells through differential display-PCR and Western blot assays. Furthermore, we suggest that our data obtained by centrifugal sedimentation and electrophoresis strongly suggest a correlation between calpain overproduction and DNA fragmentation, since the incubation with calpain inhibitor partly reverts the latter.
Synaptic Targeting and Functional Modulation of GluK1 Kainate Receptors by the Auxiliary Neuropilin and Tolloid-Like (NETO) Proteins
Authors: Copits Bryan A. , Robbins John S. , Frausto Shanti , Swanson Geoffrey T.
Published: May 2011

Auxiliary proteins modify the biophysical function and pharmacological properties of ionotropic glutamate receptors and likely are important components of receptor signaling complexesin vivo. The neuropilin and tolloid-like proteins (NETO) 1 and NETO2, two closely related CUB domain-containing integral membrane proteins, were identified recently as auxiliary proteins that slowed GluK2a kainate receptor current kinetics without impacting receptor membrane localization. Here we demonstrate that NETO2 profoundly slows the desensitization rate of GluK1 kainate receptors, promotes plasma membrane localization of transfected receptors in heterologous cells and rat hippocampal neurons, and targets GluK1-containing receptors to synapses. Conversely, the closely related protein NETO1 increases the rate of GluK1 receptor desensitization. Incorporation of NETO proteins into kainate receptor-signaling complexes therefore extends the temporal range of receptor gating by over an order of magnitude. The presence of these auxiliary proteins could underlie some of the unusual aspects of kainate receptor function in the mammalian CNS.
Dopamine–Galanin Receptor Heteromers Modulate Cholinergic Neurotransmission in the Rat Ventral Hippocampus
Authors: Moreno Estefanía , Vaz Sandra H. , Cai Ning-Sheng , Ferrada Carla , Quiroz César , Barodia Sandeep Kumar , Kabbani Nadine , Canela Enric I. , McCormick Peter J. , Lluis Carme , Franco Rafael , Ribeiro Joaquim A. , Sebastião Ana M. , Ferré Sergi
Published: May 2011

Previous studies have shown that dopamine and galanin modulate cholinergic transmission in the hippocampus, but little is known about the mechanisms involved and their possible interactions. By using resonance energy transfer techniques in transfected mammalian cells, we demonstrated the existence of heteromers between the dopamine D1-like receptors (D1and D5) and galanin Gal1, but not Gal2receptors. Within the D1–Gal1and D5–Gal1receptor heteromers, dopamine receptor activation potentiated and dopamine receptor blockade counteracted MAPK activation induced by stimulation of Gal1receptors, whereas Gal1receptor activation or blockade did not modify D1-like receptor-mediated MAPK activation. Ability of a D1-like receptor antagonist to block galanin-induced MAPK activation (cross-antagonism) was used as a “biochemical fingerprint” of D1-like–Gal1receptor heteromers, allowing their identification in the rat ventral hippocampus. The functional role of D1-like–Gal receptor heteromers was demonstrated in synaptosomes from rat ventral hippocampus, where galanin facilitated acetylcholine release, but only with costimulation of D1-like receptors. Electrophysiological experiments in rat ventral hippocampal slices showed that these receptor interactions modulate hippocampal synaptic transmission. Thus, a D1-like receptor agonist that was ineffective when administered alone turned an inhibitory effect of galanin into an excitatory effect, an interaction that required cholinergic neurotransmission. Altogether, our results strongly suggest that D1-like–Gal1receptor heteromers act as processors that integrate signals of two different neurotransmitters, dopamine and galanin, to modulate hippocampal cholinergic neurotransmission.
A New Role for the Parahippocampal Cortex in Representing Space
Authors: Mullally Sinéad L. , Maguire Eleanor A.
Published: May 2011

The debate surrounding the function of the human posterior parahippocampal cortex (PHC) is currently dominated by two competing theories. The spatial layout hypothesis proposes that PHC processes information about the shape of space embodied in layout-defining scene features. The contextual association hypothesis rejects this notion, proposing instead that PHC responds to highly contextualized, but not necessarily spatial, stimuli. Here we present a novel concept that suggests PHC is primarily concerned with any representation that depicts three-dimensional local space, be it scenes or even single objects. Specifically, we identified space-defining (SD) and space-ambiguous (SA) single objects, where SD objects consistently evoke a strong sense of the surrounding space while SA objects do not, in the absence of any background, spatial layout, or context. We found that participants could easily identify and distinguish between SD and SA objects. This distinction was subsequently affirmed at a neural level, where visualizing or viewing single SD objects compared with SA objects engaged PHC, despite these single SD objects offering no information about the shape or layout of the space. Moreover, this PHC response was robust and not accounted for by other factors, including contextual associations. Instead, it was linked to intrinsic object properties, specifically a combination of perceived object size and portability. By showing that PHC is responsive to the awareness of surrounding local space suggests its role in scene processing is basic and fundamental, such that it is not dependent on complex scene properties such as geometric structure, scene schema, or contextual associations.
Synaptic Glutamate Release Is Modulated by the Na+-Driven Cl−/HCO3−Exchanger Slc4a8
Authors: Sinning Anne , Liebmann Lutz , Kougioumtzes Alexandra , Westermann Martin , Bruehl Claus , Hübner Christian A.
Published: May 2011

On the one hand, neuronal activity can cause changes in pH; on the other hand, changes in pH can modulate neuronal activity. Consequently, the pH of the brain is regulated at various levels. Here we show that steady-state pH and acid extrusion were diminished in cultured hippocampal neurons of mice with a targeted disruption of the Na+-driven Cl−/HCO3−exchanger Slc4a8. Because Slc4a8 was found to predominantly localize to presynaptic nerve endings, we hypothesize that Slc4a8 is a key regulator of presynaptic pH. Supporting this hypothesis, spontaneous glutamate release in the CA1 pyramidal layer was reduced but could be rescued by increasing the intracellular pH. The reduced excitabilityin vitrocorrelated with an increased seizure thresholdin vivo. Together with the altered kinetics of stimulated synaptic vesicle release, these data suggest that Slc4a8 modulates glutamate release in a pH-dependent manner.
In VivoEvidence for Lactate as a Neuronal Energy Source
Authors: Wyss Matthias T. , Jolivet Renaud , Buck Alfred , Magistretti Pierre J. , Weber Bruno
Published: May 2011

Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based onin vitrodata; only a few recentin vivoresults have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the firstin vivodemonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[11C]l-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 ± 0.009 to 0.105 ± 0.007 min−1. Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [18F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.
Stable BrainATMMessage and Residual Kinase-Active ATM Protein in Ataxia-Telangiectasia
Authors: Li Jiali , Chen Jianmin , Vinters Harry V. , Gatti Richard A. , Herrup Karl
Published: May 2011

The gene that is mutated in ataxia-telangiectasia (A-T), ATM, is catalytically activated in response to DNA damage. Yet a full accounting for the CNS deficits in human A-T or its mouse models remains elusive. We have analyzed the CNS phenotypes of two mouseAtmalleles—Atmtm1Bal(Bal) andAtmtm1Awb(Awb). Neither mutant has detectable mRNA or protein in peripheral tissues. In brain, althoughBal/Balmice have no ATM protein, they have nearly normal amounts ofAtmmRNA.Bal/Balneurons exhibit extensive cell cycle reentry and degeneration in both cortex and cerebellum. Unexpectedly, inAwb/Awbmice a novel mRNA is found in which the engineered mutation is excised. This mRNA is apparently translated and produces a catalytically active ATM protein that responds to DNA damage by phosphorylating p53 and Chk2. Prompted by these results, we examined eight cases of human A-T and found evidence for residual ATM protein in seven of them. These findings offer important new insights into the human disease and the role of brain ATM activity in the severity of the neurological symptoms of A-T.
Deletion of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Auxiliary Subunit TRIP8b Impairs HippocampalIhLocalization and Function and Promotes Antidepressant Behavior in Mice
Authors: Lewis Alan S. , Vaidya Sachin P. , Blaiss Cory A. , Liu Zhiqiang , Stoub Travis R. , Brager Darrin H. , Chen Xiangdong , Bender Roland A. , Estep Chad M. , Popov Andrey B. , Kang Catherine E. , Van Veldhoven Paul P. , Bayliss Douglas A. , Nicholson Daniel A. , Powell Craig M. , Johnston Daniel , Chetkovich Dane M.
Published: May 2011

Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization-activated current,Ih, is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reducedIhexpression in hippocampal pyramidal neurons. Loss ofIh-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels andIhin vivo, and suggest that targetingIhmay provide a novel approach to treatment of depression.
BAM8–22 Peptide Produces Itch and Nociceptive Sensations in Humans Independent of Histamine Release
Authors: Sikand Parul , Dong Xinzhong , LaMotte Robert H.
Published: May 2011

Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8–22 peptide (BAM8–22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8–22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8–22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8–18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine-induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8–22. We show that BAM8–22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8–22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.
NeuroD Factors Regulate Cell Fate and Neurite Stratification in the Developing Retina
Authors: Cherry Timothy J. , Wang Sui , Bormuth Ingo , Schwab Markus , Olson James , Cepko Constance L.
Published: May 2011

Members of the basic helix-loop-helix (bHLH) family of transcription factors have been shown to control critical aspects of development in many tissues. To identify bHLH genes that might regulate specific aspects of retinal cell development, we investigated the expression of bHLH genes in single, developing mouse retinal cells, with particular emphasis on the NeuroD family. Two of these factors, NeuroD2 and NeuroD6/NEX, had not been previously reported as expressed in the retina. A series of loss- and gain-of-function experiments was performed, which suggested that NeuroD genes have both similarities and differences in their activities. Notably, misexpression of NeuroD genes can direct amacrine cell processes to two to three specific sublaminae in the inner plexiform layer. This effect is specific to cell type and NeuroD gene, as the AII amacrine cell type is refractory to the effects of NeuroD1 and NeuroD6, but uniquely sensitive to the effect of NeuroD2 on neurite targeting. Additionally, NeuroD2 is endogenously expressed in AII amacrine cells, among others, and loss of NeuroD2 function results in a partial loss of AII amacrine cells. The effects of misexpressing NeuroD genes on retinal cell fate determination also suggested shared and divergent functions. Remarkably, NeuroD2 misexpression induced ganglion cell production even after the normal developmental window of ganglion cell genesis. Together, these data suggest that members of the NeuroD family are important for neuronal cell type identity and may be involved in several cell type-specific aspects of retinal development, including fate determination, differentiation, morphological development, and circuit formation.
Syntaxin 1B Suppresses Macropinocytosis and Semaphorin 3A-Induced Growth Cone Collapse
Authors: Kabayama Hiroyuki , Takeuchi Makoto , Taniguchi Masahiko , Tokushige Naoko , Kozaki Shunji , Mizutani Akihiro , Nakamura Takeshi , Mikoshiba Katsuhiko
Published: May 2011

Growth cone collapse is a crucial process for repulsive axon guidance and is accompanied by a reduction in growth cone surface area. This process of reduction may be regulated by endocytosis; however, its molecular mechanism is unclear. Macropinocytosis is a clathrin-independent form of endocytosis in which large areas of plasma membrane can be engulfed. We have reported previously that macropinocytosis is induced in growth cones of chick dorsal root ganglion neurons by semaphorin 3A (Sema3A), a repulsive axon guidance cue, and that Sema3A-induced reduction in growth cone surface area and macropinocytic vacuole area were correlated, suggesting a positive role for macropinocytosis in Sema3A-induced growth cone collapse. In the present study, we found that syntaxin 1B (Syx1B), a membrane trafficking protein, is a negative regulator of macropinocytosis, and its expression is downregulated by Sema3A signaling. Macropinocytosis inhibitor ethylisopropylamiloride or Syx1B overexpression suppressed Sema3A-induced macropinocytosis and growth cone collapse. These results indicate that Syx1B couples macropinocytosis-mediated massive internalization of the plasma membrane to Sema3A-induced growth cone collapse.
Effective Treatment of Chronic Low Back Pain in Humans Reverses Abnormal Brain Anatomy and Function
Authors: Seminowicz David A. , Wideman Timothy H. , Naso Lina , Hatami-Khoroushahi Zeinab , Fallatah Summaya , Ware Mark A. , Jarzem Peter , Bushnell M. Catherine , Shir Yoram , Ouellet Jean A. , Stone Laura S.
Published: May 2011

Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n= 18) and 6 months after (spine surgery or facet joint injections;n= 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities—specifically in the left DLPFC—are reversible, suggesting that treating chronic pain can restore normal brain function in humans.
Duration of Inhibition of Ventral Tegmental Area Dopamine Neurons Encodes a Level of Conditioned Fear
Authors: Mileykovskiy Boris , Morales Marisela
Published: May 2011

It is widely accepted that midbrain dopamine (DA) neurons encode actual and expected reward values by phasic alterations in firing rate. However, how DA neurons encode negative events in the environment is still unclear because some DA neurons appear to be depressed and others excited by aversive stimuli. Here, we show that exposing fear-conditioned rats to stimuli predicting electrical shock elicited three types of biphasic responses, each of which contained an inhibitory pause, in neurochemically identified ventral tegmental area (VTA) DA neurons. The duration of the inhibitory pause in these responses of VTA DA neurons was in direct proportion to the increase in respiratory rate reflecting the level of conditioned fear. Our results suggest that the duration of inhibition of VTA DA neurons encodes negative emotional values of signals predicting aversive events in the environment.
Serotonin Induces Long-Term Depression at Corticostriatal Synapses
Authors: Mathur Brian N. , Capik Nicole A. , Alvarez Veronica A. , Lovinger David M.
Published: May 2011

The striatum has important roles in motor control and action learning and, like many brain regions, receives multiple monoaminergic inputs. We have examined serotonergic modulation of rat and mouse corticostriatal neurotransmission and find that serotonin (5-HT) activates 5-HT1breceptors resulting in a long-term depression (LTD) of glutamate release and striatal output that we have termed 5-HT–LTD. 5-HT–LTD is presynaptically mediated, cAMP pathway dependent, and inducible by endogenous striatal 5-HT, as revealed by application of a selective 5-HT reuptake inhibitor. 5-HT–LTD is mutually occlusive with dopamine/endocannabinoid-dependent LTD, suggesting that these two forms of LTD act on the same corticostriatal terminals. Thus, serotonergic and dopaminergic mechanisms exist that may interact to persistently sculpt corticostriatal circuits, potentially influencing action learning and striatal-based disorders.
Alzheimer's Disease Brain-Derived Amyloid-β-Mediated Inhibition of LTPIn VivoIs Prevented by Immunotargeting Cellular Prion Protein
Authors: Barry Andrew E. , Klyubin Igor , Mc Donald Jessica M. , Mably Alexandra J. , Farrell Michael A. , Scott Michael , Walsh Dominic M. , Rowan Michael J.
Published: May 2011

Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrPC), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβin vitrois controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampusin vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrPC, prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrPC, a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrPCin mediating synaptic plasticity disruption by soluble Aβ.
Homeostatic Synaptic Plasticity through Changes in Presynaptic Calcium Influx
Authors: Zhao CongJian , Dreosti Elena , Lagnado Leon
Published: May 2011

Chronic perturbations of electrical activity within neural circuits lead to compensatory changes in synaptic strength collectively termed homeostatic synaptic plasticity. The postsynaptic mechanisms underlying these modifications have been characterized in some detail, but the presynaptic mechanisms that alter the efficiency of evoked neurotransmitter release are less clear. To investigate the role of presynaptic calcium influx, we have combined the use of two fluorescent proteins in cultured hippocampal neurons: a calcium reporter localized to synaptic vesicles, SyGCaMP2, and a reporter of vesicle fusion, SypHy. We find that a decrease in the activity of the network causes an increase in the amount of calcium entering the synaptic bouton in response to an action potential and an increase in the probability of vesicle fusion. Homeostatic changes in release probability varied as the third power of calcium influx. These results indicate that changes in the number and/or function of presynaptic calcium channels are major determinants of homeostatic changes in synaptic strength.
Abnormal Neuronal Migration Changes the Fate of Developing Neurons in the Postnatal Olfactory Bulb
Authors: Belvindrah Richard , Nissant Antoine , Lledo Pierre-Marie
Published: May 2011

Neuronal precursors are continuously integrated into the adult olfactory bulb (OB). The vast majority of these precursor cells originates from the subventricular zone and migrates along the rostral migratory stream (RMS) en route to the OB. This process, called postnatal neurogenesis, results from intricate pathways depending both on cell-autonomous factors and extrinsic regulation provided by the local environment. Using electroporation in postnatal mice to label neuronal precursors with green fluorescent protein (GFP) and to reduce the expression levels of doublecortin (DCX) with short-hairpin (Sh) RNA, we investigated the consequences of impairing migration on the fate of postnatal-formed neurons. First, we showed that electroporation of Dcx ShRNA plasmid efficiently knocks down the expression of DCX and disrupts cells migration along the RMS. Second, we found misplaced anomalous migrating cells that displayed defects in polarity and directionality. Third, patch-clamp recordings performed at 5–7 days post-electroporation (dpe) revealed increased density of voltage-dependent Na+channels and enhanced responsiveness to GABAAreceptor agonist. At later time points (i.e., 12 and 30 dpe), most of the Dcx ShRNA+cells developed in the core of the OB and displayed aberrant dendritic length and branching. Additional analysis revealed the formation of GABAergic and glutamatergic synaptic inputs on the mispositioned neurons. Finally, quantifying fate determination by numbering the proportion of GFP+/calretinin+newborn neurons revealed that Dcx ShRNA+cells acquire mature phenotype despite their immature location. We conclude that altering the pace of migration at early stages of postnatal neurogenesis profoundly modifies the tightly orchestrated steps of neuronal maturation, and unveils the influence of microenvironment on controlling neuronal development in the postnatal forebrain.
Review of Different Quantification Methods for the Diagnosis of Digital Vascular Abnormalities in Hand‐arm Vibration Syndrome
Authors: Mahbub MH , Harada Noriaki
Published: May 2011

Review of Different Quantification Methods for the Diagnosis of Digital Vascular Abnormalities in Hand‐arm Vibration Syndrome: MH Mahbub, et al. Department of Hygiene, Yamaguchi University Graduate School of Medicine—

Objective

This study was undertaken to review the diagnostic ability of different quantification methods in the assessment of vibration‐induced white inger (VWF), the typical clinical manifestation of vascular injuries in Hand‐arm Vibration Syndrome (HAVS).

Methods

A literature search of original and major review articles related to the Quantification techniques for diagnosing vascular injuries in HAVS was performed. Relevant data from the publications were extracted and included in this study for reporting and discussion.

Results

Few studies were available to substantiate the diagnostic techniques using the nail press test and nailfold capillaroscopy. Also, few studies were found to conclusively demonstrate the diagnostic ability using thermometry and thermography incorporated with cold provocation. Some recent reports raised the question regarding the diagnostic ability of inger plethysmography; but by virtue of its comparable assessment parameters and better diagnostic performance, plethysmography appears to be a suitable diagnostic method. In noninvasive Quantification of vascular injuries, diagnostic techniques like laser Doppler perfusion imaging and nailfold capillaroscopy require further evaluation in future studies.

Conclusions

For a reliable objective diagnosis of VWF at present, Quantification of vascular responses using a test battery including established methods like thermometry or thermography and strain gauge plethysmography appears to be useful.
Pulmonary Toxicity Following an Intratracheal Instillation of Nickel Oxide Nanoparticle Agglomerates
Authors: Morimoto Yasuo , Hirohashi Masami , Ogami Akira , Oyabu Takako , Myojo Toshihiko , Hashiba Masayoshi , Mizuguchi Yohei , Kambara Tatsunori , Lee Byeong Woo , Kuroda Etsushi , Tanaka Isamu
Published: May 2011

Pulmonary Toxicity Following an Intratracheal Instillation of Nickel Oxide Nanoparticle Agglomerates: Yasuo Morimoto, et al. Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan—

Objective

We examined the pulmonary toxicity of nickel oxide nanoparticle agglomerates in the rat lung following an intratracheal instillation.

Methods

The weighted average surface primary diameter of nickel oxide nanoparticles was 8.41 nm, and the count median diameter of nickel oxide nanoparticle agglomerates suspended in saline was 1.34 µm. Male Wistar rats were exposed to 1 mg (3.3 mg/kg) of nickel oxide nanoparticles intratracheally. The control group Received intratracheal instillation of saline. Rats were dissected 3 days, 1 wk, 1 mo, 3 mo, and 6 mo after the instillation. Cytokine‐induced neutrophil chemoattractant (CINC)2αβ in the lung tissue was determined by quantitative measurement of protein by ELISA.

Results

The total cell count in bronchoalveolar lavage luid (BALF) was increased persistently from 3 days to 6 mo. The neutrophil counts in BALF were also increased at 3days, 1 wk, 3 mo, and 6 mo. In the lung tissue, iniltration of mainly neutrophils and alveolar macrophages was observed in alveoli from 3 days to 6 mo. The CINC‐2αβ concentration was elevated from 3 days to 6 mo in the lung tissue.

Conclusions

These results showed that micron‐sized nickel oxide nanoparticle agglomerates also induced a persistent inlammatory response.