bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulated Hematopoiesis Caused by Mammary Cancer Is Associated with Epigenetic Changes and Hox Gene Expression in Hematopoietic Cells
Authors: Sio Alexander , Chehal Manreet K. , Tsai Kevin , Fan Xueling , Roberts Morgan E. , Nelson Brad H. , Grembecka Jolanta , Cierpicki Tomasz , Krebs Danielle L. , Harder Kenneth W.
Published: August 2013

Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes. Cancer Res; 73(19); 5892–904. ©2013 AACR.
Hypoxia-Dependent Modification of Collagen Networks Promotes Sarcoma Metastasis
Authors: Eisinger-Mathason T.S. Karin , Zhang Minsi , Qiu Qiong , Skuli Nicolas , Nakazawa Michael S. , Karakasheva Tatiana , Mucaj Vera , Shay Jessica E.S. , Stangenberg Lars , Sadri Navid , Puré Ellen , Yoon Sam S. , Kirsch David G. , Simon M. Celeste
Published: August 2013

Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α–deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.

Significance: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifically the collagen-modifying enzyme PLOD2. Cancer Discov; 3(10); 1190–1205. ©2013 AACR.

See related commentary by Vanharanta and Massagué, p. 1103

This article is highlighted in the In This Issue feature, p. 1083
Increased Atherosclerotic Lesion Formation and Vascular Leukocyte Accumulation in Renal Impairment Are Mediated by Interleukin-17A
Authors: Ge Shuwang , Hertel Barbara , Koltsova Ekaterina K. , Sörensen-Zender Inga , Kielstein Jan T. , Ley Klaus , Haller Hermann , von Vietinghoff Sibylle
Published: August 2013

Rationale:

Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation, and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood.

Objective:

This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes.

Methods and Results:

Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in 2 murine atherosclerosis models, apolipoprotein E (
Apoe
−/−
) and low-density lipoprotein (LDL) receptor–deficient (
LDLr
−/−
) mice. The number of aortic myeloid cells increased significantly. They took-up less oxidized LDL, whereas CD11c expression, interaction with T cells, and aortic T cell proliferation were significantly enhanced in renal impairment. In human peripheral blood mononuclear cell cultures, chronic kidney disease serum decreased lipid uptake and increased human leukocyte antigen II (HLA II) expression. Supplementation with interleukin-17A similarly increased HLA II and CD11c expression and impaired oxidized LDL uptake. Interleukin-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of interleukin-17A in
LDLr
−/−
mice by lethal irradiation and reconstitution with
Il17a
−/−
bone marrow abolished the effect of renal impairment on aortic CD11b
+
myeloid cell accumulation, CD11c expression, and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function.

Conclusions:

Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for interleukin-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.
Temporal Relationship and Prognostic Significance of Atrial Fibrillation in Heart Failure Patients With Preserved Ejection Fraction
Authors: Zakeri Rosita , Chamberlain Alanna M. , Roger Véronique L. , Redfield Margaret M.
Published: August 2013

Background—

In patients with heart failure and preserved ejection fraction (HFpEF), atrial fibrillation (AF) may predate, concur with, or develop after HFpEF diagnosis. We sought to define the temporal relationship between AF and HFpEF, to identify factors associated with AF, and to determine the prognostic impact of prevalent and incident AF in HFpEF.

Method and Results—

From 1983 to 2010, 939 Olmsted County, Minnesota, residents (age, 77±12 years; 61% female) newly diagnosed with HFpEF (EF ≥0.50) were evaluated. Baseline rhythm classification included prior AF (>3 months before HFpEF diagnosis), concurrent AF (±3 months), or sinus rhythm. Incident AF (>3 months after HFpEF diagnosis) and all-cause mortality were ascertained through February 2012. Prior AF (29%) and concurrent AF (23%) were associated with older age, higher brain-type natriuretic peptide, and larger left atrial volume index at HFpEF diagnosis compared with sinus rhythm. Of HFpEF patients in sinus rhythm at diagnosis, 32% developed AF over a median follow-up of 3.7 years (interquartile range, 1.5–6.7 years; 69 events per 1000 person-years). Age and diastolic dysfunction were positively and statin use was inversely associated with incident AF. With no AF used as the referent, prior or concurrent AF (combined hazard ratio, 1.3; 95% confidence interval, 1.0–1.6;
P
=0.03) and incident AF, modeled as a time-dependent covariate (hazard ratio, 2.1; 95% confidence interval, 1.4–3.0;
P
<0.001), were independently associated with death after adjustment for pertinent covariates.

Conclusions—

AF occurs in two thirds of HFpEF patients at some point in the natural history and confers a poor prognosis. Further study is required to determine whether intervention for AF may improve outcomes or if statin use can prevent AF in HFpEF.
Perfusion MR Predicts Outcome in High-Risk Transient Ischemic Attack/Minor Stroke
Authors: Asdaghi Negar , Hill Michael D. , Coulter Jonathan I. , Butcher Kenneth S. , Modi Jayesh , Qazi Abdul , Goyal Mayank , Demchuk Andrew M. , Coutts Shelagh B.
Published: August 2013

Background and Purpose—

Transient or minor ischemic stroke is associated with an early risk of deterioration. Baseline perfusion–diffusion mismatch may predict clinical deterioration and infarct growth in this population.

Methods—

High-risk transient ischemic attack and minor stroke (National Institutes of Health Stroke Scale ≤3) subjects were prospectively enrolled and imaged with MRI within 24 hours of symptom onset as part of sequential derivation and validation cohorts. Baseline diffusion-weighted imaging, perfusion-weighted imaging (
T
max
≥4 s), mismatch (
T
max
≥4 s-diffusion-weighted imaging), and follow-up fluid-attenuated inversion recovery infarct volumes were measured. Primary outcome was infarct growth on fluid-attenuated inversion recovery, and secondary outcome was symptom progression.

Results—

One hundred thirty-seven and 281 subjects were included in the derivation and validation cohorts, respectively. Infarct growth occurred in 18.5% of the derivation and 5.5% of the validation cohorts. Symptom progression occurred in 9.5% of the derivation and 4.5% of the validation cohorts. In the derivation cohort, subjects with baseline mismatch were significantly more likely to show infarct growth on fluid-attenuated inversion recovery (relative risk [RR], 13.5; 95% confidence interval [CI], 4.2–38.9) and symptom progression (RR, 7.0; 95% CI, 2.0–7.3). A baseline mismatch volume of 10 mL in the derivation cohort was the optimal threshold to predict infarct growth (area under the curve, 0.89; 95% CI, 0.80–0.98). This threshold was highly predictive of infarct growth in the validation cohort (
P
=0.001). Baseline mismatch was associated with clinical deterioration in the derivation (area under the curve, 0.81; 95% CI, 0.67–0.96) and validation cohorts (area under the curve, 0.66; 95% CI, 0.46–0.85).

Conclusions—

Among subjects with high-risk transient ischemic attack and minor stroke, diffusion-weighted imaging–perfusion-weighted imaging mismatch predicts infarct growth and clinical deterioration. These findings suggest that reperfusion strategies would be beneficial in this population.
Monitoring Neuroprotective Effects Using Positron Emission Tomography With [
11
C]ITMM, a Radiotracer for Metabotropic Glutamate 1 Receptor
Authors: Yui Joji , Xie Lin , Fujinaga Masayuki , Yamasaki Tomoteru , Hatori Akiko , Kumata Katsushi , Nengaki Nobuki , Zhang Ming-Rong
Published: August 2013

Background and Purpose—

Recent pharmacological evidence shows that antagonists for the metabotropic glutamate 1 (mGlu1) receptor exhibit neuroprotective effects in an ischemic brain. The aim of this study was to visualize the mGlu1 receptor and to monitor neuroprotective effects in a rat model of mild focal ischemia using positron emission tomography (PET) with
N
-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[
11
C]methoxy-
N-
methylbenzamide ([
11
C]ITMM), a radiotracer for mGlu1.

Methods—

Rats were subjected to a 30-minute transient right middle cerebral artery occlusion. Saline or minocycline, a neuroprotective agent, was intravenously injected immediately after surgery and then daily during the subsequent 7 days. PET imaging with [
11
C]ITMM was performed on the rats on days 1 to 7 after ischemia. In vitro autoradiography and histopathologic staining were conducted to confirm the results of in vivo PET.

Results—

PET with [
11
C]ITMM demonstrated a gradual decrease of radioactivity in the ipsilateral sides of the ischemic brains. The radioactivity uptake ratio between the ipsilateral and contralateral sides also decreased with time. Minocycline treatment slowed down the decrease in the radioactivity level in the ipsilateral sides. Pretreatment with JNJ16259685, an mGlu1-selective ligand, significantly reduced brain radioactivity, confirming that the uptake of [
11
C]ITMM primarily reflects mGlu1 levels in the brain regions, including the ischemic area. In vitro autoradiography and histopathology confirmed the changes in mGlu1 levels in the brains.

Conclusions—

[
11
C]ITMM-PET may be a useful technique for characterizing the change in mGlu1 level during the occurrence and progression of neuronal damage and for evaluating the neuroprotective effects of drugs after ischemia.
Prospective, Multicenter, Single-Arm Study of Mechanical Thrombectomy Using Solitaire Flow Restoration in Acute Ischemic Stroke
Authors: Pereira Vitor M. , Gralla Jan , Davalos Antoni , Bonafé Alain , Castaño Carlos , Chapot René , Liebeskind David S. , Nogueira Raul G. , Arnold Marcel , Sztajzel Roman , Liebig Thomas , Goyal Mayank , Besselmann Michael , Moreno Antonio , Schroth Gerhard , Alamovitch S , Arquizan C , Dohmen C , Killer-Oberpfalzer M , Broussalis E , Krause L , Lopez-Ibor L , Macho J , Amaro S , Menon B , Millàn M , Miteff F , Faulder K , Piotin M , Weber R , Parrilla G
Published: August 2013

Background and Purpose—

Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke.

Methods—

Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0–2).

Results—

A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic.

Conclusions—

In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01327989.
Styloid and Hyoid Bone Proximity Is a Risk Factor for Cervical Carotid Artery Dissection
Authors: Renard Dimitri , Azakri Souhayla , Arquizan Caroline , Swinnen Bart , Labauge Pierre , Thijs Vincent
Published: August 2013

Background and Purpose—

Carotid artery dissection (CAD) is more common with increased styloid process length. Our goal was to determine whether proximity of the styloid process and the hyoid bone to the internal carotid artery (ICA) was a risk factor for CAD.

Methods—

We studied axial slices on computed tomography angiograms of 88 patients with nonaneurysmal CAD, from 88 age- and sex-matched controls without dissection, and from 32 nonage-/sex-matched nonaneurysmal vertebral artery dissection control patients. We measured the nearest distance between the ICA and both the styloid and the hyoid bones, blinded to clinical information and radiological reports.

Results—

Styloid-ICA and hyoid-ICA distances were significantly shorter on the side of the CAD as compared with nondissection control patients (
P
<0.0001 for the styloid-ICA distance; and
P
=0.0037 for the hyoid-ICA distance). Styloid-ICA distances, regardless of the side of the dissection, were shorter in CAD patients compared with the nondissection control group (right side,
P
=0.001; left side,
P
=0.0002) and the vertebral artery dissection control group (right side,
P
=0.0031; left side,
P
=0.0067). Direct mechanical contact of the styloid with the ICA was more common in CAD patients.

Conclusions—

Shorter distances between the styloid and ICA (and possibly also the hyoid and the ICA) are important risk factors for CAD. Further study is needed to determine whether dissections result from direct injury to the outer vessel wall of the carotid artery.
User Experience of a Centralized Hyperacute Stroke Service
Authors: Moynihan Barry , Paul Selina , Markus Hugh S.
Published: August 2013

Background and Purpose—

Centralizing hyperacute stroke unit (HASU) care services allows improved access to thrombolysis but could be associated with worse patient experience, particularly when early repatriation to a local stroke recovery unit occurs as this may result in discontinuity of care. A centralized model of care was introduced in London, United Kingdom, with 8 HASUs providing acute care for the whole 8.3 million population, with repatriation on day 3 to a local stroke recovery unit. The patient and carer experience of this model of care has not been previously reported.

Methods—

We undertook a prospective observational study of the new model of care in the South West London sector. Patient and carer experiences were evaluated using a modified Picker Questionnaire. Separate questionnaires were used for patients discharged directly home from the HASU, those repatriated to local stroke recovery units, and for carers of patients admitted to the HASU.

Results—

Despite moving from a selected to nonselected admission pattern, thrombolysis rates increased from 6% to 9%. High satisfaction rates were reported among both patients and carers. Patients discharged directly home had higher satisfaction levels than those requiring repatriation to their local stroke unit, who were older and had more severe stroke. A total of 47% of carers expressed anxiety over the repatriation from the HASU back to the local stroke recovery unit, but few patients and carers reported an impact of this move on patient recovery.

Conclusion—

Centralized HASU care is associated with good levels of patient and carer satisfaction.
Patent Foramen Ovale and Cryptogenic Stroke
Authors: Furlan Anthony J. , Jauss Marek
Published: August 2013

Despite 3 recent randomized clinical trials, the management of patients with cryptogenic stroke and patent foramen ovale remains unsettled. The primary results of Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale (CLOSURE), Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Stroke (PC), and Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) were the same; the intent to treat analysis for the primary end point in all 3 trials failed to demonstrate superiority of device closure compared with medical therapy. CLOSURE put the brakes on indiscriminate device closure of patent foramen ovales in patients with cryptogenic stroke or transient ischemic attack. RESPECT suggested, but did not prove, that highly selected patients without vascular risk factors, with a cortical infarct on baseline magnetic resonance imaging and a substantial patent foramen ovale shunt may benefit from the Amplatzer device during a multiple-year period. In the absence of definitive clinical trial results, the precise definition of which patient subgroups should be considered for patent foramen ovale device closure should be agreed to by the stakeholder societies and the Food and Drug Administration.
Influence of Age on Thrombolysis Outcome in Wake-Up Stroke
Authors: Manawadu Dulka , Bodla Shankaranand , Keep Jeff , Kalra Lalit
Published: August 2013

Background and Purpose—

Thrombolysis in patients >80 years remains controversial; we hypothesized that >80-year-old patients with wake-up ischemic stroke (WUIS) will benefit from thrombolysis despite risks because of poor outcomes with no treatment.

Methods—

The study included 68 thrombolysed patients with WUIS (33 [48%] >80 years), 54 nonthrombolysed patients with WUIS (21 [39%] >80 years), and 117 patients (>80 years old) thrombolysed within 4.5 hours of symptom onset (reference group). Mortality and modified Rankin Scale (mRS) were assessed at 90 days.

Results—

Baseline characteristics of thrombolysed and nonthrombolysed >80 and ≤80-year-old patients with WUIS were comparable. Thrombolysis outcomes in >80-year-old patients with WUIS were better than in nonthrombolysed >80-year-old patients with WUIS (90-day mortality: 24% versus 47%,
P
=0.034; mRS 0–2: 30% versus 5%,
P
=0.023; mRS 0–1: 15% versus 5%,
P
=0.24) and comparable with thrombolysed ≤80-year-old patients with WUIS. Thrombolysis was associated with odds ratio 0.27 (95% confidence interval, 0.05–0.97) for mortality and odds ratio 28.6 (95% confidence interval, 1.8–448) for mRS 0 to 2 at 90 days in >80-year-old patients with WUIS after adjusting for stroke severity and risk factors.

Conclusions—

Thrombolysis may be associated with greater benefit in >80-year-old patients with WUIS but a selection bias favoring thrombolysis in those most likely to benefit may significantly reduce interpretability of these findings.
MMP9 Variation After Thrombolysis Is Associated With Hemorrhagic Transformation of Lesion and Death
Authors: Inzitari Domenico , Giusti Betti , Nencini Patrizia , Gori Anna Maria , Nesi Mascia , Palumbo Vanessa , Piccardi Benedetta , Armillis Alessandra , Pracucci Giovanni , Bono Giorgio , Bovi Paolo , Consoli Domenico , Guidotti Mario , Nucera Antonia , Massaro Francesca , Micieli Giuseppe , Orlandi Giovanni , Perini Francesco , Tassi Rossana , Tola Maria Rosaria , Sessa Maria , Toni Danilo , Abbate Rosanna
Published: August 2013

Background and Purpose—

Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection.

Methods—

We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA–pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6.

Results—

Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11–2.26];
P
=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02–1.92];
P
=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman
P
from <0.001 to 0.040).

Conclusions—

Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.
Internal Variability in Projections of Twenty-First-Century Arctic Sea Ice Loss: Role of the Large-Scale Atmospheric Circulation
Authors: Wettstein Justin J. , Deser Clara
Published: August 2013

Internal variability in twenty-first-century summer Arctic sea ice loss and its relationship to the large-scale atmospheric circulation is investigated in a 39-member Community Climate System Model, version 3 (CCSM3) ensemble for the period 2000–61. Each member is subject to an identical greenhouse gas emissions scenario and differs only in the atmospheric model component's initial condition.

September Arctic sea ice extent trends during 2020–59 range from −2.0 × 106 to −5.7 × 106 km2 across the 39 ensemble members, indicating a substantial role for internal variability in future Arctic sea ice loss projections. A similar nearly threefold range (from −7.0 × 103 to −19 × 103 km3) is found for summer sea ice volume trends.

Higher rates of summer Arctic sea ice loss in CCSM3 are associated with enhanced transpolar drift and Fram Strait ice export driven by surface wind and sea level pressure patterns. Over the Arctic, the covarying atmospheric circulation patterns resemble the so-called Arctic dipole, with maximum amplitude between April and July. Outside the Arctic, an atmospheric Rossby wave train over the Pacific sector is associated with internal ice loss variability. Interannual covariability patterns between sea ice and atmospheric circulation are similar to those based on trends, suggesting that similar processes govern internal variability over a broad range of time scales. Interannual patterns of CCSM3 ice–atmosphere covariability compare well with those in nature and in the newer CCSM4 version of the model, lending confidence to the results. Atmospheric teleconnection patterns in CCSM3 suggest that the tropical Pacific modulates Arctic sea ice variability via the aforementioned Rossby wave train. Large ensembles with other coupled models are needed to corroborate these CCSM3-based findings.
Error Covariance Estimation for Coupled Data Assimilation Using a Lorenz Atmosphere and a Simple Pycnocline Ocean Model
Authors: Han Guijun , Wu Xinrong , Zhang Shaoqing , Liu Zhengyu , Li Wei
Published: August 2013

Coupled data assimilation uses a coupled model consisting of multiple time-scale media to extract information from observations that are available in one or more media. Because of the instantaneous exchanges of information among the coupled media, coupled data assimilation is expected to produce self-consistent and physically balanced coupled state estimates and optimal initialization for coupled model predictions. It is also expected that applying coupling error covariance between two media into observational adjustments in these media can provide direct observational impacts crossing the media and thereby improve the assimilation quality. However, because of the different time scales of variability in different media, accurately evaluating the error covariance between two variables residing in different media is usually very difficult. Using an ensemble filter together with a simple coupled model consisting of a Lorenz atmosphere and a pycnocline ocean model, which characterizes the interaction of multiple time-scale media in the climate system, the impact of the accuracy of coupling error covariance on the quality of coupled data assimilation is studied. Results show that it requires a large ensemble size to improve the assimilation quality by applying coupling error covariance in an ensemble coupled data assimilation system, and the poorly estimated coupling error covariance may otherwise degrade the assimilation quality. It is also found that a fast-varying medium has more difficulty being improved using observations in slow-varying media by applying coupling error covariance because the linear regression from the observational increment in slow-varying media has difficulty representing the high-frequency information of the fast-varying medium.
Simulation of a Flash Flooding Storm at the Steep Edge of the Himalayas*
Authors: Kumar Anil , Houze Robert A. , Rasmussen Kristen L. , Peters-Lidard Christa
Published: August 2013

A flash flood and landslide in the Leh region of the Indus Valley in the Indian state of Jammu and Kashmir on 5–6 August 2010 resulted in hundreds of deaths and great property damage. Observations have led to the hypothesis that the storm, which formed over the Tibetan Plateau, was steered over the steep edge of the plateau by 500-hPa winds and then energized by the ingestion of lower-level moist air, which was approaching from the Arabian Sea and Bay of Bengal and rose up the Himalayan barrier. A coupled land surface and atmospheric model simulation validates this hypothesized storm scenario, with the model storm taking the form of a traveling mesoscale squall line with a leading convective line, trailing stratiform region, and midlevel inflow jet. In this region, the development of a mesoscale storm over high terrain is highly unusual, especially one in the form of a propagating squall line system. This unusual storm occurrence and behavior could serve as a warning sign in flash flood prediction. The coupled atmosphere and land surface model showed that the excessive runoff leading to the flood and landslide were favored by the occurrence of this unusual meteorological event coinciding temporally and spatially with favorable hydrologic conditions. Additionally, the model simulations showed that previous rainstorms had moistened the soil during the entire season and especially over the few days leading up to the Leh flood, so the normally arid mountainsides were likely not able to rapidly absorb the additional rainfall of the sudden 5 August squall line.
On Well-Posedness of the Viscous–Plastic Sea Ice Model
Authors: Guba Oksana , Lorenz Jens , Sulsky Deborah
Published: August 2013

This study examines the well-posedness of the initial-value problems that arise in common models of sea ice. The model equations describe the balance of linear momentum combined with simplified thermodynamics represented by two continuity equations for effective ice thickness and ice concentration. The constitutive model for sea ice is given by two possible variants of the viscous–plastic model: the viscous–plastic model with pressure replacement and the viscous–plastic model with pressure replacement plus a tensile cutoff. The authors identify regimes of well- and ill-posedness for both models in one and two space dimensions. In one space dimension, the study finds that the viscous–plastic model and viscous–plastic model with pressure replacement behave similarly: there is ill-posedness when the divergent flow rate is larger than a minimum value. On the other hand, the viscous–plastic model with pressure replacement plus a tensile cutoff is ill-posed for all divergent flows. In two space dimensions the analysis is inconclusive for the viscous–plastic model with pressure replacement, but with the tensile cutoff the problem is ill-posed for certain divergent flows. The authors also discuss energy bounds and the difference between ill-posedness and stability of a solution. The study shows by examples that boundedness of solutions does not imply well-posedness and that it is possible for well-posed problems to have unstable solutions. The analysis shows that previous arguments in the literature, which state that a bound on the energy in sea ice models provides control over ill-posedness, are flawed.
The Decay Rate of Ocean Swell Observed by Altimeter
Authors: Young I. R. , Babanin A. V. , Zieger S.
Published: August 2013

Altimeter data from transects across the Southern Ocean are analyzed to determine the decay of oceanic swell. The resulting decay rate is shown to be proportional to wavenumber squared and swell amplitude cubed. Such a decay relationship is consistent with turbulent interaction with the background, either in the air or water. The present data cannot distinguish between these two cases. The results are consistent with the limited previous studies and present a source term suitable for use in wave prediction models.
Self-Regulation in the Regulatory Void
Authors: Short Jodi L.
Published: August 2013

Corporate self-regulation has been blamed for many of the worst environmental and financial catastrophes of the twenty-first century, but the failure of self-regulation in these catastrophes has been rivaled by failures of government regulation. This article explores the consequences of adopting self-regulation under conditions of failed or deficient government regulation. First, it identifies the conditions that produce the phenomenon of “blue moon” self-regulation, or self-regulation that successfully achieves public regulatory goals. Second, it develops a typology of regulatory voids in which self-regulation is commonly adopted and analyzes its prospects for success under each set of conditions. It concludes that prospects for self-regulatory success are particularly bleak in regulatory voids that have been created by the concerted political opposition of regulated entities.
Enforcing Food Quality and Safety Standards in Brazil
Authors: Coslovsky Salo
Published: August 2013

In numerous product lines, globalization of production has been accompanied by increasingly austere product quality and safety regulations. These regulations are particularly stringent in the food and beverage sectors and put enormous strain on producers from developing nations. This article examines a cooperative of sugarcane, sugar, and ethanol producers from Brazil that, when confronted with the challenge of new regulations, adopted three policies that encouraged its members to upgrade quality and safety standards, enabling them to compete successfully in a demanding business environment. I argue that the co-op’s success was due to (1) a new cost accounting methodology that monetized some of the differences in product quality, attenuating tensions among members; (2) a low-cost, high-powered system of regulatory incentives that empowered middle managers vis-à-vis top executives within regulated firms; and (3) external auditors who acted not as police officers or consultants but as conduits, reestablishing information flows and helping to create a business atmosphere conducive to productive change.
Voting with Your Fork? Industrial Free-Range Eggs and the Regulatory Construction of Consumer Choice
Authors: Parker Christine
Published: August 2013

Labeling and information disclosure to support consumer choice are often proposed as attractive policy alternatives to onerous mandatory business regulation. This article argues that choices available to consumers are constructed and constrained by actors in the chains of production, distribution, and exchange who bring products to retail. It traces how “free-range” eggs come to market in Australia, finding that the “industrial free-range” label dominating the market is not substantially different from caged-egg production in the way that it addresses animal welfare, public health, and agro-ecological values. I show how the product choices available to consumers have been constructed not just by the regulation (or nonregulation) of marketing and labeling, but also by the regulatory paths taken and not taken all along the food chain.
Regulating Performance-Enhancing Technologies
Authors: Reichman Nancy , Sefiha Ophir
Published: August 2013

This article compares the efforts to govern performance enhancement technologies in two seemingly different competitive arenas—financial markets and professional cycling—where the pressures to outperform are enormous. In the two decades prior to the 2007 financial crisis, new derivative financial commodities such as collateralized debt obligations (CDOs) were created to “juice up” investment returns for extraordinary profits. Over roughly the same period, the development and use of blood boosting drugs and technologies brought so-called doping by cyclists to new levels of complexity and sophistication with extraordinary race results and new levels of commercialization of the sport. The efforts to “turbocharge” their respective competitive spaces took place within complicated regimes of self-regulation that had strikingly dissimilar narratives about performance enhancement and, consequently, different technologies for control. Looking across these seemingly disparate cases draws our attention to how regulation fits into the assemblage of competition and prospects for reform.
Three Risks, One Solution? Exploring the Relationship between Risk and Regulation
Authors: Haines Fiona
Published: August 2013

The risks at the heart of regulation are most often understood as unwanted by-products of an essentially productive endeavor. They are to be captured and managed through dedicated technical and bureaucratic effort, the preserve of those skilled in the assessment of probability and impact and accomplished in the design of effective—and efficient—regulatory strategies. Yet such a view seriously misunderstands the complexity of risk that regulation must address. When regulation is viewed from a social and organizational vantage point, risks of a more social and political character emerge. This article teases apart three fundamental ideal types of risk inherent in regulatory processes, only one of which (labeled as actuarial risk) is apprehensible from a scientific or bureaucratic frame of reference. Of equal importance are sociocultural and political risks, risks that cannot be relegated to a lesser priority by an understanding that labels their impact on regulation variously as unwarranted, irrational, or emotional.
Resilience in the Middle
Authors: Heimer Carol A.
Published: August 2013

We generally think of regulations as being applied to regulated organizations, which are then expected to comply with those regulations. Yet this way of thinking often misunderstands regulated organizations and misrepresents the complexity of their responses to regulation. This article uses evidence from an ethnographic study of the global regulation of HIV treatment and research to offer a fresh interpretation of the nature of regulated organizations and the part they play in complex regulatory systems. I show that regulated organizations do a great deal of interpretive work to decipher the rules, adjust rules to local realities, and translate local practices into the categories used by rule-makers. Such adjustments are especially required when regulators have an inaccurate picture of the structure of regulated organizations and the physical and sociocultural contexts in which they are embedded. HIV clinics themselves play a crucial role in correcting misinformation and in wrangling both regulations and regulated entities to bring them into closer alignment.
Constructing Consequences for Noncompliance
Authors: Huising Ruthanne , Silbey Susan S.
Published: August 2013

We examine academic research laboratories as examples of intractable governance sites. These spaces often elude regulatory warnings and rules because of the professional status of faculty members, the opacity of scientific work to outsiders, and loose coupling of policy and practice in organizations. We describe one university’s efforts to create a system for managing laboratory health, safety, and environmental hazards, thereby constraining conventional faculty habit to ignore administrative and legal procedures. We demonstrate the specific struggles safety managers face in creating system responsiveness, that is, feedback to re-channel noncompliant laboratory practices. We show how faculty members are buffered from the consequences of their activities, thus impeding the goals of responsibility and accountability. We conclude by asking where such pockets of intractability reside in other organizations and whether the surrounding buffer, if there is one, may nonetheless paradoxically create an effective margin of safety.
Immune dysregulation and autoimmunity in bipolar disorder: Synthesis of the evidence and its clinical application
Authors: Rege Sanil , Hodgkinson Suzanne J
Published: August 2013

Objective:

Increasing evidence suggests that inflammation and immune dysregulation play an important role in the pathogenesis of bipolar disorder. Because the brain can be affected by various autoimmune processes, it is possible that some psychiatric disorders may have an autoimmune basis.

Method:

This article reviews the literature on peripheral and central immune dysregulation and autoimmunity in bipolar disorder. The mechanisms of the innate and adaptive immune systems in the pathophysiology of bipolar disorder are explored. The clinical features and pathogenesis of neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are summarized.

Results:

Neuroinflammation and peripheral immune dysregulation may play a role in the pathophysiology of bipolar disorder. This involves a complex interaction between immune cells of the central nervous system and periphery resulting in cellular damage through mechanisms involving excitotoxicity, oxidative stress, and mitochondrial dysfunction. Neuropsychiatric systemic lupus erythematosus, anti-NMDA encephalitis, and Hashimoto’s encephalopathy are important differentials for a psychiatrist to consider when suspecting autoimmune encephalopathy.

Conclusions:

The link between immune dysregulation, autoimmunity, and bipolar disorder may be closer than previously thought. Psychiatrists should be vigilant for autoimmunity in presentations of bipolar disorder due to its high morbidity and therapeutic implications. Advances in neuroimaging and biomarker identification related to immune dysregulation and neuroinflammation will contribute to our knowledge of the pathophysiology of bipolar disorder.
A Skew-Normal Mixture Regression Model
Authors: Liu Min , Lin Tsung-I
Published: August 2013

A challenge associated with traditional mixture regression models (MRMs), which rest on the assumption of normally distributed errors, is determining the number of unobserved groups. Specifically, even slight deviations from normality can lead to the detection of spurious classes. The current work aims to (a) examine how sensitive the commonly used model selection indices are in class enumeration of MRMs with nonnormal errors, (b) investigate whether a skew-normal MRM can accommodate nonnormality, and (c) illustrate the potential of this model with a real data analysis. Simulation results indicate that model information criteria are not useful for class determination in MRMs unless errors follow a perfect normal distribution. The skew-normal MRM can accurately identify the number of latent classes in the presence of normal or mildly skewed errors, but fails to do so in severely skewed conditions. Furthermore, across the experimental conditions it is seen that some parameter estimates provided by the skew-normal MRM become more biased as skewness increases whereas others remain unbiased. Discussion of these results in the context of the applicability of skew-normal MRMs is provided.
Advances in the Regulation of Osteoclasts and Osteoclast Functions
Authors: Boyce B.F.
Published: August 2013

Osteoclasts are derived from mononuclear hematopoietic myeloid lineage cells, which are formed in the bone marrow and are attracted to the bloodstream by factors, including sphingsine-1 phosphate. These circulating precursors are attracted to bone surfaces undergoing resorption by chemokines and other factors expressed at these sites, where they fuse to form multinucleated bone-resorbing cells. All aspects of osteoclast formation and functions are regulated by macrophage-colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), cytokines essential for osteoclast formation and expressed by a variety of cell types, including osteoblast lineage cells. Since the discovery of RANKL in the mid-1990s, mouse genetic and molecular studies have revealed numerous signaling pathways activated by RANKL and M-CSF. More recent studies indicate that osteoclasts and their precursors regulate immune responses and osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and plexins, and through expression of clastokines. There is also growing recognition that osteoclasts are immune cells with roles in immune responses beyond mediating the bone destruction that can accompany them. This article reviews recent advances in the understanding of the molecular mechanisms regulating osteoclast formation and functions and their interactions with other cells in normal and pathologic states.
Examining the Effects of Linking Student Performance and Progression in a Tier 2 Kindergarten Reading Intervention
Authors: Simmons Deborah C. , Kim Minjung , Kwok Oi-man , Coyne Michael D. , Simmons Leslie E. , Oslund Eric , Fogarty Melissa , Hagan-Burke Shanna , Little Mary E. , Rawlinson D’Ann
Published: August 2013

Despite the emerging evidence base on response to intervention, there is limited research regarding how to effectively use progress-monitoring data to adjust instruction for students in Tier 2 intervention. In this study, we analyzed extant data from a series of randomized experimental studies of a kindergarten supplemental reading intervention to determine whether linking performance on formative assessments to curriculum progression improved kindergarten reading outcomes over standard implementation. We were interested in whether specific progression adjustments would enhance the effects of supplemental reading intervention. Growth-mixture modeling using data from kindergarteners ( n = 136) whose intervention progression (e.g. repeat lessons, skip lessons) was adjusted every 4 weeks based on mastery data identified four latent classes characterized by unique profiles of curriculum progression adjustments. Multilevel analyses comparing the performance of students in the four classes with that of propensity matched groups whose intervention was not adjusted ( n = 101) indicated positive effects of curriculum progression for (a) students whose formative assessment performance exceeded 90% and received early and sustained lesson acceleration and (b) students who initially performed below 70% on assessments and who repeated early lessons and progressed to conventional implementation. Effects of curriculum adjustments for the two smallest groups were less clear.
Creation, temporality and the Lord’s Supper in Friedrich Schleiermacher’s dogmatic theology
Authors: Jackson Ruth
Published: August 2013

Friedrich Schleiermacher’s dogmatic project The Christian Faith is shaped by a powerful doctrine of eternal divine creation. Furthermore, it is characterized not only by a sensibility for the historical nature of the theological task but also by an emphasis upon the Incarnation as the temporal fulfilment of God’s will. This article seeks to demonstrate how these three points about Schleiermacher’s system play out in his depiction of Eucharistic practice.
Elizabeth Johnson, the United States Bishops, and Thomas Aquinas: An evaluation
Authors: Rothrock Brad
Published: August 2013

This essay evaluates one important aspect of the assessment made by the United States Conference of Catholic Bishops in their recent Notification of supposed doctrinal errors made by Elizabeth Johnson in Quest for the Living God. Taking up the Committee’s own reference to Thomas Aquinas as a legitimating authority, and using the work of both Rudi Te Velde and W. Norris Clarke, I argue that both the Bishop’s Committee and Johnson have trouble straddling the middle ground of the analogical language and thinking that they nevertheless advocate. Ultimately I contend that in their defensive critique of Johnson the Committee tends toward an objectivism that is explicitly eschewed by Aquinas, while Johnson’s concern for God’s ineffability leads her to marginalize consideration of the analogical similarity between God and creatures.