bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)
Authors: Amadori Sergio , Suciu Stefan , Stasi Roberto , Salih Helmut R. , Selleslag Dominik , Muus Petra , De Fabritiis Paolo , Venditti Adriano , Ho Anthony D. , Lübbert Michael , Thomas Xavier , Latagliata Roberto , Halkes Constantijn J.M. , Falzetti Franca , Magro Domenico , Guimaraes José E. , Berneman Zwi , Specchia Giorgina , Karrasch Matthias , Fazi Paola , Vignetti Marco , Willemze Roel , de Witte Theo , Marie Jean-Pierre
Published: October 2013

Purpose

This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML).

Patients and Methods

Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m2 on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m2 on day 0). The primary end point was overall survival (OS).

Results

The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality.

Conclusion

As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.
Hematopoietic Cell Transplantation–Specific Comorbidity Index Predicts Inpatient Mortality and Survival in Patients Who Received Allogeneic Transplantation Admitted to the Intensive Care Unit
Authors: Bayraktar Ulas D. , Shpall Elizabeth J. , Liu Ping , Ciurea Stefan O. , Rondon Gabriela , de Lima Marcos , Cardenas-Turanzas Marylou , Price Kristen J. , Champlin Richard E. , Nates Joseph L.
Published: October 2013

Purpose

To investigate the prognostic value of the Hematopoietic Cell Transplantation–Specific Comorbidity Index (HCT-CI) in patients who received transplantation admitted to the intensive care unit (ICU).

Patients and Methods

We investigated the association of HCT-CI with inpatient mortality and overall survival (OS) among 377 patients who were admitted to the ICU within 100 days of allogeneic stem-cell transplantation (ASCT) at our institution. HCT-CI scores were collapsed into four groups and were evaluated in univariate and multivariate analyses using logistic regression and Cox proportional hazards models.

Results

The most common pretransplantation comorbidities were pulmonary and cardiac diseases, and respiratory failure was the primary reason for ICU admission. We observed a strong trend for higher inpatient mortality and shorter OS among patients with HCT-CI values ≥ 2 compared with patients with values of 0 to 1 in all patient subsets studied. Multivariate analysis showed that patients with HCT-CI values ≥ 2 had significantly higher inpatient mortality than patients with values of 0 to 1 and that HCT-CI values ≥ 4 were significantly associated with shorter OS compared with values of 0 to 1 (hazard ratio, 1.74; 95% CI, 1.23 to 2.47). The factors associated with lower inpatient mortality were ICU admission during the ASCT conditioning phase or the use of reduced-intensity conditioning regimens. The overall inpatient mortality rate was 64%, and the 1-year OS rate was 15%. Among patients with HCT-CI scores of 0 to 1, 2, 3, and ≥ 4, the 1-year OS rates were 22%, 17%, 18%, and 9%, respectively.

Conclusion

HCT-CI is a valuable predictor of mortality and survival in critically ill patients after ASCT.
Delivering High-Quality and Affordable Care Throughout the Cancer Care Continuum
Authors: Shih Ya-Chen Tina , Ganz Patricia A. , Aberle Denise , Abernethy Amy , Bekelman Justin , Brawley Otis , Goodwin James S. , Hu Jim C. , Schrag Deborah , Temel Jennifer S. , Schnipper Lowell
Published: October 2013

The national cost of cancer care is projected to reach $173 billion by 2020, increasing from $125 billion in 2010. This steep upward cost trajectory has placed enormous an financial burden on patients, their families, and society as a whole and raised major concern about the ability of the health care system to provide and sustain high-quality cancer care. To better understand the cost drivers of cancer care and explore approaches that will mitigate the problem, the National Cancer Policy Forum of the Institute of Medicine held a workshop entitled “Delivering Affordable Cancer Care in the 21st Century” in October 2012. Workshop participants included bioethicists, health economists, primary care physicians, and medical, surgical, and radiation oncologists, from both academic and community settings. All speakers expressed a sense of urgency about the affordability of cancer care resulting from the future demographic trend as well as the high cost of emerging cancer therapies and rapid diffusion of new technologies in the absence to evidence indicating improved outcomes for patients. This article is our summary of presentations at the workshop that highlighted the overuse and underuse of screening, treatments, and technologies throughout the cancer care continuum in oncology practice in the United States.
Spinal Cord Stimulation in Treatment of Chronic Benign Pain: Challenges in Treatment Planning and Present Status, a 22-Year Experience
Authors: Kumar Krishna , Hunter Gary , Demeria Denny
Published: October 2013

OBJECTIVE:

To present an in-depth analysis of clinical predictors of outcome including age, sex, etiology of pain, type of electrodes used, duration of pain, duration of treatment, development of tolerance, employment status, activities of daily living, psychological status, and quality of life. Suggestions for treatment of low back pain with a predominant axial component are addressed. We analyzed the complications and proposed remedial measures to improve the effectiveness of this modality.

METHODS:

Study group consists of 410 patients (252 men, 58 women) with a mean age of 54 years and a mean follow-up period of 97.6 months. All patients were gated through a multidisciplinary pain clinic. The study was conducted over 22 years.

RESULTS:

The early success rate was 80% (328 patients), whereas the long-term success rate of internalized patients was 74.1% (243 patients) after the mean follow-up period of 97.6 months. Hardware-related complications included displaced or fractured electrodes, infection, and hardware malfunction. Etiologies demonstrating efficacy included failed back syndrome, peripheral vascular disease, angina pain, complex regional pain syndrome I and II, peripheral neuropathy, lower limb pain caused by multiple sclerosis. Age, sex, laterality of pain or number of surgeries before implant did not play a role in predicting outcome. The percentage of pain relief was inversely related to the time interval between pain onset and time of implantation. Radicular pain with axial component responded better to dual Pisces electrode or Specify-Lead implantation.

CONCLUSION:

Spinal cord stimulation can provide significant long-term pain relief with improved quality of life and employment. Results of this study will be effective in better defining prognostic factors and reducing complications leading to higher success rates with spinal cord stimulation.
Motor Cortex Stimulation for the Enhancement of Recovery from Stroke: A Prospective, Multicenter Safety Study
Authors: Brown Jeffrey A. , Lutsep Helmi L. , Weinand Martin , Cramer Steven C.
Published: October 2013

OBJECTIVE:

Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke.

METHODS:

This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure.

RESULTS:

Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P = 0.001 overall).

CONCLUSION:

The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.
Unique Features of Herniated Discs at the Cervicothoracic Junction: Clinical Presentation, Imaging, Operative Management, and Outcome after Anterior Decompressive Operation in 10 Patients
Authors: Post Nicholas H. , Cooper Paul R. , Frempong-Boadu Anthony K. , Costa Mary Ellen
Published: October 2013

OBJECTIVE:

Disc herniations at the C7–T1 level are unusual (4% of all herniated cervical discs) and are often incorrectly diagnosed because of unusual neurological findings and suboptimal imaging studies. Furthermore, the anterior approach may be problematic because the manubrium and slope of the vertebral bodies away from the surgeon obscures the end plates. The recurrent laryngeal nerve and the thoracic duct may be injured by respective right- or left-sided approaches. A posterior approach to this level has, therefore, been advocated, but results of C7–T1 herniations treated anteriorly have not been specifically addressed in the literature. We, therefore, reviewed our experience in the operative management of patients undergoing single level anterior cervical discectomy and fusion at the C7–T1 interspace for the 10 years ending June 2004 with regard to clinical presentation, imaging, problems of operative exposure, and neurological outcome.

METHODS:

Of 268 patients with single level anterior cervical discectomy and fusions (ACDFs), 10 (3.7%) had C7–T1 disc herniations. We retrospectively reviewed the medical records, operative reports, and imaging studies of these 10 patients.

RESULTS:

All patients presented with C8 motor deficit without myelopathy. The operation was carried out through an anterior approach with a skin incision 3 cm above the clavicle. Visualization of the C7–T1 disc space was achieved in all without difficulty. Eight of 10 patients are neurologically intact.

CONCLUSION:

The C7–T1 disc herniates laterally because of the absence of Luschka joints at this level. Central herniation with myelopathy is rare. An anterior approach was easily accomplished in all patients. Recovery of motor function was related to duration and severity of preoperative deficit.
Subsidence of Stand-alone Cervical Carbon Fiber Cages
Authors: Bartels Ronald H.M.A. , Donk Roland D. , Feuth Ton
Published: October 2013

OBJECTIVE:

To investigate the number of subsidences of inserted cervical carbon fiber cages and to define predictive factors for subsidence.

METHODS:

All patients treated for a cervical herniated disc and fusion with a cervical carbon fiber cage between January 2002 and December 2003 were retrospectively identified. The radiological examinations were reviewed, and, especially, the presence of subsidence was noted. Possible predictive factors for subsidence were determined before the investigation.

RESULTS:

In 69 patients, there were 96 cages inserted, of which 29.2% subsided. Of all factors investigated, only smoking seemed to be predictive for subsidence, whereas insertion at C6 to C7 clearly had a higher risk at subsidence. Subsidence was not related to outcome or fusion.

CONCLUSION:

Although the high number of subsidence of cages has never been described before, clinical outcome and fusion rate is comparable with the literature.
Cystic Dilation of the Conus Ventriculus Terminalis Presenting as an Acute Cauda Equina Syndrome Relieved by Decompression and Cyst Drainage: Case Report
Authors: Brisman Jonathan L. , Li Maria , Hamilton Dean , Mayberg Marc R. , Newell David W.
Published: October 2013

OBJECTIVE AND IMPORTANCE:

The ventriculus terminalis of the conus, or "fifth ventricle" refers to the ependymal-lined space in the middle of the conus that is present in childhood and whose persistence into adulthood is rare. A number of cases of cystic dilatation of the ventriculus terminalis have been described in adulthood. Patients tend to present with either pain alone or gradually progressive conus or cauda equina syndromes with varying degrees of recovery after cyst drainage. Presentation with an acute cauda equina syndrome and its successful surgical management has not been previously reported.

CLINICAL PRESENTATION:

A 57-year-old woman experienced back pain and bilateral sciatica ascribed to diabetic neuropathy for 2 years. Over a 24-hour period she developed bilateral lower extremity weakness, saddle anesthesia, and bowel and bladder incontinence. Lumbosacral magnetic resonance imaging demonstrated a large cystic dilatation of the ventriculus terminalis.

INTERVENTION:

She was taken for emergency surgical decompression and cyst drainage. Immediately after surgery, she experienced significant increase in lower extremity strength and has since regained continence.

CONCLUSION:

Cystic dilation of the ventriculus terminalis should be part of the differential diagnosis for a cauda equina syndrome; surgical decompression with simple cyst drainage can result in excellent clinical results.
Stent-assisted Intracranial Recanalization for Acute Stroke: Early Results
Authors: Levy Elad I. , Ecker Robert D. , Horowitz Michael B. , Gupta Rishi , Hanel Ricardo A. , Sauvageau Eric , Jovin Tudor G. , Guterman Lee R. , Hopkins L Nelson
Published: October 2013

OBJECTIVE:

In patients who are not candidates for intravenous tissue plasminogen activator, intra-arterial (IA) therapy is an alternative. Current recanalization rates are 50 to 60% for IA thrombolysis. Stent-assisted recanalization in the setting of acute stroke after failed thrombolysis may improve recanalization rates.

METHODS:

A retrospective analysis was performed of 19 patients treated at two institutions between July 2001 and March, 2005 with intracranial stenting of a vessel resistant to standard thrombolytic techniques. Demographics, clinical, and radiographic presentation and outcomes were studied.

RESULTS:

Thirteen men and six women with a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 16 (range, 15–22) were included. Eight lesions were located at the internal carotid artery terminus, seven in the M1/M2 segment, and four in the basilar artery. Average time-to-treatment was 210 ± 160 minutes. Overall recanalization rate (Thrombolysis in Cerebral Infarction Grade 2 or 3) was 79%. There were six deaths: five due to progression of stroke and withdrawal of care at the family's request and one as the result of a delayed carotid injury after tracheostomy. One postoperative asymptomatic intracranial hemorrhage occurred without adverse affect on outcome. Median discharge NIHSS score of surviving patients was 5 (range, 2.5-11.5). Lesions at the internal carotid artery terminus (P<0.009), older age (P<0.003), and higher baseline NIHSS score (P<0.009) were significant negative outcome predictors, as measured by >3 modified Rankin scale score at discharge.

CONCLUSION:

Stent-assisted recanalization for acute stroke resulting from intracranial thrombotic occlusion is associated with a high recanalization rate and low intracranial hemorrhage rate. These initial results suggest that stenting may be an option for recalcitrant cerebral arterial occlusions.
Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation
Authors: Andres Sarah F. , Simmons James G. , Mah Amanda T. , Santoro M. Agostina , Van Landeghem Laurianne , Lund P. Kay
Published: October 2013

Despite evidence for impact of insulin on intestinal epithelial physiology and pathophysiology, the expression patterns, roles, and regulation of insulin receptor (IR) and IR isoforms in the intestinal epithelium are not well characterized. IR-A is thought to mediate proliferative effects of insulin or IGFs in fetal or cancer cells. IR-B is considered the metabolic receptor for insulin in specialized tissues. This study employed a novel Sox9-EGFP reporter mouse that permits isolation of intestinal epithelial stem cells (IESC), progenitors, enteroendocrine cells, and differentiated lineages, the ApcMin/+ mouse model of precancerous adenoma, and normal human intestinal and colorectal cancer cell (CRC) lines. We tested the hypothesis that there is differential expression of IR-A or IR-B in stem and tumor cells versus differentiated intestinal epithelial cells (IEC) and that IR-B impacts cell proliferation. Our findings provide novel evidence that IR-B expression is significantly lower in highly proliferative IESC and progenitor cells versus post-mitotic, differentiated IEC and in subconfluent/undifferentiated versus differentiated Caco-2 cells. IR-B is also reduced in ApcMin/+ tumors and highly tumorigenic CRC cells. These differences in IR-B were accompanied by altered levels of mRNAs encoding muscleblind-like 2, a known regulator of IR alternative splicing. Forced IR-B expression in subconfluent/undifferentiated Caco-2 cells reduced proliferation and increased biomarkers of differentiation. Our findings indicate that impact of insulin on different cell types in the intestinal epithelium may differ depending on relative IR-B∶ IR-A expression levels and provide new evidence for roles of IR-B to limit proliferation of CRC.
Phosphorylation of moesin by c-Jun N-terminal kinase is important for podosome rosette formation in Src-transformed fibroblasts
Authors: Pan Yi-Ru , Tseng Wei-Shan , Chang Po-Wei , Chen Hong-Chen
Published: October 2013

Podosomes are actin-based membrane protrusions that facilitate extracellular matrix degradation and invasive cell motility. Podosomes can self-organize into large rosette-like structures in Src-transformed fibroblasts, osteoclasts, and some highly invasive cancer cells. However, the mechanism of this assembly remains obscure. In this study, we show that the suppression of c-Jun N-terminal kinase (JNK) by the JNK inhibitor SP600125 or short-hairpin RNA inhibited podosome rosette formation in SrcY527F-transformed NIH3T3 fibroblasts. In addition, SrcY527F was less potent to induce podosome rosettes in JNK1-null or JNK2-null mouse embryo fibroblasts than in their wild-type counterparts. The kinase activity of JNK was essential for promoting podosome rosette formation but not for its localization to podosome rosettes. Moesin, a member of the ERM (ezrin, radixin, and moesin) protein family, was identified as a substrate of JNK. We show that the phosphorylation of moesin at Thr558 by JNK was important for podosome rosette formation in SrcY527F-transformed NIH3T3 fibroblasts. Taken together, our results unveil a novel role of JNK in podosome rosette formation by phosphorylating moesin.
Petrological Investigations of Oligocene Coals from Foreland Basin of Northeast India
Authors: Singh Alok K , Singh Mahendra P , Singh Prakash K
Published: October 2013

The results of the petrological investigations carried out on coal samples from the Oligocene deposits of Northeastern India (Assam, Arunachal Pradesh and Nagaland) have been discussed. These deposits occur in the Tikak Parbat Formation (Barail Group) and were probably deposited in the foreland basin. Petrographically, these coals are enriched in vitrinite macerals (65.8–96.6 vol %, mean 87.2 vol %) with variable concentrations of liptinite macerals (2.7–35.4 vol %, mean 11.9 vol %). They contain low concentration of inertinite (nil-3.3 vol %, mean 0.9 vol %) macerals. The microlithotype is dominated by vitrite (61.5–100 vol %, mean 90.8 vol %). An elevated volatile matter (44.15 – 60.20 wt %, mean 52.90 wt %, d.a.f. basis) and reflectance values (VRr 0.39–0.61%) put their rank as sub-bituminous type ‘C’ to high volatile bituminous type ‘C’. The GI and TPI values favour telmatic conditions of origin with high tree density and prolonged wet conditions. This is in agreement with the paleoenvironment interpreted from the vitrinite and liptinite-rich microlithotypes, which suggested a forest and reed facies. However, the presence of inertinite in some coal seams indicates tectonic upheavals / regression of the sea resulting to periodic and short span dryness of the basin.
Buffering the pH of the culture medium does not extend yeast replicative lifespan
Authors: Wasko Brian M , Carr Daniel T , Tung Herman , Doan Ha , Schurman Nathan , Neault Jillian R , Feng Joey , Lee Janet , Zipkin Ben , Mouser Jacob , Oudanonh Edward , Nguyen Tina , Stetina Torin , Shemorry Anna , Lemma Mekedes , Kaeberlein Matt
Published: October 2013

During chronological aging of budding yeast cells, the culture medium can become acidified, and this acidification limits cell survival.  As a consequence, buffering the culture medium to pH 6 significantly extends chronological life span under standard conditions in synthetic medium.  In this study, we assessed whether a similar process occurs during replicative aging of yeast cells.  We find no evidence that buffering the pH of the culture medium to pH levels either higher or lower than the initial pH of the medium is able to significantly extend replicative lifespan.  Thus, we conclude that, unlike chronological life span, replicative life span is not limited by acidification of the culture medium or by changes in the pH of the environment.
Present status and perspective of pharmacogenetics in Mexico
Authors: Cuautle-Rodríguez Patricia , Llerena Adrián , Molina-Guarneros Juan
Published: October 2013

Drug costs account for up to 24% of the country’s health expenditure and there are 13,000 registered drugs being prescribed. Diabetes is the main cause of death in the country, with over 85% of diabetic patients currently under drug treatment. The importance of knowing interindividual variability in drug metabolism on Mexican populations is thus evident. The purpose of this article is to provide an overlook of the current situation of pharmacogenetic research in Mexico, focusing on drug-metabolizing enzymes, and the possibility of developing a phenotyping cocktail for Mexican populations. So far, 21 pharmacogenetic studies on Mexican population samples (Mestizos and Amerindian) have been published. These have reported interindividual variability through phenotyping and/or genotyping cytochromes: CYP2D6, 2C19, 2C9, 2E1, and phase II enzymes UGT and NAT2. Some cytochromes with important clinical implications have not yet been phenotyped in Mexican populations. The development of a cocktail adapted to them could be a significant contribution to a larger knowledge on drug response variability at a lower price and shorter time. There are validated phenotyping cocktails that present several practical advantages, being valuable, safe, and inexpensive tools in drug metabolism characterization, which require only a single experiment to provide information on several cytochrome activities.
Two-Stage Weighted Least Squares Estimation of Nonstationary Random Coefficient Autoregressions
Authors: Aknouche Abdelhakim
Published: October 2013

This paper proposes a two-stage weighted least squares (2S-WLS) estimate for the autoregressive parameter and the random coefficient variance of a non-(strictly) stationary random coefficient autoregression (RCA). In the first stage, the autoregressive parameter is estimated from the conditional mean equation by a weighted least squares (WLS) method in which the weight is the conditional variance evaluated at any arbitrary known parameter value. In the second stage, based on the estimated conditional variance equation, the random coefficient variance is estimated again using the WLS method, but weighted by the squared conditional variance arbitrarily evaluated. It will be shown that the 2S-WLS estimate is asymptotically Gaussian with the same asymptotic variance as the quasi-maximum likelihood estimate under very mild conditions. Applications to the Gaussian double autoregression and the Markov bilinear model are given.
Real-Time Monitoring Test for Realized Volatility
Authors: Shin-Huei Wang Cindy , Hsiao Cheng
Published: October 2013

This paper proposes a monitoring cumulative sum of squares (CUSQ)-type test for structural breaks inreal timevia an autoregressive (AR) approximation framework where data generating process (DGP) is a long memory process. The limiting distribution of the monitoring test follows a Brownian bridge and is free of long memory parameters under the null hypothesis of no break. The test is easy to implement and avoids the issue of spurious breaks found for some retrospective tests for long memory process. Neither does it need to use the bootstrap procedure to find the critical values. Monte Carlo simulations appear to confirm that there exists negligible size distortion and satisfactory power performances in finite samples. The procedure is then applied to monitor the real-time pattern of realized volatilities of dollar–Deutschmark and dollar–Japanese Yen.
Morphological effects on the darkness of English intervocalic /l/
Authors: Lee-Kim Sang-Im , Davidson Lisa , Hwang Sangjin
Published: October 2013

Articulatory and acoustic studies have provided evidence that in word- initial and word-final positions, English /l/ exhibits substantial differences in ‘darkness‐: dark [ɫ] in word-final position is produced with a more retracted tongue dorsum and lowered tongue body than light [l] in word-initial position. The darkness of intervocalic /l/, however, is variable. While Sproat and Fujimura (1993) argue that /l/ darkness is on a continuum strongly affected by duration, Hayes (2000) maintains that the morphological status of intervocalic /l/s should affect whether they are produced as light or dark variants. In this study, ultrasound imaging is used to investigate whether the morphological affiliation of the /l/ affects the degree of tongue dorsum retraction and tongue body lowering and the acoustic characteristics of /l/ darkness. Six American English speakers produced three types of stimuli which were predicted to increase in darkness in the following order: (1) when /l/ corresponded with the onset of a suffix (e.g., flaw-less), (2) when /l/ corresponded with the final position of the stem word (e.g., tall-est), and (3) when /l/ was the final consonant of a stem word (e.g., tall). For both articulatory and acoustic measures, the predicted order was upheld. The strongest articulatory correlate of darkness was tongue body lowering, and acoustic differences were mainly manifested in F1 and normalized intensity. Phonological implications of these findings are discussed.
Diverse Suppressive Influences in Area MT and Selectivity to Complex Motion Features
Authors: Cui Yuwei , Liu Liu D. , Khawaja Farhan A. , Pack Christopher C. , Butts Daniel A.
Published: October 2013

Neuronal selectivity results from both excitatory and suppressive inputs to a given neuron. Suppressive influences can often significantly modulate neuronal responses and impart novel selectivity in the context of behaviorally relevant stimuli. In this work, we use a naturalistic optic flow stimulus to explore the responses of neurons in the middle temporal area (MT) of the alert macaque monkey; these responses are interpreted using a hierarchical model that incorporates relevant nonlinear properties of upstream processing in the primary visual cortex (V1). In this stimulus context, MT neuron responses can be predicted from distinct excitatory and suppressive components. Excitation is spatially localized and matches the measured preferred direction of each neuron. Suppression is typically composed of two distinct components: (1) a directionally untuned component, which appears to play the role of surround suppression and normalization; and (2) a direction-selective component, with comparable tuning width as excitation and a distinct spatial footprint that is usually partially overlapping with excitation. The direction preference of this direction-tuned suppression varies widely across MT neurons: approximately one-third have overlapping suppression in the opposite direction as excitation, and many other neurons have suppression with similar direction preferences to excitation. There is also a population of MT neurons with orthogonally oriented suppression. We demonstrate that direction-selective suppression can impart selectivity of MT neurons to more complex velocity fields and that it can be used for improved estimation of the three-dimensional velocity of moving objects. Thus, considering MT neurons in a complex stimulus context reveals a diverse set of computations likely relevant for visual processing in natural visual contexts.
Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition
Authors: Vetter Irina , Hein Alexander , Sattler Simon , Hessler Sabine , Touska Filip , Bressan Elisangela , Parra Andres , Hager Ulrich , Leffler Andreas , Boukalova Stepana , Nissen Matthias , Lewis Richard J. , Belmonte Carlos , Alzheimer Christian , Huth Tobias , Vlachova Viktorie , Reeh Peter W. , Zimmermann Katharina
Published: October 2013

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of Kv7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol—like camphor—potently inhibits Kv7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.
Glycine Transporter-1 Inhibition Promotes Striatal Axon Sprouting via NMDA Receptors in Dopamine Neurons
Authors: Schmitz Yvonne , Castagna Candace , Mrejeru Ana , Lizardi-Ortiz José E. , Klein Zoe , Lindsley Craig W. , Sulzer David
Published: October 2013

NMDA receptor activity is involved in shaping synaptic connections throughout development and adulthood. We recently reported that brief activation of NMDA receptors on cultured ventral midbrain dopamine neurons enhanced their axon growth rate and induced axonal branching. To test whether this mechanism was relevant to axon regrowth in adult animals, we examined the reinnervation of dorsal striatum following nigral dopamine neuron loss induced by unilateral intrastriatal injections of the toxin 6-hydroxydopamine. We used a pharmacological approach to enhance NMDA receptor-dependent signaling by treatment with an inhibitor of glycine transporter-1 that elevates levels of extracellular glycine, a coagonist required for NMDA receptor activation. All mice displayed sprouting of dopaminergic axons from spared fibers in the ventral striatum to the denervated dorsal striatum at 7 weeks post-lesion, but the reinnervation in mice treated for 4 weeks with glycine uptake inhibitor was approximately twice as dense as in untreated mice. The treated mice also displayed higher levels of striatal dopamine and a complete recovery from lateralization in a test of sensorimotor behavior. We confirmed that the actions of glycine uptake inhibition on reinnervation and behavioral recovery required NMDA receptors in dopamine neurons using targeted deletion of the NR1 NMDA receptor subunit in dopamine neurons. Glycine transport inhibitors promote functionally relevant sprouting of surviving dopamine axons and could provide clinical treatment for disorders such as Parkinson's disease.
Large-Scale Brain Networks in the Awake, Truly Resting Marmoset Monkey
Authors: Belcher Annabelle M. , Yen Cecil C. , Stepp Haley , Gu Hong , Lu Hanbing , Yang Yihong , Silva Afonso C. , Stein Elliot A.
Published: October 2013

Resting-state functional MRI is a powerful tool that is increasingly used as a noninvasive method for investigating whole-brain circuitry and holds great potential as a possible diagnostic for disease. Despite this potential, few resting-state studies have used animal models (of which nonhuman primates represent our best opportunity of understanding complex human neuropsychiatric disease), and no work has characterized networks in awake, truly resting animals. Here we present results from a small New World monkey that allows for the characterization of resting-state networks in the awake state. Six adult common marmosets (Callithrix jacchus) were acclimated to light, comfortable restraint using individualized helmets. Following behavioral training, resting BOLD data were acquired during eight consecutive 10 min scans for each conscious subject. Group independent component analysis revealed 12 brain networks that overlap substantially with known anatomically constrained circuits seen in the awake human. Specifically, we found eight sensory and “lower-order” networks (four visual, two somatomotor, one cerebellar, and one caudate–putamen network), and four “higher-order” association networks (one default mode-like network, one orbitofrontal, one frontopolar, and one network resembling the human salience network). In addition to their functional relevance, these network patterns bear great correspondence to those previously described in awake humans. This first-of-its-kind report in an awake New World nonhuman primate provides a platform for mechanistic neurobiological examination for existing disease models established in the marmoset.
Musical Training Enhances Neural Processing of Binaural Sounds
Authors: Parbery-Clark Alexandra , Strait Dana L. , Hittner Emily , Kraus Nina
Published: October 2013

While hearing in noise is a complex task, even in high levels of noise humans demonstrate remarkable hearing ability. Binaural hearing, which involves the integration and analysis of incoming sounds from both ears, is an important mechanism that promotes hearing in complex listening environments. Analyzing inter-ear differences helps differentiate between sound sources–a key mechanism that facilitates hearing in noise. Even when both ears receive the same input, known as diotic hearing, speech intelligibility in noise is improved. Although musicians have better speech-in-noise perception compared with non-musicians, we do not know to what extent binaural processing contributes to this advantage. Musicians often demonstrate enhanced neural responses to sound, however, which may undergird their speech-in-noise perceptual enhancements. Here, we recorded auditory brainstem responses in young adult musicians and non-musicians to a speech stimulus for which there was no musician advantage when presented monaurally. When presented diotically, musicians demonstrated faster neural timing and greater intertrial response consistency relative to non-musicians. Furthermore, musicians' enhancements to the diotically presented stimulus correlated with speech-in-noise perception. These data provide evidence for musical training's impact on biological processes and suggest binaural processing as a possible contributor to more proficient hearing in noise.
An Empirical Study of Historical Patterns in Musical Rhythm
Authors: Daniele Joseph R. , Patel Aniruddh D.
Published: October 2013

This paper introduces a new approach for the historical study of musical rhythm based on an empirical measure of rhythm known as the nPVI (‘normalized pairwise variability index’). The nPVI is an equation that measures the degree of durational contrast between successive events in a sequence. While the nPVI is increasingly used for comparative studies of rhythm in music and language, we show that it can also be used for historical research. A historical analysis of musical nPVI values from German/Austrian and Italian instrumental classical music between ∼1600-1900 reveals different patterns in the two cultures: German/Austrian music shows a steady increase in nPVI values over this period, while Italian music shows no salient increase. These patterns are discussed in light of the idea (from historical musicology) that the influence of Italian music on German music began to wane in the second half of the 1700s due to a rise of musical nationalism in Germany. The nPVI data prove to be consistent with this idea, illustrating how nPVI analysis can reveal patterns that enrich and inform historical research.
Is Higher Music Faster? Pitch–Speed Relationships in Western Compositions
Authors: Broze Yuri , Huron David
Published: October 2013

We conducted four tests of the conjecture that higher musical pitch coincides with faster musical speeds in composition and performance. First, a ‘notewise’ examination of Western musical scores tested whether longer (i.e., slower) notes tend to have lower pitches. Results were genre-dependent, with three of six sampled styles exhibiting the predicted effect. A second study considered an independent sample of Western music part-by-part and found that lower musical voices tend to have significantly fewer notes than higher voices. The third study used instrumental recordings to directly measure event onset densities in notes per second. A strong correlation (rs = .74, p < .002) between performed note speed and an instrument’s pitch range (tessitura) was found. Finally, a fourth study indicated that Baroque ornaments are more likely to appear in higher musical parts. Considered together, these four studies suggest a pitch-speed relationship that is most evident when the methodology preserves the notion of musical ‘line.’ We outline several possible origins for the observed effect.
The Use of Large Corpora to Train a New Type of Key-Finding Algorithm
Authors: Albrecht Joshua , Shanahan Daniel
Published: October 2013

Computational models of key estimation have struggled to emulate the accuracy levels of human listeners, especially with pieces in the minor mode. The current study proposes a new key-finding algorithm, which utilizes Euclidean distance, rather than correlation, and is trained on the statistical properties of a large musical sample. A model was trained on a dataset of 490 pieces encoded into the Humdrum “kern” format, in which the key was known. This model was tested on a reserve dataset of 492 pieces, and was found to have a significantly higher overall accuracy than previous models. In addition, we determined separate accuracy ratings for major mode and minor mode works for the existing key-finding models and report that most existing models provide greater accuracy for major mode rather than minor mode works. The proposed key-finding algorithm performs more accurately on minor mode works than all of the other models tested, although it does not perform significantly better than the models created by Aarden (2003), Bellman (2005), or Sapp (2011). Finally, an algorithm that combines the Aarden-Essen model (2003) and the proposed algorithm is suggested, and results in significantly more accurate key assessments than all of the other extant models.
Building a Representative Corpus of Classical Music
Authors: London Justin
Published: October 2013

This paper presents an object lesson in the challenges and considerations involved in assembling a musical corpus for empirical research. It develops a model for the construction of a representative corpus of classical music of the “common practice period” (1700-1900), using both specific composers as well as broader historical styles and musical genres (e.g., symphony, chamber music, songs, operas) as its sampling parameters. Five sources were used in the construction of the model: (a) The Oxford History of Western Music by Richard Taruskin (2005), (b) amalgamated Orchestral Repertoire Reports for the years 2000-2007, from the League of American Orchestras, (c) a list of titles from the Naxos.com “Music in the Movies” web-based library, (d) Barlow and Morgenstern’s Dictionary of Musical Themes (1948), and (e) for the composers listed in sources (a)-(d), counts of the number of recordings each has available from Amazon.com. General considerations for these sources are discussed, and specific aspects of each source are then detailed. Intersource agreement is assessed, showing strong consensus among all sources, save for the Taruskin History. Using the Amazon.com data to determine weighting factors for each parameter, a preliminary sampling model is proposed. Including adequate genre representation leads to a corpus of ≈300 pieces, suggestive of the minimum size for an adequately representative corpus of classical music. The approaches detailed here may be applied to more specialized contexts, such as the music of a particular geographic region, historical era, or genre.
The evolution of viviparity: molecular and genomic data from squamate reptiles advance understanding of live birth in amniotes
Authors: Van Dyke James U , Brandley Matthew C , Thompson Michael B
Published: October 2013

Squamate reptiles (lizards and snakes) are an ideal model system for testing hypotheses regarding the evolution of viviparity (live birth) in amniote vertebrates. Viviparity has evolved over 100 times in squamates, resulting in major changes in reproductive physiology. At a minimum, all viviparous squamates exhibit placentae formed by the appositions of maternal and embryonic tissues, which are homologous in origin with the tissues that form the placenta in therian mammals. These placentae facilitate adhesion of the conceptus to the uterus as well as exchange of oxygen, carbon dioxide, water, sodium, and calcium. However, most viviparous squamates continue to rely on yolk for nearly all of their organic nutrition. In contrast, some species, which rely on the placenta for at least a portion of organic nutrition, exhibit complex placental specializations associated with the transport of amino acids and fatty acids. Some viviparous squamates also exhibit reduced immunocompetence during pregnancy, which could be the result of immunosuppression to protect developing embryos. Recent molecular studies using both candidate-gene and next-generation sequencing approaches have suggested that at least some of the genes and gene families underlying these phenomena play similar roles in the uterus and placenta of viviparous mammals and squamates. Therefore, studies of the evolution of viviparity in squamates should inform hypotheses of the evolution of viviparity in all amniotes, including mammals.
Rare Bleeding Disorders in Children: Identification and Primary Care Management
Authors: Acharya Suchitra S.
Published: October 2013

Bleeding symptoms are common in healthy children but occasionally may indicate an underlying congenital or acquired bleeding diathesis. The rare bleeding disorders (RBDs) comprise inherited deficiencies of coagulation factors I (congenital fibrinogen deficiencies), II, V, VII, X, XI, and XIII and combined factor deficiencies, most notably of factors V and VIII and of vitamin K–dependent factors. These disorders often manifest during childhood and may present with recurrent or even serious or life-threatening bleeding episodes, particularly during the neonatal period. Accordingly, primary care and other nonhematologist pediatric providers should be familiar with the clinical presentation and initial evaluation of these rare disorders. Bleeding manifestations generally vary within the same RBD and may be indistinguishable from 1 RBD to another or from other more common bleeding disorders. Serious bleeding events such as intracranial hemorrhage may be heralded by less serious bleeding symptoms. The results of initial coagulation studies, especially prothrombin time and activated partial thromboplastin time, are often helpful in narrowing down the potential factor deficiency, with factor XIII deficiency being an exception. Consultation with a hematologist is advised to facilitate accurate diagnosis and to ensure proper management and follow-up. The approach to bleeding episodes and invasive procedures is individualized and depends on the severity, frequency, and, in the case of procedures, likelihood of bleeding. Prophylaxis may be appropriate in children with recurrent serious bleeding and specifically after life-threatening bleeding episodes. When available, specific purified plasma-derived or recombinant factor concentrates, rather than fresh frozen plasma or cryoprecipitate, are the treatment of choice.
Pulmonary Capillaritis in Monozygotic Twin Boys
Authors: Kupfer Oren , Ridall Leslie A. , Hoffman Lindsey M. , Dishop Megan K. , Soep Jennifer B. , Wagener Jeffrey S. , Fan Leland L.
Published: October 2013

Pulmonary hemorrhage can be classified as either proximal or distal (alveolar). Causes of proximal hemorrhage include infection, foreign body aspiration, pulmonary embolus, trauma, vascular malformation, and pulmonary hypertension. Causes of distal or diffuse alveolar hemorrhage are divided by the histologic presence or absence of capillaritis, which is characterized by inflammation of the alveolar interstitium and pulmonary capillary structure. Pulmonary capillaritis is a rare event in children and is associated with higher morbidity and mortality than diffuse alveolar hemorrhage without capillaritis. This is a report of 17-month-old previously healthy monozygotic twins presenting simultaneously with diffuse alveolar hemorrhage, pulmonary capillaritis, and an otherwise negative serologic workup. This suggests a role of genetic predisposition in this rare disease.