bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-62: Direct visualization of circulating sarcoma cells by whole-blood fluorescence in-situ hybridization
Authors: Morozov Alexei , Leversha Margaret , Keohan Mary-Louise , D'Adamo David R. , Schwartz Gary K. , Meyers Paul , Maki Robert G. , Moore Malcolm A.S.
Published: February 2011

Background: Several sarcoma subtypes are characterized by well-defined genetic events such as chromosomal translocations or gene amplification. In translocation-associated sarcomas, the presence of the fusion transcript can be detected in peripheral blood by RT-PCR. However, sarcoma cells have never been directly visualized in peripheral blood due to the absence of specific immunocytochemical markers.

Methods: We developed a novel method to examine large numbers of peripheral blood cells for the presence of sarcoma-associated genetic changes. Using an IRB-approved biospecimen collection protocol, peripheral blood was collected from 20 patients with translocation-associated sarcomas or well-differentiated/dedifferentiated liposarcomas (WD/DD LS), which are characterized by MDM2 amplification. In this exploratory phase, the analysis was limited to patients with high burden of disease, evidence of disease progression or recurrence. Immuno-FISH was performed using CD45 immunostaining to identify hematopoietic cells and the corresponding FISH probe, either a break-apart probe (SYT, DDIT3) or MDM2 probe to detect amplification.

Results: ADW2-amplified cells were detected in a subset of WD/DD LS peripheral blood samples, while translocation-positive cells were detected in samples of synovial sarcoma (using the SYT breakapart probe) and myxoid/round cell liposarcoma (using the DDIT3 breakapart probe). We are currently developing the techniques to quantitate the frequencies of such CD45(-) Probe(+) cells.

Conclusions: To our knowledge this is the first report of direct visualization of sarcoma cells in peripheral blood using whole-blood FISH analysis. We are currently characterizing these cells morphologically and immunocytochemically. In addition, we are developing tools necessary to perform quantitative analysis of circulating tumor cell frequencies in peripheral blood samples, to begin to establish whether the levels of circulating tumor cells correlate with tumor burden and response to therapy. This method may be applicable to other tumors where defined genetic lesions exist that are amenable to FISH analysis, such as chromosomal translocations or genomic gains or losses. The goal is to use such genotype-based analysis to explore the phenotypic diversity of circulating tumor cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-62.
Abstract LB-64: Synuclein gamma inhibits BubR1 function and renders resistance to antimicrotubule drug
Authors: Shi Yuenian Eric , Wu Kejing , Liu Yiliang Ellie , DelRowe John , Chen Yiding
Published: February 2011

The microtubule (MT) cytoskeleton is an effective and validated target for cancer chemotherapeutic drugs. Currently, anti-MT drug taxane, e.g. docetaxel, is the first-line chemotherapeutic agent to treat patients with locally advanced or metastatic breast cancer and is also one of the most effective chemotherapeutic agents in clinical use in six different cancers (breast, ovarian, non-small cell lung, prostate, gastric, and head and neck). Nearly half of the treated breast and ovarian cancer patients, however, do not respond to chemotherapy. Although general mechanisms of drug resistance may apply to docetaxel resistance, more specifically, the current research paradigm on docetaxel resistance focus on acquired -tubulin mutations and altered expression of β-tubulin isotypes that interfere with drug target binding. Synuclein gamma (SNCG) is a new unfavorable prognostic marker for breast cancer and a potential target for cancer treatment. At the cellular level, SNCG increases metastasis and promotes genetic instability. At the molecular level, SNCG functions like a tumor specific chaperone and regulates many pathways in growth and progression of cancer, including an interaction with mitotic checkpoint kinase BubR1. Here, we show that expression of SNCG is sufficient to induce specific resistance to docetaxel-caused mitotic arrest and apoptosis in breast cancer cells and in breast cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1, interferes with its interaction with other checkpoint proteins of p55cdc20-APC and Mda2, reduces BubR1's kinase activity, and thus attenuates docetaxel-caused mitotic cell death. The working mechanism of anti-MT drugs heavily relies on the normal function of the checkpoint machinery in which BubR1 is a critical component, this inhibitory effect of SNCG on BubR1 function may lead to the inactivation of checkpoint and thus renders docetaxel resistance. To test the clinical relevance, in a pilot neoadjuvant trial, 20 women with histological proven locally advanced breast cancer were treated with 3 cycles of neoadjuvant TE regimen (docetaxel + epirubicin). SNCG-positive tumors are resistant to anticancer effect of neoadjuvant therapy as assayed by reduction in primary tumor size, an increase in apoptotic index, and a decrease in Ki67 proliferation index. These data show that SNCG renders docetaxel resistance by inhibiting BubR1 activity and is new biomarker for predicting anti-MT drug resistance.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-64.
Abstract LB-67: Global DNA methylation in fetal human germ cells and germ cell tumors: correlation with differentiation and cisplatin resistance
Authors: Looijenga Leendert H.J , Wermann Hendrik , Gillis Ad , Honecker Friedemann , Ammerpohl Ole , Richter Julie , Oosterhuis Wolter , Bokemeyer Carsten
Published: February 2011

Differences in the global methylation pattern, i.e. hyper- as well as hypomethylation, are observed in cancer, including germ cell tumors (GCTs). Related to their precursor cells, GCT methylation status differs according to histology. We investigated the methylation pattern of normal fetal, infantile, and adult germ cells (n=103) and GCTs (n=251) by immunohistochemical staining for 5-mCytidine. The global methylation pattern of male germ cells changes from hypomethylation to hypermethylation, while female germ cells remain unmethylated at all stages. Undifferentiated GCTs (seminomas, carcinoma in situ and gonadoblastomas) are hypomethylated, whereas more differentiated GCTs (teratomas, yolk sac tumors, choriocarcinomas) show a higher degree of methylation. Embryonal carcinomas show an intermediate pattern. Resistance to cisplatin was assessed in the seminomatous cell line TCam-2 before and after demethylation using 5-azacytidine. Exposure to 5-azacytidine resulted in decreased resistance to cisplatin. Furthermore, after demethylation, the stem cell markers NANOG and POU5F1 (OCT3/4), as well as the germ cell specific marker VASA showed increased expression. Upon treatment with 5-azacytidine, TCam-2 cells were analyzed by high throughput methylation screen for changes in methylation sites of 14,000 genes. Among the genes revealing changes, interesting targets were identified, i.e. demethylation of KLF11, a putative tumor suppressor gene, and hypermethylation of CFLAR, a gene previously described in treatment resistance in GCTs.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-67.
Abstract LB-75: Concomitant use of panitumumab (Pmab) had no clinically significant effect on irinotecan (Iri) pharmacokinetics (PK)
Authors: Kennecke Hagen , Wu Chi-Yuan , Chen Eric , Infante Jeffrey , Chen Alin , Gao Bing , Smith Brian , Litten Jason , Yang Bing-Bing
Published: February 2011

Background: Pmab, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFR), is indicated for treatment of EGFR-expressing, chemorefractory, metastatic colorectal cancer (mCRC). This study examined effects of Pmab on Iri PK when used as combination therapy in patients (pts) with mCRC.

Methods: This phase 1, open-label, multicenter, single-arm study enrolled pts with mCRC without prior exposure to an EGFR inhibitor. Pts could not have CYP3A4 inhibiting or inducing medications ≥ 2 weeks before enrollment or UGT1A1*28 TA7/7, TA7/8, and TA8/8 polymorphisms. Pts received Iri (180 mg/m2, 90-min IV infusion) on day 1 cycle 1 followed by Pmab (6 mg/kg, 60-min IV infusion) on day 4 cycle 1. After 2 weeks (day 1 cycle 2), pts received Pmab followed immediately by Iri. Pmab and Iri were administered thereafter every 2 weeks until disease progression or intolerability. Plasma samples for Iri and its active metabolite SN-38 were collected pre-dose and up to 72 hours after Iri infusion in cycles 1 and 2. Primary endpoints were Cmax and AUC of Iri (PK subset), and secondary endpoints included rates of adverse events (AEs).

Results: 28 pts enrolled; 19 of 27 pts who received treatment met PK evaluability criteria (dosed per protocol for 2 cycles with no reductions/delays). PK profiles of Iri with or without Pmab were nearly superimposable. 90% confidence intervals for the ratios of geometric means for Iri Cmax and AUC with or without Pmab were within a prespecified 0.70 to 1.43 interval, suggesting that Pmab had no impact on Iri PK. Similar results were seen for SN-38 PK. AEs were as expected for Iri plus Pmab combination therapy.

Conclusions: Pmab in combination with Iri was generally well tolerated by pts with mCRC. Pmab had no significant effects on Iri PK.PK Profiles of Iri and SN-38   Ratio of Geometric Means Point Estimate Cycle (N = 19)Geometric Mean(Cycle 2 vs Cycle 1)90% CIIri    Cmax (ng/mL)115400.9800.894 - 1.074 21510  AUC0-inf (ng·hr/mL)1112000.8980.819-0.985 210100  SN-38    Cmax (ng/mL)125.90.8230.731-0.926 221.3  AUC0-inf (ng·hr/mL)1a3260.8650.773 - 0.968 2b282  aN = 17; bN = 16; CI, Confidence interval; Iri, Irinotecan

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-75.
Abstract LB-89: Claudin-11 (CLDN11): A potential marker of gastric carcinogenesis
Authors: Agarwal Rachana , Mori Yuriko , Cheng Yulan , Jin Zhe , Olaru Alexandru , Hamilton James P. , David Stefan , Selaru Florin M. , Yang Jian , Abraham John , Duncan Mark , Harmon John , Montgomery Elizabeth , Morin Patrice J. , Meltzer Stephen J.
Published: February 2011

Gastric cancer (GC) remains the second most-common cause of cancer deaths globally, with an overall 5-year survival rate below 20%. The poor prognosis of this cancer, due largely to delayed diagnosis, would be greatly improved by the identification of biomarkers to stratify risk and accelerate diagnosis. In search of such markers, a pilot microarray-based genome-wide search conducted by our group identified claudin-11 (CLDN11), a tight junction (TJ) protein, as a potential target of epigenetic inactivation in gastric cancers. Claudin-11 belongs to the family of claudin proteins, which contains more than 23 members. In recent years, it has been demonstrated by us and others that members of the claudin gene family are involved in various human cancers. Our data identified the CLDN11 promoter region as being heavily hypermethylated in GC tissues and cell lines. Moreover, CLDN11 mRNA was found to be expressed only in primary noncancerous gastric mucosal tissues, as well as in an immortalized normal gastric epithelial cell line, whereas it was silenced in all GC tissues and cell lines examined. Interestingly, siRNA-mediated downregulation of CLDN11 in CLDN11-expressing gastric cells was also associated with cancer-related phenotypic changes, specifically increased cell motility and invasiveness. Our recent data also demonstrates that CLDN11 methylation levels can differentiate GC from its corresponding non-cancerous normal gastric mucosae with 100% sensitivity and specificity. A deeper understanding of the timing of CLDN11 inactivation during the development and progression of gastric neoplasia will lead to the development of potential early detection and prognostic biomarkers. Further, large-scale prospective validation studies of this alteration as a predictive biomarker for GC development are warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-89.
Abstract LB-9: DNA binding distinguishes wild-type and mutant p53 activity
Authors: Ray Debolina , Gal Susannah
Published: February 2011

Cell cycle regulation is a function of several regulatory genes such as cyclin G, p21, etc. controlled by p53. Several other genes such as pcna, puma, noxa involved in DNA repair and apoptotic pathways are also coordinated by p53. It is thus understandable that mutations in p53 could result in de-regulation of cell cycle progression, DNA repair, apoptosis, etc. Any imbalance in the above mentioned processes normally culminates in cancer. Our present focus of study is breast cancer where the cells harbor either wild-type or mutant p53. Progression of cancer in cell lines with wild-type p53 indicates a different regulatory switch/pathway responsible for the establishment of this disease. In an effort to understand the functional effect of both wild-type and mutant p53, we have done p53 DNA binding with nuclear extracts from several breast cancer cell lines using two assays. The DNA sequences being considered as target for p53 binding are from genes involved in cell cycle regulatory pathways, DNA repair, apoptosis and p53 regulation. We have observed differences in binding of p53 to some of these gene sequences. Cell lines with wild-type p53 and functional estrogen receptor (ER) bind more to the promoter for pcna and cyclin G than cell lines with mutant p53. The binding to the promoter of the puma gene is more similar between cell lines with mutant and wild-type p53 than the other genes analyzed. We anticipate a certain trend in DNA binding based on the functional status of p53 and its interaction with other proteins such as ER. This trend of p53 binding to different gene sequences may be utilized to better understand the causes of breast cancer, its subsequent progression as well as for designing treatment protocols.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-9.
Abstract LB-91: Identification and feasibility test of novel methylation biomarkers for stool DNA-based colorectal cancer screening
Authors: An Sungwhan , Oh TaeJeong , Moon YoungHo , Kim Nayoung , Lee Seung-Hoon , Kim Nam Kyu , Chung Hyun Cheol , Oh HyunIl
Published: February 2011

Aberrant DNA methylation event is known to be early and frequent process in tumorigenesis and could therefore serve as a convenient biomarker for early detection of cancers. For the identification of novel methylation markers we compared each methylation profiles in super normal tissues (n=2) of healthy individuals and primary tumors and their matched normal appearing adjacent tissues (non-tumor) from colorectal cancer patients (n=12) relative to that of common reference DNA through genome-wide CpG microarray analysis following methylated DNA enrichment with a minimum size of methyl binding domain. Unsupervised hierarchical clustering of with entire methylation pattern data successfully discriminated normal, match-paired normal and primary tumors. We then statistically selected novel methylation candidates showing high frequency of methylation in primary tumor samples and intermediate in non-tumor but no methylation in supernormal tissues for early detection and confirmed in colorectal cancer cell lines by quantitative pyrosequencing-based methylation assay. For final candidates with high specificity, we selected 4 genes, GABRA1, gt-SD, gt-SI, gt-SO which showed a low methylation level in 2 healthy normal tissues. All of 4 genes appeared to be much more frequently hypermethylated in primary tumors than in non-tumor tissues in pyrosequencing assay. For the applicability into non-invasive sample we analyzed methylation status of 4 genes in stool DNAs obtained from patients with colorectal cancer (n=106) and healthy volunteers (n=10) by modified two-round nested MSP for improving analytic sensitivity. The sensitivity and specificity of each of 4 genes were estimated as 50.5% to 60.2% and 85.7% to 100%, respectively. The sensitivity of the four-gene panel was 88.7% (94/106) and its specificity was 80.0% (2/10) in detecting colorectal cancer with stool DNA. Consequently, 4 novel genes have a great potential in noninvasive stool DNA testing for colorectal cancer screening. Further large-scale clinical validation will be needed for clinical setting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-91.
Abstract LB-96: Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex
Authors: Qian Tingting , Lee Jeong-Yeon , Kim Hyun-Jun , Kong Gu
Published: February 2011

The helix-loop-helix inhibitor of differentiation and DNA binding (Id1) is well-known as an oncogene in various tumors. Although it has been reported that Id-1 promotes several oncogenic processes, it is still unclear whether Id1 functions through epigenetic transcriptional regulation. In this study, we examined the effect of Id1 on polycomb group (PcG) proteins, which are crucial epigenetic gene silencers, and found that Id1 regulated the expression of Mel-18 and Bmi-1, both of which belong to PRC1 but not PRC2 complex. We also confirmed that Id1 induced Mel-18 downregulation which was mediated by the Akt pathway, and consequently upregulated the transcription of its target gene c-Myc. Using a promoter-reporter, we demonstrated that Id1 regulated Bmi-1 transcription through c-Myc binding to its E-box in the promoter. Finally, we examined the activity of E3 ligase RING1b whose catalytic activity is increased by binding with the RING finger protein Bmi-1, and found that Id1 over-expression enhanced RING1b E3 ligase activity leading to accumulation of H2A ubiquitination and ubiquitin/proteasome-mediated degradation of Geminin. Taken together, our study provided a novel link between Id1 and PcG proteins and suggested that Id1 may contribute to tumor development through PcG-mediated epigenetic regulation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-96.
Abstract LB-98: DDB1 interacts with Cdh1 and modulates the function of APCCdh1
Authors: Lv Xiao-Bin , Zeng Yi-Xin , Kang Tiebang
Published: February 2011

Control of cell cycle division by the anaphase promoting complex or cyclosome (APC/C) ubiquitin ligase depends on its coactivators, two WD40 repeat proteins, Cdc20 and Cdh1. APC/CCdh1 becomes active during mitotic exit and has essential targets in G1 phase by poorly understood mechanisms. In this report, we provide evidence that DDB1 (Damaged DNA-binding protein 1), a recently identified protein interacting with numerous proteins containing WD40 domains, is capable of binding with the WD40 domains of Cdh1, but not of Cdc20, through its BPA and BPC domains. Moreover, cells lacking DDB1 exhibit markedly elevated protein levels of the substrates for APC/CCdh1, and mitotic cells depleting DDB1 significantly delay mitotic exit, demonstrating that such an interaction between DDB1 and Cdh1 plays a critical role in regulating APC/CCdh1 activity. On the contrary, cells depleting Cdh1 have no effect on the UV-induced degradation of Cdt1, the main function of DDB1 as an E3 ligase. Strikingly, the APCCdh1 substrates are normal in the cells knock-down of Cul4A and CulB, which along with DDB1 forms an E3 ligase complex, indicating that DDB1 modulates the function of APCCdh1 in a manner independent on the Cul4-DDB1 complex. Taken together, DDB1 may functionally regulate the normal mitotic exit by modulating APCCdh1 activity, revealing for the first time that three E3 ligases, DDB1, Cdh1, and Skp2, may cooperate to tightly control cell cycle division.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-98.
Melatonin and the Metabolic Syndrome: Physiopathologic and Therapeutical Implications
Authors: Cardinali Daniel P. , Cano Pilar , Jiménez-Ortega Vanesa , Esquifino Ana I.
Published: February 2011

Metabolic syndrome (MS) patients exhibit sleep/wake disturbances and other circadian abnormalities, and these may be associated with more rapid weight increase and development of diabetes and atherosclerotic disease. On this basis, the successful management of MS may require an ideal drug that besides antagonizing the trigger factors of MS could also correct the disturbed sleep-wake rhythm. Melatonin is an effective chronobiotic agent able to change the phase and amplitude of circadian rhythms. Melatonin has also significant cytoprotective properties preventing a number of MS sequelae in animal models of diabetes and obesity. A small number of controlled trials indicate that melatonin is useful to treat the metabolic and cardiovascular comorbidities of MS. Whether the recently introduced melatonergic agents (ramelteon, agomelatine, tasimelteon) have the potential for treating sleep disorders in MS patients and, more generally, for arresting the progression of disease, merits further investigation.
Hand2 Loss-of-Function in
Hand1
-Expressing Cells Reveals Distinct Roles in Epicardial and Coronary Vessel Development
Authors: Barnes Ralston M. , Firulli Beth A. , VanDusen Nathan J. , Morikawa Yuka , Conway Simon J. , Cserjesi Peter , Vincentz Joshua W. , Firulli Anthony B.
Published: February 2011

Rationale:

The basic helix–loop–helix (bHLH) transcription factors Hand1 and Hand2 are essential for embryonic development. Given their requirement for cardiogenesis, it is imperative to determine their impact on cardiovascular function.

Objective:

To deduce the role of
Hand2
within the epicardium.

Method and Results:

We engineered a
Hand1
allele expressing
Cre
recombinase. Cardiac
Hand1
expression is largely limited to cells of the primary heart field, overlapping little with
Hand2
expression.
Hand1
is expressed within the septum transversum, and the
Hand1
lineage marks the proepicardial organ and epicardium. To examine Hand factor functional overlap, we conditionally deleted
Hand2
from
Hand1
-expressing cells.
Hand2
mutants display defective epicardialization and fail to form coronary arteries, coincident with altered extracellular matrix deposition and
Pdgfr
expression.

Conclusions:

These data demonstrate a hierarchal relationship whereby transient
Hand1
septum transversum expression defines epicardial precursors that are subsequently dependent on Hand2 function.
Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles
Authors: Chua Su-Kiat , Chang Po-Cheng , Maruyama Mitsunori , Turker Isik , Shinohara Tetsuji , Shen Mark J. , Chen Zhenhui , Shen Changyu , Rubart-von der Lohe Michael , Lopshire John C. , Ogawa Masahiro , Weiss James N. , Lin Shien-Fong , Ai Tomohiko , Chen Peng-Sheng
Published: February 2011

Rationale:

Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF).

Objective:

We hypothesized that activation of apamin-sensitive small-conductance Ca
2+
-activated K
+
(SK) channels is responsible for the postshock APD shortening in failing ventricles.

Methods and Results:

A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca
2+
and membrane potential (
V
m
) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF and increased postshock APD
80
in the SVF group from 126±5 to 153±4 ms (
P
<0.05) and from 147±2 to 162±3 ms (
P
<0.05) in the no-SVF group but did not change APD
80
in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K
+
current (
I
KAS
) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial
I
KAS
density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca
2+
response of
I
KAS
was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca
2+
sensitivity of
I
KAS
in failing ventricles. The
K
d
was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (
P
=0.002).

Conclusions:

Heart failure heterogeneously increases the sensitivity of
I
KAS
to intracellular Ca
2+
, leading to upregulation of
I
KAS
, postshock APD shortening, and recurrent SVF.
Angiographic Vasospasm Is Strongly Correlated With Cerebral Infarction After Subarachnoid Hemorrhage
Authors: Crowley R. Webster , Medel R. , Dumont Aaron S. , Ilodigwe Don , Kassell Neal F. , Mayer Stephan A. , Ruefenacht Daniel , Schmiedek Peter , Weidauer Stephan , Pasqualin Alberto , Macdonald R. Loch
Published: February 2011

Background and Purpose—

The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage.

Methods—

We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%–33% decrease in arterial diameter), moderate (34%–66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction.

Results—

Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7–23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction.

Conclusions—

A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.
Subtherapeutic Warfarin Is Not Associated With Increased Hemorrhage Rates in Ischemic Strokes Treated With Tissue Plasminogen Activator
Authors: Vergouwen Mervyn D.I. , Casaubon Leanne K. , Swartz Richard H. , Fang Jiming , Stamplecoski Melissa , Kapral Moira K. , Silver Frank L.
Published: February 2011

Background and Purpose—

Concern exists that preadmission warfarin use may be associated with an increased risk of intracerebral hemorrhage in patients with ischemic stroke receiving intravenous tissue plasminogen activator, even in those with an international normalized ratio <1.7. However, evidence to date has been derived from a small single-center cohort of patients.

Methods—

We used data from Phase 3 of the Registry of the Canadian Stroke Network. We compared the rates of post-tissue plasminogen activator hemorrhage, including any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and gastrointestinal hemorrhage in patients with and without preadmission warfarin use. For those receiving warfarin, we restricted the analysis to patients with an international normalized ratio <1.7 on presentation. Secondary outcomes included functional status and mortality. Multivariate analyses were performed to adjust for other prognostic factors.

Results—

Our cohort included 1739 patients with acute ischemic stroke treated with intravenous tissue plasminogen activator of whom 125 (7.2%) were receiving warfarin before admission and had an international normalized ratio <1.7. Preadmission warfarin use was not associated with any secondary intracerebral hemorrhage (OR, 1.2; 95% CI, 0.7 to 2.2), symptomatic intracerebral hemorrhage (OR, 1.1; 95% CI, 0.5 to 2.3), or gastrointestinal hemorrhage (OR, 1.1; 95% CI, 0.2 to 5.6). Multivariate analysis showed that preadmission warfarin use was independently associated with a reduced risk of poor functional outcome (OR, 0.6; 95 CI, 0.3 to 0.9), but not with in-hospital mortality (OR, 0.6; 95% CI, 0.3 to 1.0).

Conclusions—

The results from the present study suggest that tissue plasminogen activator treatment appears to be safe in patients with acute ischemic stroke taking warfarin with an international normalized ratio <1.7 and may reduce the risk of poor functional outcome.
Genes Associated With Adult Cerebral Venous Thrombosis
Authors: Marjot Thomas , Yadav Sunaina , Hasan Nazeeha , Bentley Paul , Sharma Pankaj
Published: February 2011

Background and Purpose—

Quantitative predictions of the risk of cerebral venous thrombosis (CVT) conferred by certain genotypes have yet to be reliably established. We conducted a comprehensive meta-analysis of all candidate genes studied to assess their genetic contribution to the etiology of CVT. We compared our findings against equivalent analyses for pediatric CVT and adult ischemic stroke.

Methods—

Databases were searched to August 2010 for all genes investigated in adult CVT, and odds ratios (ORs) for each gene-disease association were calculated. A mendelian randomization strategy was also undertaken to determine whether a causal relation to one gene could be ascertained.

Results—

We identified 26 case-control studies investigating 6 polymorphisms in 6 genes and included 1183 CVT cases and 5189 controls. Statistically significant associations with CVT were found for factor V Leiden/G1691A (OR=2.40; 95% CI, 1.75 to 3.30;
P
<0.00001) and prothrombin/G20210A (OR=5.48; 95% CI, 3.88 to 7.74;
P
<0.00001). After iterative analysis controlling for interstudy heterogeneity, methylene tetrahydrofolate reductase/C677T was also found to be significantly associated (OR=2.30; 95% CI, 1.20 to 4.42;
P
=0.02). Variants in the remaining 3 genes (Janus kinase-2, plasminogen activator inhibitor-1, and protein Z) were not significantly associated. Pooled ORs for CVT risk in adults for factor V Leiden and prothrombin were significantly greater when compared against childhood CVT and adult arterial ischemic stroke. A causal relation with methylene tetrahydrofolate reductase may exist.

Conclusions—

CVT has a genetic basis. Genes involved in the clotting cascade provide a greater level of thrombosis risk in the cerebral venous circulation compared with its arterial circulation, and a greater level of risk exists for adults compared with children.
Increases in Cerebral Atherosclerosis According to CHADS
2
Scores in Patients With Stroke With Nonvalvular Atrial Fibrillation
Authors: Kim Young Dae , Cha Myoung Jin , Kim Jinkwon , Lee Dong Hyun , Lee Hye Sun , Nam Chung Mo , Nam Hyo Suk , Heo Ji Hoe
Published: February 2011

Background and Purpose—

The CHADS
2
score is used for risk stratification of ischemic stroke in patients with nonvalvular atrial fibrillation and high CHADS
2
scores are associated with increased risk of stroke. Most components of the CHADS
2
score are also risk factors for atherosclerosis. Therefore, high CHADS
2
scores can be associated with concomitant cerebral atherosclerosis and subsequently atherothrombotic stroke. The aim of this study was to determine whether there are differences in the presence and burden of concomitant cerebral atherosclerosis according to CHADS
2
scores in patients with stroke with nonvalvular atrial fibrillation.

Methods—

We included 780 consecutive patients with nonvalvular atrial fibrillation who had undergone angiographic studies at index stroke between August 1994 and March 2010 in the present study. We investigated the relationships between the CHADS
2
score and the presence, severity, and pattern of cerebral atherosclerosis and stroke mechanism.

Results—

Of the 780 patients, concomitant arterial stenosis (≥50%) was found in 231 patients (29.6%). The number of arteries with atherosclerosis increased as the CHADS
2
score increased (
P
<0.001) as did the proportion of combined extracranial and intracranial atherosclerosis (
P
<0.001). Multivariate analyses showed that high risk based on the CHADS
2
score was an independent predictor of concomitant cerebral atherosclerosis (OR, 3.121; 95% CI, 1.770 to 5.504) and the presence of proximal stenosis at the symptomatic artery (OR, 3.043; 95% CI, 1.458 to 6.350).

Conclusions—

The CHADS
2
score can predict the presence of concomitant cerebral artery atherosclerosis. Increased risk of stroke in patients with high CHADS
2
scores may be partly explained by increased frequency and burden of cerebral atherosclerosis.
Increased Thyroid Function and Elevated Thyroid Autoantibodies in Pediatric Patients With Moyamoya Disease
Authors: Li Hao , Zhang Zheng-Shan , Dong Zhen-Nan , Ma Mai-Juan , Yang Wei-Zhong , Han Cong , Du Ming-Mei , Liu Yun-Xi , Yang Hong , Liu Wei , Duan Lian , Cao Wu-Chun
Published: February 2011

Background and Purpose—

The purpose of this study was to investigate whether thyroid function and thyroid autoantibodies were associated with the risk of moyamoya disease in pediatric subjects.

Methods—

Thyroid function and thyroid autoantibodies were evaluated in patients with moyamoya disease and control subjects, and their associations with moyamoya disease were estimated using multivariate analysis.

Results—

We included 114 pediatric patients and 114 healthy control subjects. The patients displayed higher prevalence of increased thyroid function and elevated thyroid autoantibodies in comparison with control subjects. These remained significant after multivariate adjustment; the ORs (95% CI) for increased thyroid function and evaluated thyroid autoantibodies were evaluated as 12.47 (1.55 to 100.51) and 4.33 (1.29 to 14.59), respectively.

Conclusions—

Increased thyroid function and elevated thyroid autoantibodies are associated with moyamoya disease and therefore monitoring of thyroid function and thyroid autoantibodies in patients with moyamoya disease is suggested, which might help to guide subsequent clinical management.
Sea Surface Temperature Biases under the Stratus Cloud Deck in the Southeast Pacific Ocean in 19 IPCC AR4 Coupled General Circulation Models
Authors: Zheng Yangxing , Shinoda Toshiaki , Lin Jia-Lin , Kiladis George N.
Published: February 2011

This study examines systematic biases in sea surface temperature (SST) under the stratus cloud deck in the southeast Pacific Ocean and upper-ocean processes relevant to the SST biases in 19 coupled general circulation models (CGCMs) participating in the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). The 20 years of simulations from each model are analyzed. Pronounced warm SST biases in a large portion of the southeast Pacific stratus region are found in all models. Processes that could contribute to the SST biases are examined in detail based on the computation of major terms in the upper-ocean heat budget. Negative biases in net surface heat fluxes are evident in most of the models, suggesting that the cause of the warm SST biases in models is not explained by errors in net surface heat fluxes. Biases in heat transport by Ekman currents largely contribute to the warm SST biases both near the coast and the open ocean. In the coastal area, southwestward Ekman currents and upwelling in most models are much weaker than observed owing to weaker alongshore winds, resulting in insufficient advection of cold water from the coast. In the open ocean, warm advection due to Ekman currents is overestimated in models because of the larger meridional temperature gradient, the smaller zonal temperature gradient, and overly weaker Ekman currents.
Physical activity based professional development for teachers
Authors: Till Jude , Ferkins Lesley , Handcock Phil
Published: February 2011

Objective: This study sought to investigate teachers’ perceptions of a physical activity-related professional development intervention.

Design: Interview-based qualitative approach founded on the interpretive paradigm.

Setting: Purposive selection of one high-rated independent, and one low-rated public primary school from Auckland, New Zealand.

Method: A qualitative approach was used, incorporating a questionnaire used for purposive sampling and a total of eighteen semi-structured interviews with six teachers from two primary schools.

Results: Participants highly valued the inclusion of all teachers in onsite professional development and felt supported by a strong, positive organizational culture.

Conclusion: Participant teachers believed physical activity played an important role within the school setting, and recognized their role in the provision of opportunities for their students. However, they did not necessarily feel confident and competent to facilitate opportunities. A specific professional development intervention was introduced as one form of support to address this need. Teachers valued first-hand experience of professional development and reported particular enjoyment if they participated alongside their colleagues.
B Lymphocyte Subsets in Patients with Rhinoscleroma
Authors: Fusconi Massimo , Gallo Andrea , De Virgilio Armando , Natalizi Stefania , Greco Antonio , Zambetti Giampietro , de Vincentiis Marco
Published: February 2011

Objective

To identify the presence of B lymphocytes in the rhinoscleroma granulomas as a possible precursor of plasma cells, whose presence has always been described but whose role is still unclear.

Study Design

Case series with chart review.

Setting

Sapienza University of Rome.

Methods

The study was carried out on 6 patients (3 women, 3 men). The following parameters were examined for each patient: clinical manifestations, number of leukocytes, lymphocytes and lymphocyte subsets (CD3+, CD4+, CD8+, and CD19+) in blood samples, time from the onset of symptoms, biopsies, and expression of CD3, CD4, CD8, and CD20 antigens in tissue samples with immunohistochemical techniques.

Results

In this study, the values of CD3+, CD4+, and CD8+ T lymphocyte subsets in venous peripheral blood are in line with previously reported data, whereas CD19+ lymphocyte cells tended to show an ambiguous behavioral pattern. In tissue samples, approximately one‐third of the T lymphocyte population showed a CD3+/CD8+ immunophenotype (cytotoxic/suppressor), and two‐thirds of the T lymphocytes expressed a CD3+/CD4+ immunophenotype (helper/inducer). The authors also identified an unexpected large amount of CD20+ non‐plasmacellular B cells in addition to the plasma cells usually detected in rhinoscleroma biopsies.

Conclusions

This study demonstrates the presence of B lymphocytes in rhinoscleroma tissue. It is presumable that the mature B cells activated by antigenic stimulation of Klebsiella rhinoscleromatis are the precursors of the plasma cells typically found in the granuloma of rhinoscleroma.
The Art of Tonsillectomy
Authors: Charaklias Napoleon , Mamais Constantinos , Kumar B. Nirmal
Published: February 2011

Tonsillectomy is one of the commonest ear, nose, and throat procedures performed in the United Kingdom. In the drive to reduce complication rates and improve patients’ satisfaction, numerous adaptations to the traditional technique have evolved. In this article, the authors explore the changes that have been happening in the United Kingdom during the past 100 years and conclude that revisiting the traditional techniques may still be the answer to a successful procedure.
Is there a need for weekend face-to-face inpatient assessments by hospital specialist palliative care services? Evaluation of an out-of-hours service
Authors: Birks Theodore , Krikos Dimitrios , McGowan Catherine , Stone Patrick
Published: February 2011

There is an increasing demand for hospital specialist palliative care services to be made more accessible outside of normal working hours. However, it has been argued that extended service provision could be misused and that specialist telephone advisory services are an adequate response to this demand. A ‘routine’ Saturday face-to-face visiting service was introduced into a hospital palliative care team and the service was evaluated to determine whether it was being utilised appropriately. A retrospective notes review of out-of-hours assessments was undertaken. Anonymised data relating to the nature of the interaction with the palliative care team and the outcome of the consultation were entered into an electronic database. A random sample of routine weekday interactions was also evaluated. A total of 336 Saturday and 93 weekday assessments were analysed. Most of the Saturday assessments resulted in a significant change in management (57%) or were undertaken on patients close to death (10%). There were 39/336 (12%) new referrals assessed on Saturdays. There were few differences between the nature of the Saturday and the weekday service and no evidence of ‘inappropriate’ referrals. We found clear evidence of the need for a specialist out-of-hours face-to-face inpatient visiting service for hospital palliative care.
Arthroscopic Rotator Cuff Repair Using a Suture Bridge Technique
Authors: Cho Nam Su , Lee Bong Gun , Rhee Yong Girl
Published: February 2011

Background: Suture bridge repair has been recognized to have superior biomechanical characteristics, as shown in previous biomechanical studies. However, it is not clear whether the tendon heals better in vivo after suture bridge repair.

Purpose: To evaluate the clinical results and repair integrity after arthroscopic rotator cuff repair using a suture bridge technique for patients with rotator cuff tears.

Study Design: Case series; Level of evidence, 4.

Methods: One hundred twenty-three shoulders (120 patients) that underwent arthroscopic suture bridge repair for full-thickness rotator cuff tear were enrolled for this study. The mean duration of follow-up was 25.2 months (range, 16-34 months). The postoperative repair integrity was analyzed with use of magnetic resonance imaging (MRI) in 87 shoulders. According to the retear patterns on postoperative MRI, the cases were divided into type 1 (failure at the original repair site) or 2 (failure around the medial row).

Results: At the last follow-up, the University of California at Los Angeles (UCLA) score improved from the preoperative mean of 13.2 points to 29.7 points ( P < .001). The rotator cuff was completely healed in 58 (66.7%) of the 87 shoulders, and there was a recurrent tear in 29 shoulders (33.3%). The incidence of retear tended to increase with age older than 60 years at the time of surgery ( P = .002). When there was a larger intraoperative tear, the rate of retear was also higher ( P = .002). When the severity of preoperative fatty degeneration of the cuff muscles was higher, there was a greater chance of a recurrent tear ( P < .001). The retear patterns on postoperative MRI in 29 shoulders with recurrent failures were classified as type 1 in 12 shoulders (41.4%) and type 2 in 17 shoulders (58.6%). The preoperative cuff tear size did not have an influence on retear patterns ( P = .236), but the percentage of type 1 retear increased with the severity of fatty degeneration or muscle atrophy ( P = .041, .023).

Conclusion: Arthroscopic suture bridge repair of full-thickness rotator cuff tears led to a relatively high rate of recurrent defects. However, the mean 25-month follow-up demonstrated excellent pain relief and improvement in the ability to perform the activities of daily living, despite the structural failures. The factors affecting tendon healing were the patient’s age, the size and extent of the tear, and the presence of fatty degeneration in the rotator cuff muscle. The retear in cases with a suture bridge technique tended to be more frequently at the musculotendinous junction.
Comparison of Rotatory Stability After Anterior Cruciate Ligament Reconstruction Between Single-Bundle and Double-Bundle Techniques
Authors: Izawa Toshiaki , Okazaki Ken , Tashiro Yasutaka , Matsubara Hirokazu , Miura Hiromasa , Matsuda Shuichi , Hashizume Makoto , Iwamoto Yukihide
Published: February 2011

Background: Controversy persists as to whether double-bundle reconstruction of the anterior cruciate ligament (ACL) has any clinical advantage over single-bundle reconstruction. Several studies have used subjective and nonquantitative manual tests to evaluate the rotatory stability of the knee. The authors have developed a method to quantitate the rotatory stability of the ACL-deficient knee using open magnetic resonance imaging (MRI).

Hypothesis: Anatomic double-bundle reconstruction restores rotatory stability significantly better than does single-bundle reconstruction.

Study Design: Cohort study; Level of evidence, 3.

Methods: Twenty-three consecutive patients treated with the single-bundle reconstruction (group S) and 25 consecutive patients treated with the anatomic double-bundle reconstruction (group D) were evaluated. Both reconstruction procedures were performed using hamstring tendon autografts. The Slocum anterolateral rotatory instability (ALRI) test was performed 1 year after surgery using open MRI. To assess rotatory stability, we measured the difference in anterior tibial translation between medial and lateral compartments in the sagittal plane and defined this difference as the ALRI value. In addition, clinical examinations consisting of the Lysholm knee score, Tegner activity score, KT-2000 arthrometer anterior translation examination, and the pivot-shift test were carried out.

Results: The mean side-to-side difference in ALRI values was significantly less ( P < .001) in double-bundle reconstruction (mean, 1.2 mm) than in single-bundle reconstruction (mean, 4.1 mm). The mean side-to-side difference in KT-2000 arthrometer measurements was significantly less ( P = .014) in double-bundle reconstruction (mean, 1.2 mm) than in single-bundle reconstruction (mean, 2.6 mm). The difference in the incidence of positive pivot-shift tests between group S (43%) and group D (16%) did not reach the level of statistical significance ( P = .058). No significant differences in Lysholm score or Tegner score between the groups were observed.

Conclusion: The rotatory stability of anatomic double-bundle reconstruction was significantly better than the rotatory stability of single-bundle reconstruction.