bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited Paper—A Keyword History of Marketing Science
Authors: Mela Carl F. , Roos Jason , Deng Yiting
Published: January 2013

This paper considers the history of keywords used in Marketing Science to develop insights on the evolution of marketing science. Several findings emerge. First, “pricing” and “game theory” are the most ubiquitous words. More generally, the three C's and four P's predominate, suggesting that keywords and common practical frameworks align. Various trends exist. Some words, like “pricing,” remain popular over time. Others, like “game theory” and “hierarchical Bayes,” have become more popular. Finally, some words are superseded by others, like “diffusion” by “social networking.” Second, the overall rate of new keyword introductions has increased, but the likelihood they will remain in use has decreased. This suggests a maturation of the discipline or a long-tail effect. Third, a correspondence analysis indicates three distinct eras of marketing modeling, comporting roughly with each of the past three decades. These eras are driven by the emergence of new data and business problems, suggesting a fluid field responsive to practical problems. Fourth, we consider author publication survival rates, which increase up to six papers and then decline, possibly as a result of changes in ability or motivation. Fifth, survival rates vary with the recency and nature of words. We conclude by discussing the implications for additional journal space and the utility of standardized classification codes.
The Oswestry Risk Index
Authors: Balain B. , Jaiswal A. , Trivedi J. M. , Eisenstein S. M. , Kuiper J. H. , Jaffray D. C.
Published: January 2013

The revised Tokuhashi, Tomita and modified Bauer scores are commonly used to make difficult decisions in the management of patients presenting with spinal metastases. A prospective cohort study of 199 consecutive patients presenting with spinal metastases, treated with either surgery and/or radiotherapy, was used to compare the three systems. Cox regression, Nagelkerke’s R2and Harrell’s concordance were used to compare the systems and find their best predictive items. The three systems were equally good in terms of overall prognostic performance. Their most predictive items were used to develop the Oswestry Spinal Risk Index (OSRI), which has a similar concordance, but a larger coefficient of determination than any of these three scores. A bootstrap procedure was used to internally validate this score and determine its prediction optimism.

The OSRI is a simple summation of two elements: primary tumour pathology (PTP) and general condition (GC): OSRI = PTP + (2 – GC).

This simple score can predict life expectancy accurately in patients presenting with spinal metastases. It will be helpful in making difficult clinical decisions without the delay of extensive investigations.

Cite this article: Bone Joint J 2013;95-B:210–16.
Hand disorders in musicians
Authors: Sheibani-Rad S. , Wolfe S. , Jupiter J.
Published: January 2013

Like athletes, musicians are vulnerable to musculoskeletal injuries that can be career ending or have a severe negative financial impact. All ages are affected, with a peak incidence in the third and fourth decades. Women are slightly more likely to be affected than men. It is incumbent upon orthopaedic surgeons to be able to complete a thorough physical assessment, be aware of the risk factors associated with musculoskeletal symptoms in musicians, and have a detailed knowledge of the specific syndromes they suffer and their appropriate treatment.

In this paper we review the common hand injuries that afflict musicians and discuss their treatment.

Cite this article: Bone Joint J 2013;95-B:146–50.
Unilateral lower limb loss following combat injury
Authors: Bennett P. M. , Sargeant I. D. , Midwinter M. J. , Penn-Barwell J. G.
Published: January 2013

This is a case series of prospectively gathered data characterising the injuries, surgical treatment and outcomes of consecutive British service personnel who underwent a unilateral lower limb amputation following combat injury. Patients with primary, unilateral loss of the lower limb sustained between March 2004 and March 2010 were identified from the United Kingdom Military Trauma Registry. Patients were asked to complete a Short-Form (SF)-36 questionnaire. A total of 48 patients were identified: 21 had a trans-tibial amputation, nine had a knee disarticulation and 18 had an amputation at the trans-femoral level. The median New Injury Severity Score was 24 (mean 27.4 (9 to 75)) and the median number of procedures per residual limb was 4 (mean 5 (2 to 11)). Minimum two-year SF-36 scores were completed by 39 patients (81%) at a mean follow-up of 40 months (25 to 75). The physical component of the SF-36 varied significantly between different levels of amputation (p = 0.01). Mental component scores did not vary between amputation levels (p = 0.114). Pain (p = 0.332), use of prosthesis (p = 0.503), rate of re-admission (p = 0.228) and mobility (p = 0.087) did not vary between amputation levels.

These findings illustrate the significant impact of these injuries and the considerable surgical burden associated with their treatment. Quality of life is improved with a longer residual limb, and these results support surgical attempts to maximise residual limb length.

Cite this article: Bone Joint J 2013;95-B:224–9.
Long-term outcome of reconstruction of the hip in young children with cerebral palsy
Authors: Dhawale A. A. , Karatas A. F. , Holmes L. , Rogers K. J. , Dabney K. W. , Miller F.
Published: January 2013

We reviewed the long-term radiological outcome, complications and revision operations in 19 children with quadriplegic cerebral palsy and hip dysplasia who underwent combined peri-iliac osteotomy and femoral varus derotation osteotomy. They had a mean age of 7.5 years (1.6 to 10.9) and comprised 22 hip dislocations and subluxations. We also studied the outcome for the contralateral hip. At a mean follow-up of 11.7 years (10 to 15.1) the Melbourne cerebral palsy (CP) hip classification was grade 2 in 16 hips, grade 3 in five, and grade 5 in one. There were five complications seen in four hips (21%, four patients), including one dislocation, one subluxation, one coxa vara with adduction deformity, one subtrochanteric fracture and one infection. A recurrent soft-tissue contracture occurred in five hips and ten required revision surgery.

In pre-adolescent children with quadriplegic cerebral palsy good long-term outcomes can be achieved after reconstruction of the hip; regular follow-up is required.

Cite this article: Bone Joint J 2013;95-B:259–65.
Implant sonication increases the diagnostic accuracy of infection in patients with delayed, but not early, orthopaedic implant failure
Authors: Puig-Verdié L. , Alentorn-Geli E. , González-Cuevas A. , Sorlí L. , Salvadó M. , Alier A. , Pelfort X. , Portillo M. E. , Horcajada J. P.
Published: January 2013

The purpose of this study was to compare the diagnostic accuracy for the detection of infection between the culture of fluid obtained by sonication (SFC) and the culture of peri-implant tissues (PITC) in patients with early and delayed implant failure, and those with unsuspected and suspected septic failure. It was hypothesised that SFC increases the diagnostic accuracy for infection in delayed, but not early, implant failure, and in unsuspected septic failure. The diagnostic accuracy for infection of all consecutive implants (hardware or prostheses) that were removed for failure was compared between SFC and PITC. This prospective study included 317 patients with a mean age of 62.7 years (9 to 97). The sensitivity for detection of infection using SFC was higher than using PITC in an overall comparison (89.9% versus 67%, respectively; p < 0.001), in unsuspected septic failure (100% versus 48.5%, respectively; p < 0.001), and in delayed implant failure (88% versus 58%, respectively; p < 0.001). PITC sensitivity dropped significantly in unsuspected compared with suspected septic failure (p = 0.007), and in delayed compared with early failure (p = 0.013). There were no differences in specificity.

Sonication is mainly recommended when there is implant failure with no clear signs of infection and in patients with delayed implant failure. In early failure, SFC is not superior to PITC for the diagnosis of infection and, therefore, is not recommended as a routine diagnostic test in these patients.

Cite this article: Bone Joint J 2013;95-B:244–9.
Combined trabecular metal acetabular shell and augment for acetabular revision with substantial bone loss
Authors: Abolghasemian M. , Tangsataporn S. , Sternheim A. , Backstein D. , Safir O. , Gross A. E.
Published: January 2013

Trabecular metal (TM) augments are a relatively new option for reconstructing segmental bone loss during acetabular revision. We studied 34 failed hip replacements in 34 patients that were revised between October 2003 and March 2010 using a TM acetabular shell and one or two augments. The mean age of the patients at the time of surgery was 69.3 years (46 to 86) and the mean follow-up was 64.5 months (27 to 107). In all, 18 patients had a minor column defect, 14 had a major column defect, and two were associated with pelvic discontinuity. The hip centre of rotation was restored in 27 patients (79.4%). The Oxford hip score increased from a mean of 15.4 points (6 to 25) before revision to a mean of 37.7 (29 to 47) at the final follow-up. There were three aseptic loosenings of the construct, two of them in the patients with pelvic discontinuity. One septic loosening also occurred in a patient who had previously had an infected hip replacement. The augments remained stable in two of the failed hips. Whenever there was a loose acetabular component in contact with a stable augment, progressive metal debris shedding was evident on the serial radiographs. Complications included another deep infection treated without revision surgery. Good clinical and radiological results can be expected for bone-deficient acetabula treated by a TM cup and augment, but for pelvic discontinuities this might not be a reliable option.

Cite this article: Bone Joint J 2013;95-B:166–72.
Long-term follow-up of Van Nes rotationplasty in patients with congenital proximal focal femoral deficiency
Authors: Ackman J. , Altiok H. , Flanagan A. , Peer M. , Graf A. , Krzak J. , Hassani S. , Eastwood D. , Harris G. F.
Published: January 2013

Van Nes rotationplasty may be used for patients with congenital proximal focal femoral deficiency (PFFD). The lower limb is rotated to use the ankle and foot as a functional knee joint within a prosthesis. A small series of cases was investigated to determine the long-term outcome. At a mean of 21.5 years (11 to 45) after their rotationplasty, a total of 12 prosthetic patients completed the Short-Form (SF)-36, Faces Pain Scale-Revised, Harris hip score, Oswestry back pain score and Prosthetic Evaluation Questionnaires, as did 12 age- and gender-matched normal control participants. A physical examination and gait analysis, computerised dynamic posturography (CDP), and timed ‘Up & Go’ testing was also completed. Wilcoxon Signed rank test was used to compare each PFFD patient with a matched control participant with false discovery rate of 5%.

There were no differences between the groups in overall health and well-being on the SF-36. Significant differences were seen in gait parameters in the PFFD group. Using CDP, the PFFD group had reduced symmetry in stance, and reduced end point and maximum excursions.

Patients who had undergone Van Nes rotationplasty had a high level of function and quality of life at long-term follow-up, but presented with significant differences in gait and posture compared with the control group.

Cite this article: Bone Joint J 2013;95-B:192–8.
Torsades De Pointes after Administration of Low-Dose Aripiprazole
Authors: Nelson Sarah , Leung Jonathan G
Published: January 2013

OBJECTIVE:

To describe a case of torsades de pointes (TdP) in a patient treated with aripiprazole.

CASE SUMMARY:

A 42-year-old white male with schizophrenia, diabetes, hypertension, and a history of stroke was admitted to the intensive care unit following 2 days of fever, diarrhea, and altered mental status. Following the resolution of his acute illness, previous therapy with quetiapine 400 mg orally at bedtime was resumed for schizophrenia and presumed delirium. Quetiapine was discontinued after 1 dose because of QTc interval prolongation. Twenty-three days later, with a baseline Q Tc interval of 414 milliseconds, aripiprazole 2.5 mg orally once daily was initiated. Following 5 days of aripiprazole therapy, the patient had a cardiac arrest due to TdP. Normal sinus rhythm was restored after 30 seconds of cardiopulmonary resuscitation, 1 shock of 200 Joules, and 4 g of intravenous magnesium sulfate. Serial electrocardiographs obtained after aripiprazole discontinuation revealed resolution of QTc interval prolongation.

DISCUSSION:

Aripiprazole is a second-generation antipsychotic that may be selected for patients with prolonged QTc intervals and at risk for TdP. Data from trials indicate that aripiprazole has minimal effects on the QTc interval. However, in this case, aripiprazole was associated with TdP in a patient with minimal risk factors. The Naranjo probability scale was used to determine a probable association between aripiprazole and the development of TdP. To our knowledge, this is the first reported case of TdP associated with the use of aripiprazole.

CONCLUSIONS:

Five days of low-dose aripiprazole therapy was associated with the development of TdP in a man with minimal risk factors. Clinicians should be aware of this potential adverse drug event with aripiprazole.
Prevalence of Concomitant Use of Alcohol and Sedative-Hypnotic Drugs in Middle and Older Aged Persons: A Systematic Review
Authors: Ilomäki Jenni , Paljärvi Tapio , Korhonen Maarit Jaana , Enlund Hannes , Alderman Christopher P , Kauhanen Jussi , Bell J Simon
Published: January 2013

OBJECTIVE:

To systematically review the prevalence of concomitant alcohol and sedative-hypnotic use among middle-aged and older persons.

DATA SOURCES:

A bibliographic search of English-language literature was performed using MEDLINE, EMBASE, and PsycINFO (January 1990-August 2012). The reference lists of all included articles were screened for additional relevant articles not identified by any of the bibliographic searches.

STUDY SELECTION AND DATA EXTRACTION:

Population-based studies in which the mean age of participants was 40 years or older were included. For a study to be included in the review, alcohol use had to be reported in terms of the quantity or frequency consumed. Data from included articles were extracted using a standardized data extraction tool.

DATA SYNTHESIS:

Five population-based studies conducted in North America, 10 in Europe, and 1 in Australia were included in the review. Up to 88% of men and 79% of women who used sedative-hypnotics also consumed alcohol. Up to 28% of those who consumed alcohol were concomitant users of sedative-hypnotics. Alcohol was consumed at higher levels among middle-aged than older persons. Risky drinking (eg, binge drinking, heavy drinking) was more prevalent among middle-aged than older persons. In contrast, sedative-hypnotic use was more prevalent among older persons.

CONCLUSIONS:

Our review identified a higher prevalence of alcohol consumption among middle-aged than older persons. However, middle-aged persons may experience harm from alcohol/sedative-hypnotic drug interactions due to risky drinking behavior. Despite lower levels of alcohol consumption, older persons may be more susceptible to addictive central nervous system effects than younger persons because of physiologic changes in psychotropic drug and alcohol metabolism. Clinicians should consider patients' alcohol consumption patterns before prescribing sedative-hypnotic drugs.
Survival after Amphotericin B Overdose Treated with Plasmapheresis
Authors: Wang George Sam , Banerji Shireen , Roussil T Keith , Heard Kennon J
Published: January 2013

OBJECTIVE:

To report a case of accidental amphotericin B overdose that was treated with plasmapheresis.

CASE SUMMARY:

A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO2 of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 μg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities.

DISCUSSION:

The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient's serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications.

CONCLUSIONS:

We describe a patient who survived a 4-fold overdose of amphotericin B because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin B and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood.
Foodborne Botulism Treated with Heptavalent Botulism Antitoxin
Authors: Hill Stanley E , Iqbal Raza , Cadiz Christine L , Le Jennifer
Published: January 2013

OBJECTIVE:

To report a case of foodborne botulism and subsequent use of the investigational heptavalent botulism antitoxin (H-BAT).

CASE SUMMARY:

A 60-year-old man was hospitalized with blurred vision, diplopia, and dysarthria. On hospital day 2, the patient was transferred to the intensive care unit for progressive fatigable weakness with ptosis, dysphagia, dysarthria, and nausea. Secondary to worsening respiratory distress, the patient was intubated and placed on a ventilator. The patient could open his eyes only with assistance but still had normal strength in all extremities. H-BAT was administered 48 hours after presentation for possible botulism. The patient then revealed that he consumed home-canned corn several days prior to admission. On hospital day 8, botulinum neurotoxin was confirmed in the patient's serum and the home-canned corn. The patient slowly regained muscle strength and was discharged to a long-term acute care facility on hospital day 22.

DISCUSSION:

Foodborne botulism is caused by a neurotoxin from Clostridium botulinum and usually occurs after the consumption of improperly prepared home-canned food. Botulism is characterized by symmetrical descending paralysis that may progress to respiratory arrest. The standard confirmatory test for botulism is a mouse bioassay to prove the presence of botulinum neurotoxin. Outside of supportive care, the treatment options for botulism are limited. Individuals with botulism often require intensive care unit monitoring and potentially ventilatory support. H-BAT, the only treatment available for botulism in patients older than 1 year, is a purified and despeciated equine-derived immunoglobulin active against all known botulinum neurotoxins. H-BAT's despeciation significantly reduces the risk of hypersensitivity reactions, anaphylaxis, and serum sickness.

CONCLUSIONS:

In a confirmed case of foodborne botulism treated with H-BAT, the patient tolerated H-BAT and did not develop any hypersensitivity reactions or serum sickness.
Expression Patterns Suggest that Despite Considerable Functional Redundancy, Galectin-4 and -6 Play Distinct Roles in Normal and Damaged Mouse Digestive Tract
Authors: Houzelstein Denis , Reyes-Gomez Edouard , Maurer Marie , Netter Pierre , Higuet Dominique
Published: January 2013

The galectin-4 protein is mostly expressed in the digestive tract and is associated with lipid raft stabilization, protein apical trafficking, wound healing, and inflammation. While most mammalian species, including humans, have a single Lgals4 gene, some mice have two paralogues: Lgals4 and Lgals6. So far, their significant similarities have hindered the analysis of their respective expression and function. We took advantage of two antibodies that discriminate between the galectin-4 and galectin-6 proteins to document their patterns of expression in the normal and the dextran sodium sulfate (DSS)-damaged digestive tract in the mouse. In the normal digestive tract, their pattern of expression from tongue to colon is quite similar, which suggests functional redundancy. However, the presence of galectin-4, but not galectin-6, in the lamina propria of the DSS-damaged colon, its association with luminal colonic bacteria, and differences in subcellular localization of these proteins suggest that they also have distinct roles in the normal and the damaged mouse digestive tract. Our results provide a rare example of ancestral and derived functions evolving after tandem gene duplication.
High-Learners Present Larger Mid-Frontal Theta Power and Connectivity in Response to Incorrect Performance Feedback
Authors: Luft Caroline Di Bernardi , Nolte Guido , Bhattacharya Joydeep
Published: January 2013

A crucial aspect of cognitive control and learning is the ability to integrate feedback, that is, to evaluate action outcomes and their deviations from the intended goals and to adjust behavior accordingly. However, how high-learners differ from low-learners in relation to feedback processing has not been characterized. Further, little is known about the underlying brain connectivity patterns during feedback processing. This study aimed to fill these gaps by analyzing electrical brain responses from healthy adult human participants while they performed a time estimation task with correct and incorrect feedback. As compared with low-learners, high-learners presented larger mid-frontal theta (4–8 Hz) oscillations and lower sensorimotor beta (17–24 Hz) oscillations in response to incorrect feedback. Further, high-learners showed larger theta connectivity from left central, associated with motor activity, to mid-frontal, associated with performance monitoring, immediately after feedback (0–0.3 s), followed by (from 0.3 to 0.6 s after feedback) a flux from mid-frontal to prefrontal, associated with executive functioning. We suggest that these results reflect two cognitive processes related to successful feedback processing: first, the obtained feedback is compared with the expected one, and second, the feedback history is updated based on this information. Our results also indicate that high- and low-learners differ not only on how they react to incorrect feedback, but also in relation to how their distant brain areas interact while processing both correct and incorrect feedback. This study demonstrates the neural underpinnings of individual differences in goal-directed adaptive behavior.
Rod Photoreceptors Protect from Cone Degeneration-Induced Retinal Remodeling and Restore Visual Responses in Zebrafish
Authors: Saade Carole J. , Alvarez-Delfin Karen , Fadool James M.
Published: January 2013

Humans are largely dependent upon cone-mediated vision. However, death or dysfunction of rods, the predominant photoreceptor subtype, results in secondary loss of cones, remodeling of retinal circuitry, and blindness. The changes in circuitry may contribute to the vision deficit and undermine attempts at restoring sight. We exploit zebrafish larvae as a genetic model to specifically characterize changes associated with photoreceptor degenerations in a cone-dominated retina. Photoreceptors form synapses with two types of second-order neurons, bipolar cells, and horizontal cells. Using cell-specific reporter gene expression and immunolabeling for postsynaptic glutamate receptors, significant remodeling is observed following cone degeneration in thepde6cw59larval retina but not rod degeneration in theXops:mCFPq13line. In adults, rods and cones are present in approximately equal numbers, and inpde6cw59mutants glutamate receptor expression and synaptic structures in the outer plexiform layer are preserved, and visual responses are gained in these once blind fish. We propose that the abundance of rods in the adult protects the retina from cone degeneration-induced remodeling. We test this hypothesis by genetically manipulating the number of rods in larvae. We show that an increased number and uniform distribution of rods inlor/tbx2bp25bbtlorsix7morpholino-injected larvae protect frompde6cw59-induced secondary changes. The observations that remodeling is a common consequence of photoreceptor death across species, and that in zebrafish a small number of surviving photoreceptors afford protection from degeneration-induced changes, provides a model for systematic analysis of factors that slow or even prevent the secondary deteriorations associated with neural degenerative disease.
Calcium, Calpain, and Calcineurin in Low-Frequency Depression of Transmitter Release
Authors: Silverman-Gavrila Lorelei B. , Praver Moshe , Mykles Donald L. , Charlton Milton P.
Published: January 2013

Low-frequency depression (LFD) of transmitter release occurs at phasic synapses with stimulation at 0.2 Hz in both isolated crayfish (Procambarus clarkii) neuromuscular junction (NMJ) preparations and in intact animals. LFD is regulated by presynaptic activity of the Ca2+-dependent phosphatase calcineurin (Silverman-Gavrila and Charlton, 2009). Since the fast Ca2+chelator BAPTA-AM inhibits LFD but the slow chelator EGTA-AM does not, the Ca2+sensor for LFD may be close to a Ca2+source at active zones. Calcineurin can be activated by the Ca2+-activated protease calpain, and immunostaining showed that both proteins are present at nerve terminals. Three calpain inhibitors, calpain inhibitor I, MDL-28170, and PD150606, but not the control compound PD145305, inhibit LFD both in the intact animal as shown by electromyograms and by intracellular recordings at neuromuscular junctions. Analysis of mini-EPSPs indicated that these inhibitors had minimal postsynaptic effects. Proteolytic activity in CNS extract, detected by a fluorescent calpain substrate, was modulated by Ca2+and calpain inhibitors. Western blot analysis of CNS extract showed that proteolysis of calcineurin to a fragment consistent with the constitutively active form required Ca2+and was blocked by calpain inhibitors. Inhibition of LFD by calpain inhibition blocks the reduction in phosphoactin and the depolymerization of tubulin that normally occurs in LFD, probably by blocking the dephosphorylation of cytoskeletal proteins by calcineurin. In contrast, high-frequency depression does not involve protein phosphorylation- or calpain-dependent mechanisms. LFD may involve a specific pathway in which local Ca2+signaling activates presynaptic calpain and calcineurin at active zones and causes changes of tubulin cytoskeleton.
Retinotopic Patterns of Correlated Fluctuations in Visual Cortex Reflect the Dynamics of Spontaneous Perceptual Suppression
Authors: Donner Tobias H. , Sagi Dov , Bonneh Yoram S. , Heeger David J.
Published: January 2013

While viewing certain stimuli, perception changes spontaneously in the face of constant input. For example, during “motion-induced blindness” (MIB), a small salient target spontaneously disappears and reappears when surrounded by a moving mask. Models of such bistable perceptual phenomena posit spontaneous fluctuations in neuronal activity throughout multiple stages of the visual cortical hierarchy. We used fMRI to link correlated activity fluctuations across human visual cortical areas V1 through V4 to the dynamics (rate and duration) of MIB target disappearance. We computed the correlations between the time series of fMRI activity in multiple retinotopic subregions corresponding to MIB target and mask. Linear decomposition of the matrix of temporal correlations revealed spatial patterns of activity fluctuations, regardless of whether or not these were time-locked to behavioral reports of target disappearance. The spatial pattern that dominated the activity fluctuations during MIB was spatially nonspecific, shared by all subregions, but did not reflect the dynamics of perception. By contrast, the fluctuations associated with the rate of MIB disappearance were retinotopically specific for the target subregion in V4, and the fluctuations associated with the duration of MIB disappearance states were target-specific in V1. Target-specific fluctuations in V1 have not previously been identified by averaging activity time-locked to behavioral reports of MIB disappearance. Our results suggest that different levels of the visual cortical hierarchy shape the dynamics of perception via distinct mechanisms, which are evident in distinct spatial patterns of spontaneous cortical activity fluctuations.
Dysregulation of Hypoxia-Inducible Factor by Presenilin/γ-Secretase Loss-of-Function Mutations
Authors: Kaufmann Muriel R. , Barth Sandra , Konietzko Uwe , Wu Bei , Egger Sascha , Kunze Reiner , Marti Hugo H. , Hick Meike , Müller Ulrike , Camenisch Gieri , Wenger Roland H.
Published: January 2013

Presenilin (PSEN) 1 and 2 are the catalytic components of the γ-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid β that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia-inducible factors (HIFs), the master regulators of the hypoxic response. We previously identified the FK506 binding protein 38 (FKBP38) as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain-specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1α protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic γ-secretase function of PSEN1/2 was needed for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxic response, involving the generation of AICD. Together, our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade.
Properties of Ribbon and Non-Ribbon Release from Rod Photoreceptors Revealed by Visualizing Individual Synaptic Vesicles
Authors: Chen Minghui , Van Hook Matthew J. , Zenisek David , Thoreson Wallace B.
Published: January 2013

Vesicle release from rod photoreceptors is regulated by Ca2+entry through L-type channels located near synaptic ribbons. We characterized sites and kinetics of vesicle release in salamander rods by using total internal reflection fluorescence microscopy to visualize fusion of individual synaptic vesicles. A small number of vesicles were loaded by brief incubation with FM1–43 or a dextran-conjugated, pH-sensitive form of rhodamine, pHrodo. Labeled organelles matched the diffraction-limited size of fluorescent microspheres and disappeared rapidly during stimulation. Consistent with fusion, depolarization-evoked vesicle disappearance paralleled electrophysiological release kinetics and was blocked by inhibiting Ca2+influx. Rods maintained tonic release at resting membrane potentials near those in darkness, causing depletion of membrane-associated vesicles unless Ca2+entry was inhibited. This depletion of release sites implies that sustained release may be rate limited by vesicle delivery. During depolarizing stimulation, newly appearing vesicles approached the membrane at ∼800 nm/s, where they paused for ∼60 ms before fusion. With fusion, vesicles advanced ∼18 nm closer to the membrane. Release events were concentrated near ribbons, but lengthy depolarization also triggered release from more distant non-ribbon sites. Consistent with greater contributions from non-ribbon sites during lengthier depolarization, damaging the ribbon by fluorophore-assisted laser inactivation (FALI) of Ribeye caused only weak inhibition of exocytotic capacitance increases evoked by 200-ms depolarizing test steps, whereas FALI more strongly inhibited capacitance increases evoked by 25 ms steps. Amplifying release by use of non-ribbon sites when rods are depolarized in darkness may improve detection of decrements in release when they hyperpolarize to light.
Adaptation Improves Neural Coding Efficiency Despite Increasing Correlations in Variability
Authors: Adibi Mehdi , McDonald James S. , Clifford Colin W. G. , Arabzadeh Ehsan
Published: January 2013

Exposure of cortical cells to sustained sensory stimuli results in changes in the neuronal response function. This phenomenon, known as adaptation, is a common feature across sensory modalities. Here, we quantified the functional effect of adaptation on the ensemble activity of cortical neurons in the rat whisker-barrel system. A multishank array of electrodes was used to allow simultaneous sampling of neuronal activity. We characterized the response of neurons to sinusoidal whisker vibrations of varying amplitude in three states of adaptation. The adaptors produced a systematic rightward shift in the neuronal response function. Consistently, mutual information revealed that peak discrimination performance was not aligned to the adaptor but to test amplitudes 3–9 μm higher. Stimulus presentation reduced single neuron trial-to-trial response variability (captured by Fano factor) and correlations in the population response variability (noise correlation). We found that these two types of variability were inversely proportional to the average firing rate regardless of the adaptation state. Adaptation transferred the neuronal operating regime to lower rates with higher Fano factor and noise correlations. Noise correlations were positive and in the direction of signal, and thus detrimental to coding efficiency. Interestingly, across all population sizes, the net effect of adaptation was to increase the total information despite increasing the noise correlation between neurons.
HDAC Inhibition Facilitates the Switch between Memory Systems in Young But Not Aged Mice
Authors: Dagnas Malorie , Guillou Jean-Louis , Prévôt Thomas , Mons Nicole
Published: January 2013

Chromatin modifications, especially histone acetylation, are critically involved in gene regulation required for long-term memory processes. Increasing histone acetylation via administration of histone deacetylase inhibitors before or after a learning experience enhances memory consolidation for hippocampus-dependent tasks and rescues age-related memory impairments. Whether acutely and locally enhancing histone acetylation during early consolidation processes can operate as a switch between multiple memory systems is less clear. This study examined the short- and long-term behavioral consequences of acute intra-CA1 administration of the histone deacetylase inhibitor Trichostatin A (TSA) on cue versus place learning strategy selection after a cue-guided water maze task and competition testing performed 1 or 24 h later in mice. Here, we show that intra-CA1 TSA infusion administrated immediately post-training biased young mice away from striatum-dependent cue strategy toward hippocampus-dependent place strategy under training condition that normally promotes cue strategy in vehicle controls. However, concomitant infusions of TSA with either PKA inhibitor, Rp-cAMPS, into CA1 or cAMP analog, 8Br-cAMP, into dorsal striatum failed to bias young mice to place strategy use. Behavioral and immunohistochemical analyses further indicated that post-training TSA infusion in aged mice rescued aging-associated deregulation of H4 acetylation in the CA1 but failed to reverse phosphorylated CREB deficits and to produce strategy bias on the 24 h probe test. These findings suggest that post-training intra-CA1 TSA infusion promotes dynamic shift from striatum toward the hippocampal system in young but not aged animals, and support the possibility of a role for CREB in the TSA-mediated switch between these two memory systems.
Functional Impact of Dendritic Branch-Point Morphology
Authors: Ferrante Michele , Migliore Michele , Ascoli Giorgio A.
Published: January 2013

Cortical pyramidal cells store multiple features of complex synaptic input in individual dendritic branches and independently regulate the coupling between dendritic and somatic spikes. Branch points in apical trees exhibit wide ranges of sizes and shapes, and the large diameter ratio between trunk and oblique dendrites exacerbates impedance mismatch. The morphological diversity of dendritic bifurcations could thus locally tune neuronal excitability and signal integration. However, these aspects have never been investigated. Here, we first quantified the morphological variability of branch points from two-photon images of rat CA1 pyramidal neurons. We then investigated the geometrical features affecting spike initiation, propagation, and timing with a computational model validated by glutamate uncaging experiments. The results suggest that even subtle membrane readjustments at branch points could drastically alter the ability of synaptic input to generate, propagate, and time action potentials.
Notum Homolog Plays a Novel Role in Primary Motor Innervation
Authors: Cantu Jorge A. , Flowers G. Parker , Topczewski Jacek
Published: January 2013

To form complex neuronal networks, growth cones use intermediate targets as guideposts on the path to more distant targets. In the developing zebrafish (Danio rerio), the muscle pioneers (MPs) are intermediate targets for primary motor neurons (PMNs) that innervate the trunk musculature. The mechanisms regulating PMN axon guidance at the MPs are not fully understood. We have identified a new member of the Notum family in zebrafish, Notum 2, which is expressed exclusively in the MPs during primary motor innervation. While homologs of Notum, including zebrafish Notum 1a, negatively regulate the Wnt/β-catenin signaling pathway, we discovered a novel function of Notum 2 in regulating motor axon guidance. Knockdown of Notum 2 resulted in a failure of caudal primary (CaP) axons to migrate beyond the MPs, despite the proper specification of the intermediate target. In contrast, mosaic Notum 2 overexpression induced branching of PMN axons. This effect is specific to Notum 2, as overexpression of Notum 1a does not affect PMN axon trajectory. Ectopic expression of Notum 2 by cells contacting the growing CaP axon induced the highest frequency of branching, suggesting that localized Notum 2 expression affects axon behavior. We propose a model where Notum 2 expression at the MPs provides a cue to release CaP motor axons from their intermediate targets, allowing growth cones to proceed to secondary targets in the ventral muscle. This work demonstrates an unexpected role for a Notum homolog in regulating growth cone migration, separate from the well established functions of other Notum homologs in Wnt signaling.
Top-Down Modulation of Lateral Interactions in Visual Cortex
Authors: Ramalingam Nirmala , McManus Justin N.J. , Li Wu , Gilbert Charles D.
Published: January 2013

The primary visual cortex (V1) changes its computation according to the perceptual task being performed. We propose that this cognitive modulation results from gating of V1 intrinsic connections. To test this idea, using behavioral paradigms that engage top-down modulation of V1 contextual interactions, we recorded from chronically implanted electrode arrays in macaques. We observed task-dependent changes in interactions between V1 sites measured both by correlation between spike trains and by coherence between local field potentials (LFP-LFP coherence). The direction of the changes in aggregate activity, as measured by LFPs, depended on perceptual strategy: perceptual grouping increased LFP coherence between sites crucial for the task, whereas perceptual segregation lowered the LFP coherence. Using spiking activity as a measure, we found that the behaviorally driven changes in correlation structure between neurons dramatically increased the stimulus-related information that they convey; this additional increase in encoded information at the level of neuronal ensembles equals that obtained from task-driven reconfigurations of neural tuning curves. The improvements in information encoding were strongest for stimuli with greatest discrimination difficulty.
Adolescent Cocaine Exposure Causes Enduring Macroscale Changes in Mouse Brain Structure
Authors: Wheeler Anne L. , Lerch Jason P. , Chakravarty M. Mallar , Friedel Miriam , Sled John G. , Fletcher Paul J. , Josselyn Sheena A. , Frankland Paul W.
Published: January 2013

Cocaine dependence is associated with abnormalities in brain structure in humans. However, it is unclear whether these differences in brain structure predispose an individual to drug use or are a result of cocaine's action on the brain. This study investigates the impact of chronic cocaine exposure on brain structure and drug-related behavior in mice. Specifically, mice received daily cocaine or saline injections for 20 d during two developmental time periods: adolescence (27–46 d old) and young adulthood (60–79 d old). Following 30 d of abstinence, either fixed brain T2 weighted magnetic resonance images were acquired on a 7 T scanner at 32 μm isotropic voxel dimensions or mice were assessed for sensitization to the locomotor stimulant effects of cocaine. Three automated techniques (deformation-based morphometry, striatum shape analysis, and cortical thickness assessment) were used to identify population differences in brain structure in cocaine-exposed versus saline-exposed mice. We found that cocaine induced changes in brain structure, and these were most pronounced in mice exposed to cocaine during adolescence. Many of these changes occurred in brain regions previously implicated in addiction including the nucleus accumbens, striatum, insular cortex, orbitofrontal cortex, and medial forebrain bundle. Furthermore, exposure to the same cocaine regimen caused sensitization to the locomotor stimulant effects of cocaine, and these effects were again more pronounced in mice exposed to cocaine during adolescence. These results suggest that altered brain structure following 1 month of abstinence may contribute to these persistent drug-related behaviors, and identify cocaine exposure as the cause of these morphological changes.
Dopaminergic Neurons Encode a Distributed, Asymmetric Representation of Temperature inDrosophila
Authors: Tomchik Seth M.
Published: January 2013

Dopaminergic circuits modulate a wide variety of innate and learned behaviors in animals, including olfactory associative learning, arousal, and temperature-preference behavior. It is not known whether distinct or overlapping sets of dopaminergic neurons modulate these behaviors. Here, I have functionally characterized the dopaminergic circuits innervating theDrosophilamushroom body within vivocalcium imaging and conditional silencing of genetically defined subsets of neurons. Distinct subsets of PPL1 dopaminergic neurons innervating the vertical lobes of the mushroom body responded to decreases in temperature, but not increases, with rapidly adapting bursts of activity. PAM neurons innervating the horizontal lobes did not respond to temperature shifts. Ablation of the antennae and maxillary palps reduced, but did not eliminate, the responses. Genetic silencing of dopaminergic neurons innervating the vertical mushroom body lobes substantially reduced behavioral cold avoidance, but silencing smaller subsets of these neurons had no effect. These data demonstrate that overlapping dopaminergic circuits encode a broadly distributed, asymmetric representation of temperature that overlays regions implicated previously in learning, memory, and forgetting. Thus, diverse behaviors engage overlapping sets of dopaminergic neurons that encode multimodal stimuli and innervate a single anatomical target, the mushroom body.
Distinct Modes of Dopamine and GABA Release in a Dual Transmitter Neuron
Authors: Borisovska Maria , Bensen AeSoon L. , Chong Gene , Westbrook Gary L.
Published: January 2013

We now know of a surprising number of cases where single neurons contain multiple neurotransmitters. Neurons that contain a fast-acting neurotransmitter, such as glutamate or GABA, and a modulatory transmitter, such as dopamine, are a particularly interesting case because they presumably serve dual signaling functions. The olfactory bulb contains a large population of GABA- and dopamine-containing neurons that have been implicated in normal olfaction as well as in Parkinson's disease. Yet, they have been classified as nonexocytotic catecholamine neurons because of the apparent lack of vesicular monoamine transporters. Thus, we examined how dopamine is stored and released from tyrosine hydroxylase-positive GFP (TH+-GFP) mouse periglomerular neuronsin vitro. TH+cells expressed both VMAT2 (vesicular monoamine transporter 2) and VGAT (vesicular GABA transporter), consistent with vesicular storage of both dopamine and GABA. Carbon fiber amperometry revealed that release of dopamine was quantal and calcium-dependent, but quantal size was much less than expected for large dense core vesicles, suggesting that release originated from small clear vesicles identified by electron microscopy. A single action potential in a TH+neuron evoked a brief GABA-mediated synaptic current, whereas evoked dopamine release was asynchronous, lasting for tens of seconds. Our data suggest that dopamine and GABA serve temporally distinct roles in these dual transmitter neurons.
Tuning In to Sound: Frequency-Selective Attentional Filter in Human Primary Auditory Cortex
Authors: Da Costa Sandra , van der Zwaag Wietske , Miller Lee M. , Clarke Stephanie , Saenz Melissa
Published: January 2013

Cocktail parties, busy streets, and other noisy environments pose a difficult challenge to the auditory system: how to focus attention on selected sounds while ignoring others? Neurons of primary auditory cortex, many of which are sharply tuned to sound frequency, could help solve this problem by filtering selected sound information based on frequency-content. To investigate whether this occurs, we used high-resolution fMRI at 7 tesla to map the fine-scale frequency-tuning (1.5 mm isotropic resolution) of primary auditory areas A1 and R in six human participants. Then, in a selective attention experiment, participants heard low (250 Hz)- and high (4000 Hz)-frequency streams of tones presented at the same time (dual-stream) and were instructed to focus attention onto one stream versus the other, switching back and forth every 30 s. Attention to low-frequency tones enhanced neural responses within low-frequency-tuned voxels relative to high, and when attention switched the pattern quickly reversed. Thus, like a radio, human primary auditory cortex is able to tune into attended frequency channels and can switch channels on demand.
Using Big Box Biology to Teach Diversity
Authors: Heyborne William
Published: January 2013

The increase in “big box” stores over the past decade has provided a great source of specimens for use in teaching diversity in biology.