bluuebunny/crossref_metadata_2025 huggingface dataset:
U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma
Authors: Herndon Thomas M. , Deisseroth Albert , Kaminskas Edvardas , Kane Robert C. , Koti Kallappa M. , Rothmann Mark D. , Habtemariam Bahru , Bullock Julie , Bray Jeffrey D. , Hawes Jessica , Palmby Todd R. , Jee Josephine , Adams William , Mahayni Houda , Brown Janice , Dorantes Angelica , Sridhara Rajeshwari , Farrell Ann T. , Pazdur Richard
Published: June 2013

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described. A single-arm trial enrolled 266 patients with multiple myeloma refractory to the most recent therapy who had received prior treatment with bortezomib and an immunomodulatory agent (IMID). Patients received carfilzomib by intravenous infusion over 2 to 10 minutes at a dose of 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of the 28 days of cycle 1, and at a dose of 27 mg/m2 on the same schedule in cycle 2 and subsequent cycles. The primary efficacy endpoint was overall response rate (ORR) as determined by an independent review committee using International Myeloma Working Group Uniform Response Criteria. The safety of carfilzomib was evaluated in 526 patients with multiple myeloma treated with various dosing regimens. The ORR was 23%. The median duration of response was 7.8 months. The most common adverse reactions associated with carfilzomib infusion were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and fever. The most common serious adverse events were pneumonia, acute renal failure, fever, and congestive heart failure. Infusion reactions to carfilzomib could be reduced by pretreatment with dexamethasone and intravenous fluids. On July 20, 2012, the FDA granted accelerated approval of carfilzomib for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an IMID and who have shown disease progression while on therapy or within 60 days of completion of the last therapy. Clin Cancer Res; 19(17); 4559–63. ©2013 AACR.
ZNF365 Promotes Stability of Fragile Sites and Telomeres
Authors: Zhang Yuqing , Shin Sandra J. , Liu Debra , Ivanova Elena , Foerster Friedrich , Ying Haoqiang , Zheng Hongwu , Xiao Yonghong , Chen Zhengming , Protopopov Alexei , DePinho Ronald A. , Paik Ji-Hye
Published: June 2013

Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites, including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange and formation of anaphase DNA bridges, including ultra-fine DNA bridges, and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53–ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction.

Significance: The contribution of the p53–ZNF365–telomere axis in the suppression of genomic instability illuminates how alterations in this pathway may confer increased cancer risk for individuals harboring germline alterations in the ZNF365 locus. Cancer Discov; 3(7); 798–811. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 705
Evolution in Surgical Management of Esophageal Cancer
Authors: Low Donald E.
Published: June 2013

Esophageal resection remains the primary treatment for local regional esophageal cancer, although its role in superficial (T1A) cancers and squamous cell cancer is in evolution. Mortality associated with esophagectomy has historically been high but is improving with the current expectation of in-hospital mortality rates of 2-4% in high-volume centers. Most patients with regional cancers (T2-4 N0-3) are recommended for neoadjuvant therapy, which most commonly involves radiochemotherapy. Some centers have proposed treating with definitive chemoradiation and reserving surgery for patients who have persistent or recurrent disease. ‘Salvage resections' are possible but are associated with higher levels of perioperative morbidity and mortality, and treatment decisions should routinely be based on multidisciplinary discussion in the tumor board. Although open surgical resection (both transthoracic and transhiatal operations) remain the most common approach, minimally invasive or hybrid operations are being done in up to 30% of procedures internationally. There are some indications that minimally invasive esophagectomy may decrease the incidence of respiratory complications and decrease length of stay. At this point, oncologic outcomes appear equivalent between open and minimally invasive procedures. Recent reviews from high-volume esophagectomy centers demonstrate that elderly patients can selectively undergo esophagectomy with the expectation of increased complications but similar mortality and survival to younger patients. Multiple studies confirm that quality of life following esophagectomy can be equivalent to the general population when surgery is done in experienced centers. Patients requiring surgical treatment of esophageal cancer should be referred to high-volume centers, especially those with established care pathways or enhanced recovery programs to improve outcomes including morbidity, mortality, survival, and quality of life.
Evolution of Fetal Subependymal Cysts throughout Gestation
Authors: Correa Flavia , Lara Coral , Carreras Elena , Vázquez Élida , Serra Vicente
Published: June 2013

Subependymal cysts are secondary to brain germinal matrix hemorrhage or infarction and are associated with fetal chromosomal and metabolic conditions, as well as infections. They are found in 1-3% of neonates in the first days of life and have been described in fetuses, although much less frequently. We report the prenatal diagnosis of a case of subependymal cysts first visualized at 12 weeks' gestation and its evolution throughout pregnancy and after birth. As far as we know, this is the first time that such a condition is described before 16 weeks' gestation as well as its longitudinal evolution. Knowledge that subependymal cysts can be seen as early as 12 weeks' gestation and their natural evolution is important to avoid equivocal diagnoses. The prognosis of isolated subependymal cysts remains uncertain.
Eosinophilic Esophagitis: A Bulk of Mysteries
Authors: Straumann Alex
Published: June 2013

Eosinophilic esophagitis (EoE), which was first described in the early 1990s, has rapidly evolved as a distinctive chronic inflammatory esophageal disease. The diagnosis is based clinically on the presence of symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation once other conditions leading to esophageal eosinophilia are excluded. This striking male-prevalent disease has an increasing incidence and prevalence in the Westernized countries. Currently, EoE represents the main cause of dysphagia and bolus impaction in adult patients. Despite the fact that EoE often occurs in atopic patients, the value of allergic testing is still under discussion. Topical corticosteroids lead to a rapid improvement of active EoE clinically and histologically; they are therefore regarded as first-line drug therapy. Elimination diets have similar efficacy as topical corticosteroids, but their long-term use is limited by practical issues. Esophageal dilation of EoE-induced strictures can also be effective in improving symptoms, but this therapy has no effect on the underlying inflammation. Neither the diagnostic nor the long-term therapeutic strategies have been fully defined. Currently, the list of unsolved issues - or mysteries - is still long and a concerted effort on behalf of clinicians and scientists is required to improve the understanding and the therapeutic management of this mysterious disease.
Barrett's Esophagus: The American Perspective
Authors: Spechler Stuart Jon
Published: June 2013

The American Gastroenterological Association (AGA) defines Barrett's esophagus as the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus. Although cardiac mucosa may be metaplastic, its malignant predisposition is not clear, and the AGA still requires the demonstration of intestinal metaplasia (with goblet cells) for a diagnosis of Barrett's esophagus. The AGA generally recommends endoscopic eradication therapy for patients with high-grade dysplasia, who otherwise develop esophageal adenocarcinoma at the rate of 6% per year. Endoscopic therapy is often curative for mucosal neoplasms in Barrett's esophagus because the risk of lymph node metastases is only 1-2%. American gastroenterologists generally do not recommend endoscopic therapy for patients whose neoplasms involve any portion of the submucosa because of the high rate of lymph node metastases that has been described in these cases. The management of low-grade dysplasia is disputed because of poor agreement among pathologists on the diagnosis and because of contradictory data on the natural history, but the AGA recommends that radiofrequency ablation (RFA) should be a therapeutic option for patients with confirmed low-grade dysplasia in Barrett's esophagus. Arguments for using RFA to treat nondysplastic Barrett's metaplasia are based on the premise that RFA decreases cancer risk, but no study has established that premise. In the absence of definitive data, concerns about the frequency and importance of buried metaplastic glands and recurrent metaplasia should temper enthusiasm for treating nondysplastic Barrett's esophagus with RFA.
Appendicitis/Diverticulitis: Diagnostics and Conservative Treatment
Authors: Kruis Wolfgang , Morgenstern Julia , Schanz Stefan
Published: June 2013

Appendicitis and diverticulitis are very common entities that show some similarities in diagnosis and course of disease. Both are widely believed to be simple clinical diagnoses, which is in contrast to scientific evidence. An accurate diagnosis has to describe not only the initial detection, but particularly the severity of the disease. It is based mainly on cross-sectional imaging by ultrasound (US) and computed tomography (CT). Appendectomy is the standard treatment for acute appendicitis and is mandatory in complicated cases. Antibiotic therapy is similarly effective in uncomplicated appendicitis, but long-term results are not sufficiently known. Treatment of diverticulitis is related to the disease status. Complications such as perforation and bleeding require intervention. Uncomplicated diverticulitis as graded by US or CT are subject to conservative management, in the form of outpatient or hospital care. It is an unresolved debate as to whether antibiotic treatment offers benefits. Mesalazine seems at least to improve pain. The real challenge is treatment of recurrent diverticulitis. Lifestyle measures such as nutritional habits and physical activity are found to influence diverticular disease. Besides immunosuppression, obesity is a significant risk factor for complicated diverticulitis. Whether any medication such as chronic antibiotics, probiotics or mesalazine offers benefits is unclear. The indication for sigmoid resection has changed; it is no longer given by the number of attacks, but rather by structural changes as depicted by cross-sectional imaging.
Liver Transplantation for Perihilar Cholangiocarcinoma
Authors: Gores Gregory J. , Darwish Murad Sarwa , Heimbach Julie K. , Rosen Charles B.
Published: June 2013

Perihilar cholangiocarcinoma is a complex and devastating disease. Its complexity in part arises from the difficulty of establishing a diagnosis, especially in primary sclerosing cholangitis (PSC) patients. We have found fluorescent in situ hybridization (FISH) of cytologic specimens to be helpful in establishing a diagnosis of cholangiocarcinoma. In particular, FISH polysomy is useful in establishing a diagnosis of this malignancy. Endoscopic ultrasound with fine needle aspirates of regional lymph nodes has high utility in identifying patients who have advanced disease with lymph node metastases. Patients who are resectable by conventional surgical techniques are referred for surgery. However, patients who are not resectable or who have PSC and meet highly selective criteria become eligible for liver transplantation. The protocol employs external beam radiation therapy followed by brachytherapy, and then capecitabine until a staging laparotomy is performed. There is a high dropout rate while patients await liver transplantation of approximately 30% at 12 months, due to tumor progression. Overall, survival rates are approximately 65-70% at 5 years. The disease recurrence rate is 20%. Patients who have masses greater than 3 cm or who do not meet the criteria identified above have worse outcomes. These survival rates are better than those following surgical resection. Vascular complications occur frequently after liver transplantation. Portal venous anastomotic strictures are very common and can be managed by stent placement. In summary, neoadjuvant chemoradiation plus liver transplantation achieves excellent survival for patients with early-stage perihilar cholangiocarcinoma.
Cholestatic Liver Disease
Authors: Jüngst Christoph , Lammert Frank
Published: June 2013

Cholestasis develops as a consequence of impaired bile formation and/or bile flow and can be classified as intra- or extrahepatic. Chronic cholestatic diseases are mostly intrahepatic with the exception of primary and secondary sclerosing cholangitis affecting intra- and extrahepatic bile ducts. Recent genome-wide association studies have confirmed major histocompatibility complex associations and discovered multiple susceptibility loci in primary biliary cirrhosis and primary sclerosing cholangitis, providing new insights into disease pathogenesis, which may translate into more precise therapeutic prevention and intervention in the future. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging and distinct serological studies including antimitochondrial antibodies and IgG4 levels; if the diagnosis remains unclear, liver biopsy is warranted. Genetic testing should also be considered, as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 are causative for three different forms of familial intrahepatic cholestasis. Disease severity is dependent on the genotypic variants of these transporters, ranging from mildly elevated liver enzymes in adults to cirrhosis in early childhood. Ligands of nuclear receptors, which represent important regulators of hepatobiliary transporters, and modified bile salts are new promising therapeutic options in cholestatic liver disease and are currently being investigated in clinical trials.
Dermatology Life Quality Index and Side Effects after Topical Photodynamic Therapy of Actinic Keratosis
Authors: Gholam Patrick , Kroehl Verena , Enk Alexander H.
Published: June 2013

Background: Photodynamic therapy (PDT) is an excellent treatment option for actinic keratosis. However the side effects lead to an impairment of the patients' quality of life. Objectives: To evaluate the impact of PDT on patients' quality of life and to determine the frequency and intensity of side effects over the course of 4 weeks post PDT. Patients and Methods: 22 patients with actinic keratosis in the face were included into this prospective study. Pain was measured using a visual analog scale immediately and 8 h after PDT. The Dermatology Life Quality Index (DLQI) was assessed at screening, after treatment as well as 2 and 4 weeks after PDT. The physician and patient evaluated the intensity of side effects during the treatment, 2 and 4 weeks post PDT. Additionally, the patient documented side effects daily from the 1st to the 14th day after PDT and on day 28 post PDT, using a diary. Results: We observed a significant (p < 0.001) increase in the DLQI from 1.6 ± 1.7 prior to PDT to 7.3 ± 4.9 post PDT. The DLQI normalized in the following 4 weeks. Immediately and 8 h after PDT mean pain was 4.3 ± 2.5 and 2.3 ± 2.1. Side effects documented by the patients were erythema (100%), pain, burning, edema (90.9%), itching (86.4%), scaling (81.8%) and pustules (59.1%). No scar formation, hyper-/hypopigmentation or infections were observed. Conclusion: PDT has a significant temporary impact on patients' DLQI. Transitory side effects are common and show typical kinetics.
Optimization of Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyneuropathy Evaluated by Grip Strength Measurement
Authors: Kokubun Norito , Sada Tsubasa , Yuki Nobuhiro , Okabe Momoka , Hirata Koichi
Published: June 2013

Background: Optimal dose and timing of repeated intravenous immunoglobulin therapy (IVIg) for intractable chronic inflammatory demyelinating polyneuropathy (CIDP) patients have not been determined. The aim of this study was to optimize dose and timing of IVIg for CIDP patients who need frequent IVIg using daily grip strength measurement. Methods: Repeated IVIg were administered for two intractable CIDP patients. Grip strength was recorded at home every day to access the clinical change in symptoms, and dose and timing of IVIg were optimized based on the results. Results: The decrement on grip strength was a sensitive indicator of symptom exacerbation. 100 g of IVIg had a limited effect for each patient. In one patient, symptoms maintained after monthly 60 g of IVIg. In another, 100 g of IVIg every 7 weeks resulted in a marked improvement. After receiving 20 g of IVIg weekly, each patient showed further improvement. Conclusion: Optimal dose and timing possibly vary in each individual patient. Dose titration of IVIg is necessary to avoid over- and undertreatment. The daily self-monitoring of grip strength is a helpful tool for clinical assessment in CIDP.
Predictive Value of Serum Uric Acid Levels on Mortality in Acute Coronary Syndrome Patients with Chronic Kidney Disease after Drug-Eluting Stent Implantation
Authors: Yin Zhaoxia , Fang Zhe , Yang Ming , Du Xueping , Nie Bin , Gao Kang
Published: June 2013

Objectives: Despite optimal treatments, prognosis in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD) remains poor. Elevated serum uric acid (SUA) levels may predict worse outcomes in these patients. The objective was to assess the predictive value of SUA levels on mortality in ACS patients with CKD after drug-eluting stent (DES) implantation. Methods: We retrospectively assessed ACS patients with CKD who underwent successful DES implantation between January 2007 and December 2009. Patients were followed up from January to March 2012. CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2. We assessed the association between SUA levels and mortality. Results: A total of 1,132 patients were included. The mean age was 67.7 years. During a mean follow-up of 38.5 months, 145 patients died: 50 from cardiac diseases, 28 from cerebral diseases, 14 from renal diseases and 53 from other causes. After adjustment for confounders, SUA levels increased the risk of all-cause, cerebral and other-cause mortality. Adjusted hazard ratios for quartiles 3 and 4 versus quartile 1 of SUA were: all-cause, 1.66 [95% confidence interval (CI) 1.08-2.78] and 1.99 (95% CI 1.21-3.23); cerebral, 2.24 (95% CI 0.43-11.7) and 5.89 (95% CI 1.30-26.6); and other causes, 2.81 (95% CI 1.17-6.78) and 3.89 (95% CI 1.63-9.29), respectively. SUA levels had no impact on cardiac and renal mortality rates. Conclusions: High SUA levels are associated with all-cause, cerebral and other-cause mortality rates in ACS patients with CKD after DES implantation. Future research is needed to determine if lowering SUA levels will decrease mortality in these patients.
Assessment of Pericallosal Arteries by Color Doppler Ultrasonography at 11-14 Weeks: An Early Marker of Fetal Corpus Callosum Development in Normal Fetuses and Agenesis in Cases with Chromosomal Anomalies
Authors: Díaz-Guerrero L. , Giugni-Chalbaud G. , Sosa-Olavarría A.
Published: June 2013

Objective: The aims of this study were to determine (a) whether the normal pericallosal vascular map can be visualized using color Doppler ultrasonography in normal fetuses in the first trimester of pregnancy and (b) whether an abnormal pericallosal artery (PA) vascular map can be observed in fetuses with corpus callosum agenesis early in pregnancy. Methods: In 150 consecutive women undergoing a routine ultrasound examination at 11-14 weeks of gestation in our high-risk pregnancy unit as part of screening for chromosomal abnormalities, a mid-sagittal view of the fetal head was obtained to measure nuchal translucency thickness, assess nasal bones in their corresponding two oblique planes and intracranial translucency. In this view and with color Doppler ultrasonography, we evaluated the vascular map of the PA. Results: The vascular map of the PA was observed in 97.02% of cases at the 11- to 14-week evaluation (144/150 fetuses). Two cases with an abnormal PA were identified and confirmed as corpus callosum agenesis in the second trimester, 1 due to trisomy 13 and the other due to triploidy. Conclusions: The PA can routinely be observed at the first-trimester evaluation with color Doppler ultrasonography using the mid-sagittal view of the fetal head. The presence of an abnormal vascular map of the PA by Doppler ultrasonography at 11-14 weeks raises the suspicion of corpus callosum agenesis.
Survival After Implantable Cardioverter-Defibrillator Implantation in the Elderly
Authors: Yung Derek , Birnie David , Dorian Paul , Healey Jeffrey S. , Simpson Christopher S. , Crystal Eugene , Krahn Andrew D. , Khaykin Yaariv , Cameron Douglas , Chen Zhongliang , Lee Douglas S.
Published: June 2013

Background—

The benefit of implantable cardioverter-defibrillators (ICDs) among elderly patients is controversial and may be attenuated by nonarrhythmic death. We examined the impact of age on device-delivered therapies and outcomes after primary or secondary prevention ICD.

Methods and Results—

In a prospective, inclusive registry of 5399 ICD recipients in Ontario, Canada (February 2007 to September 2010), device-delivered therapies and complications were determined at routine clinic visits. Among primary prevention ICD recipients aged 18 to 49 (n=317), 50 to 59 (n=769), 60 to 69 (n=1336), 70 to 79 (n=1242), and ≥80 (n=275) years, mortality increased with age, as follows: 2.1, 3.0, 5.4, 6.9, and 10.2 deaths per 100 person-years, respectively (
P
<0.001). Secondary prevention ICD recipients aged 18 to 49 (n=114), 50 to 59 (n=244), 60 to 69 (n=481), 70 to 79 (n=462), and ≥80 (n=159) years also exhibited increasing mortality, as follows: 2.2, 3.8, 6.1, 8.7, and 15.5 deaths per 100 person-years, respectively (
P
<0.001). However, rates of appropriate shock were similar across age groups: from 6.7 (18–49 years) to 4.2 (≥80 years) per 100 person-years after primary prevention ICDs (
P
=0.139) and from 11.4 (18–49 years) to 11.9 (≥80 years) per 100 person-years after secondary prevention ICDs (
P
=0.993). Covariate-adjusted competing risk analysis demonstrated higher risk of death (
P
trend
<0.001 for both primary and secondary prevention) but no significant decline in appropriate shocks with older age after primary (
P
=0.130) or secondary (
P
=0.810) prevention ICD implantation.

Conclusions—

Whereas elderly patients exhibited increased mortality after ICD implantation, rates of appropriate device shocks were similar across age groups. Decisions regarding ICD candidacy should not be based on age alone but should consider factors that predispose to mortality despite defibrillator implantation.
Riociguat for Patients With Pulmonary Hypertension Caused by Systolic Left Ventricular Dysfunction
Authors: Bonderman Diana , Ghio Stefano , Felix Stephan B. , Ghofrani Hossein-Ardeschir , Michelakis Evangelos , Mitrovic Veselin , Oudiz Ronald J. , Boateng Francis , Scalise Andrea-Viviana , Roessig Lothar , Semigran Marc J.
Published: June 2013

Background—

Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction.

Methods and Results—

Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (−6.1±1.3 mm Hg;
P
<0.0001 versus baseline) was not significantly different from placebo (
P
=0.10), cardiac index (0.4 L·min
−1
·m
−2
; 95% confidence interval, 0.2–0.5;
P
=0.0001) and stroke volume index (5.2 mL·m
−2
; 95% confidence interval, 2.0–8.4;
P
=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (−46.6 dynes·s
−1
·cm
−5
; 95% confidence interval, –89.4 to –3.8;
P
=0.03) and systemic vascular resistance (−239.3 dynes·s
−1
·cm
−5
; 95% confidence interval, –363.4 to –115.3;
P
=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (
P
=0.0002). Discontinuation of treatment was similar between treatment groups.

Conclusions—

Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01065454.
Tonic γ-Aminobutyric Acid–ergic Activity in the Hypothalamic Arcuate Nucleus Is Attenuated in the Spontaneously Hypertensive Rat
Authors: Kawabe Tetsuya , Kawabe Kazumi , Sapru Hreday N.
Published: June 2013

We tested the hypothesis that tonic γ-aminobutyric acid–ergic activity in the hypothalamic arcuate nucleus (ARCN) modulates blood pressure control and attenuation of this inhibitory activity contributes to hypertension in the spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA) were recorded in urethane-anesthetized, artificially ventilated, adult male SHR and Wistar-Kyoto rats (WKY). Microinjections of gabazine into the ARCN elicited significantly smaller increases in MAP, HR, and GSNA in baroreceptor-intact SHR compared with baroreceptor-intact WKY. Attenuation of the responses to gabazine in SHR persisted, despite lowering of their baseline MAP to levels of WKY or barodenervation. Microinjections of N-methyl-
d
-aspartic acid (NMDA) into the ARCN elicited decreases in MAP and GSNA and increases in HR in baroreceptor-intact WKY. However, after microinjections of gabazine into the ARCN, microinjections of NMDA into the same nucleus elicited pressor responses in baroreceptor-intact WKY. In barodenervated WKY, increases in MAP and GSNA were elicited by ARCN stimulation by NMDA and the increases in HR were exaggerated. In baroreceptor-intact SHR, ARCN stimulation by NMDA elicited increases in MAP, GSNA, and HR which persisted, despite lowering of baseline MAP or barodenervation. Increases in MAP and GSNA elicited by ARCN stimulation by NMDA in barodenervated SHR were significantly greater than corresponding increases in barodenervated WKY. These results indicated that attenuated γ-aminobutyric acid–ergic activity in the ARCN and impaired baroreflex function may contribute to increases in blood pressure and sympathetic nerve activity after ARCN stimulation by NMDA and elevation of baseline blood pressure in SHR.
Dynamic Analysis of Naive Adaptive Brain-Machine Interfaces
Authors: Kowalski Kevin C. , He Bryan D. , Srinivasan Lakshminarayan
Published: June 2013

The closed-loop operation of brain-machine interfaces (BMI) provides a context to discover foundational principles behind human-computer interaction, with emerging clinical applications to stroke, neuromuscular diseases, and trauma. In the canonical BMI, a user controls a prosthetic limb through neural signals that are recorded by electrodes and processed by a decoder into limb movements. In laboratory demonstrations with able-bodied test subjects, parameters of the decoder are commonly tuned using training data that include neural signals and corresponding overt arm movements. In the application of BMI to paralysis or amputation, arm movements are not feasible, and imagined movements create weaker, partially unrelated patterns of neural activity. BMI training must begin naive, without access to these prototypical methods for parameter initialization used in most laboratory BMI demonstrations.

Naive adaptive BMI refer to a class of methods recently introduced to address this problem. We first identify the basic elements of existing approaches based on adaptive filtering and define a decoder, ReFIT-PPF to represent these existing approaches. We then present Joint RSE, a novel approach that logically extends prior approaches. Using recently developed human- and synthetic-subjects closed-loop BMI simulation platforms, we show that Joint RSE significantly outperforms ReFIT-PPF and nonadaptive (static) decoders. Control experiments demonstrate the critical role of jointly estimating neural parameters and user intent. In addition, we show that nonzero sensorimotor delay in the user significantly degrades ReFIT-PPF but not Joint RSE, owing to differences in the prior on intended velocity. Paradoxically, substantial differences in the nature of sensory feedback between these methods do not contribute to differences in performance between Joint RSE and ReFIT-PPF. Instead, BMI performance improvement is driven by machine learning, which outpaces rates of human learning in the human-subjects simulation platform. In this regime, nuances of error-related feedback to the human user are less relevant to rapid BMI mastery.
Density-Difference Estimation
Authors: Sugiyama Masashi , Kanamori Takafumi , Suzuki Taiji , Plessis Marthinus Christoffel du , Liu Song , Takeuchi Ichiro
Published: June 2013

We address the problem of estimating the difference between two probability densities. A naive approach is a two-step procedure of first estimating two densities separately and then computing their difference. However, this procedure does not necessarily work well because the first step is performed without regard to the second step, and thus a small estimation error incurred in the first stage can cause a big error in the second stage. In this letter, we propose a single-shot procedure for directly estimating the density difference without separately estimating two densities. We derive a nonparametric finite-sample error bound for the proposed single-shot density-difference estimator and show that it achieves the optimal convergence rate. We then show how the proposed density-difference estimator can be used in L2-distance approximation. Finally, we experimentally demonstrate the usefulness of the proposed method in robust distribution comparison such as class-prior estimation and change-point detection.
Ius in Bello under Islamic International Law
Authors: Badar Mohamed Elewa
Published: June 2013

In 1966, Judge Jessup of the International Court of Justice pointed out that the appearance of an English translation of the teaching on the ‘Islamic law of nations’ of an eighth-century Islamic jurist (Shaybānī) is particularly timely and of so much interest because of the debate over the question whether the international law, of which Hugo Grotius is often called the father, is so completely Western-European in inspiration and outlook as to make it unsuitable for universal application in the context of a much wider and more varied international community of States. However, there has been little analysis of the role of Islam in shaping the modern European law of war and its progeny, international humanitarian law. This article argues that there is a room for the contribution of the Islamic civilisation within international humanitarian law and a conversation between different civilisations is needed in developing and applying international humanitarian law norms.
A revision of the genus Atelecrinus PH Carpenter (Echinodermata: Crinoidea)
Authors: MESSING CHARLES G.
Published: June 2013

The unusual bathyal comatulid crinoid genus Atelecrinus is widespread in the Atlantic and tropical Pacific Oceans and currently includes three recognized species. A re-assessment based on examination of new and existing specimens re-quires establishment of two new genera and five new species, and returns three junior synonyms to species-level status. Paratelecrinus is erected to accommodate Atelecrinus wyvilli PH Carpenter, A. conifer AH Clark, A. cubensis PH Carpen-ter, P. orthotriremis, new species, P. amenouzume new species, P. laticonulus new species and P. telo new species. Ade-latelecrinus is erected to accommodate Atelecrinus sulcatus AH Clark and Adelatelecrinus vallatus new species. Atelecrinus retains A. balanoides PH Carpenter and A. helgae AH Clark, which restricts the genus to the Atlantic. In both Paratelecrinus and Adelatelecrinus, the basals articulate with the centrodorsal via ligament bundles anchored in deep ring-like interradial pits that project into the centrodorsal cavity, whereas in Atelecrinus the centrodorsal rim has shallow inter-radial concavities and attaches to the basals via a tight junction with no obvious ligament bundles. The spoon-shaped ab-oral fossa in the basals of Paratelecrinus appears to be unique among articulate crinoids and differs from the smooth fossa found in both Atelecrinus and Adelatelecrinus. New material extends the range of the family to the Indian Ocean. A few species are now known from enough specimens to identify some ontogenetic and distributional variations. Proximal ray morphology varies substantially with size in P. cubensis and P. orthotriremis. A. balanoides generally occurs in deeper water in the Lesser Antilles than in the Bahamas and Strait of Florida, while P. orthotriremis occurs in shallower water in the Lesser Antilles and deeper in the Bahamas.
The taxonomic status of badgers (Mammalia, Mustelidae) from Southwest Asia based on cranial morphometrics, with the redescription of Meles canescens
Authors: ABRAMOV ALEXEI V. , PUZACHENKO ANDREY YU.
Published: June 2013

The Eurasian badgers (Meles spp.) are widespread in the Palaearctic Region, occurring from the British Islands in the west to the Japanese Islands in the east, including the Scandinavia, Southwest Asia and southern China. The morphometric vari-ation in 30 cranial characters of 692 skulls of Meles from across the Palaearctic was here analyzed. This craniometric anal-ysis revealed a significant difference between the European and Asian badger phylogenetic lineages, which can be further split in two pairs of taxa: meles – canescens and leucurus – anakuma. Overall, European badger populations are very sim-ilar morphologically, particularly with regards to the skull shape, but differ notably from those from Asia Minor, the Mid-dle East and Transcaucasia. Based on the current survey of badger specimens available in main world museums, we have recognized four distinctive, parapatric species: Meles meles, found in most of Europe; Meles leucurus from continental Asia; M. anakuma from Japan; and M. canescens from Southwest Asia and the mountains of Middle Asia. These results are in agreement with those based on recent molecular data analyses. The morphological peculiarities and distribution range of M. canescens are discussed. The origin and evolution of Meles species, which is yet poorly understood, is also briefly discussed.
Dependence of Precipitation Scaling Patterns on Emission Scenarios for Representative Concentration Pathways
Authors: Ishizaki Yasuhiro , Shiogama Hideo , Emori Seita , Yokohata Tokuta , Nozawa Toru , Takahashi Kiyoshi , Ogura Tomoo , Yoshimori Masakazu , Nagashima Tatsuya
Published: June 2013

Pattern scaling is an efficient way to generate projections of regional climate change for various emission scenarios. This approach assumes that the spatial pattern of changes per degree of global warming (scaling pattern) is the same among emission scenarios. The hypothesis was tested for the scaling pattern of precipitation by focusing on the scenario dependence of aerosol scaling patterns. The scenario dependence of aerosol scaling patterns induced the scenario dependence of the surface shortwave radiation scaling pattern. The scenario dependence of the surface shortwave radiation scaling pattern over the ocean tended to induce the scenario dependence of evaporation scaling patterns. The scenario dependence of evaporation scaling patterns led to the scenario dependence of precipitation scaling patterns locally and downwind. Contrariwise, when the scenario dependence of aerosol scaling patterns occurred over land, the scenario dependence of surface shortwave radiation scaling patterns induced the scenario dependence of the scaling patterns of evaporation, surface longwave radiation, and sensible heat. Consequently, the scenario dependence of evaporation scaling patterns was smaller over land, and the scenario dependence of precipitation scaling patterns tended to be insignificant. Moreover, the scenario dependence of the southern annular mode and polar amplification caused some of the scenario dependence of precipitation scaling patterns. In this study, only one global climate mode was analyzed. In addition, sensitivity experiments that remove aerosol emissions from some regions or some kinds of aerosols are ideal to separate the impacts of aerosols. Thus, an analysis of the dependencies of precipitation scaling pattern among global climate models and the sensitivity experiments are required in future work.
Principal Components of Multifrequency Microwave Land Surface Emissivities. Part I: Estimation under Clear and Precipitating Conditions
Authors: Turk F. Joseph , Haddad Ziad S. , You Yalei
Published: June 2013

The upcoming Global Precipitation Measurement mission will provide considerably more overland observations over complex terrain, high-elevation river basins, and cold surfaces, necessitating an improved assessment of the microwave land surface emissivity. Current passive microwave overland rainfall algorithms developed for the Tropical Rainfall Measuring Mission (TRMM) rely upon hydrometeor scattering-induced signatures at high-frequency (85 GHz) brightness temperatures (TBs) and are empirical in nature. A multiyear global database of microwave surface emissivities encompassing a wide range of surface conditions was retrieved from Advanced Microwave Scanning Radiometer for Earth Observing System (EOS; AMSR-E) radiometric clear scenes using companion A-Train [CloudSat, Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO), and Atmospheric Infrared Sounder (AIRS)] data. To account for the correlated emissivity structure, the procedure first derives the TRMM Microwave Imager–like nine-channel emissivity principal component (PC) structure. Relations are derived to estimate the emissivity PCs directly from the instantaneous TBs, which allows subsequent TB observations to estimate the PC structure and reconstruct the emissivity vector without need for ancillary data regarding the surface or atmospheric conditions. Radiative transfer simulations matched the AMSR-E TBs within 5–7-K RMS difference in the absence of precipitation. Since the relations are derived specifically for clear-scene conditions, discriminant analysis was performed to find the PC discriminant that best separates clear and precipitation scenes. When this technique is applied independently to two years of TRMM data, the PC-based discriminant demonstrated superior relative operating characteristics relative to the established 85-GHz scattering index, most notably during cold seasons.
A Handheld Sampler for Collecting Organic Samples from Shallow Hydrothermal Vents
Authors: Wu Shi-Jun , Yang Can-Jun , Arthur Chen Chen-Tung
Published: June 2013

This study describes a new handheld sampler, specially designed to be deployed by scuba divers, to collect fluid samples from shallow hydrothermal vents. The new sampler utilizes a syringe-like titanium sampling bottle with a regulated filling rate to collect samples. The filling rate regulation mechanism of the new sampler was studied. Through theoretical analysis and simulation, it is found that the filling rate can be regulated by either an orifice or an annular gap on the sampler. Further study indicates that the orifice is superior to the annular gap, since the former has a much lower requirement of machining accuracy. Moreover, the filling rate regulated by the orifice is independent of temperature and ambient pressure. The new sampler also features a compact structure, simple operation, and gas-tight performance. Efforts were made to minimize the organic carbon blank of the sampler by careful selection of the materials that may come into contact with the fluid samples. The sampler has been tested at the shallow hydrothermal vents off northeastern Taiwan. High-purity organic samples were successfully collected.
A Comparison of the Canadian Global and Regional Meteorological Ensemble Prediction Systems for Short-Term Hydrological Forecasting
Authors: Abaza Mabrouk , Anctil François , Fortin Vincent , Turcotte Richard
Published: June 2013

Meteorological ensemble prediction systems (M-EPS) are generally set up at lower resolution than for their deterministic counterparts. Operational hydrologists are thus more prone to selecting deterministic meteorological forecasts for driving their hydrological models. Limited-area implementation of meteorological models may become a convenient way of providing the sought after higher-resolution meteorological ensemble forecasts. This study aims to compare the Canadian operational global EPS (M-GEPS) and the experimental regional EPS (M-REPS) for short-term operational hydrological ensemble forecasting over eight watersheds, for which performance and reliability was assessed. Higher-resolution deterministic forecasts were also available for the study. Results showed that both M-EPS provided better performance than their deterministic counterparts when comparing their mean continuous ranked probability score (MCRPS) and mean absolute error (MAE), especially beyond a 24-h horizon. The global and regional M-EPS led to very similar performance in terms of RMSE, but the latter produced a larger spread and improved reliability. The M-REPS was deemed superior to its operational global counterpart, especially for its ability to better depict forecast uncertainty.
The Arab Spring and Social Media Audiences
Authors: Bruns Axel , Highfield Tim , Burgess Jean
Published: June 2013

Although popular media narratives about the role of social media in driving the events of the 2011 “Arab Spring” are likely to overstate the impact of Facebook and Twitter on these uprisings, it is nonetheless true that protests and unrest in countries from Tunisia to Syria generated a substantial amount of social media activity. On Twitter alone, several millions of tweets containing the hashtags #libya or #egypt were generated during 2011, both by directly affected citizens of these countries and by onlookers from further afield. What remains unclear, though, is the extent to which there was any direct interaction between these two groups (especially considering potential language barriers between them). Building on hashtag data sets gathered between January and November 2011, this article compares patterns of Twitter usage during the popular revolution in Egypt and the civil war in Libya. Using custom-made tools for processing “big data,” we examine the volume of tweets sent by English-, Arabic-, and mixed-language Twitter users over time and examine the networks of interaction (variously through @replying, retweeting, or both) between these groups as they developed and shifted over the course of these uprisings. Examining @reply and retweet traffic, we identify general patterns of information flow between the English- and Arabic-speaking sides of the Twittersphere and highlight the roles played by users bridging both language spheres.
Approaching the 2012 U.S. Presidential Election From a Diversity of Explanatory Principles
Authors: Holbert R. Lance , Weeks Brian E. , Esralew Sarah
Published: June 2013

The explanatory principles of understanding and consistency are used to detail the past, present, and future of individual-level political communication media effects research. It is argued that the field of political communication is at a crossroads, with preferences for a dominant explanatory principle shifting from understanding back to consistency. In addition to understanding and consistency, it is argued that political communication researchers need to begin introducing additional explanatory principles (e.g., hedonism) to the field for the generation of new lines of inquiry. A call for embracing a diversity of explanatory principles is offered, and the utility of such an approach is explored within the context of the 2012 U.S. presidential election.
Biological variation of thiopurine methyltransferase enzyme activity: when has a significant change taken place?
Authors: van Egmond Remco , Barclay Murray L , Chin Paul KL , Sies Christiaan W , Florkowski Christopher M
Published: June 2013

Background

Thiopurine methyltransferase (TPMT) enzyme activity is measured before initiating thiopurine therapy to reduce the risk of severe drug-associated myelotoxicity in patients with low enzyme activity. TPMT activity may vary over time in relation to drug treatment and patient clinical condition. What constitutes a significant change in TPMT activity can be derived from biological variation and analytical imprecision.

Methods

A large national laboratory database was used to identify patients with three or more TPMT activity measurements. Variance of TPMT activity was analysed by determining the total coefficient of variation (CVTOT) of repeated measurements and by correlation with parameters including gender and follow-up time. Between-run analytical imprecision (CVa) was determined by replicate analysis ( n = 314).

Results

Of 7383 patients with TPMT measurements, 136 were identified as having three or more measurements over time (range 3–14). Median CVTOT for individual patient results was 14.5% (range 2.5–36.7%). Analytical imprecision (CVa) was 10.3%. A reference change value (or critical difference) with 95% probability was calculated as 42%. Therefore, a change in measured TPMT activity above 42% should lead to considering sources of variation other than biological variation and analytical imprecision.

Conclusions

TPMT enzyme activity needs to change by at least 42% to determine that a true change has taken place beyond biological variation and analytical imprecision. A single measurement of TPMT activity is sufficient for most clinical purposes.