bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacogenetic Determinants of Statin-Induced Reductions in C-Reactive Protein
Authors: Chu Audrey Y. , Guilianini Franco , Barratt Bryan J. , Nyberg Fredrik , Chasman Daniel I. , Ridker Paul M
Published: January 2012

Background—

In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown.

Methods and Results—

We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (
P
<0.001 for both) and essentially uncorrelated (
r
2
<0.03). No variants in the 3 genes (
ABCG2
,
LPA
, and
APOE
) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single-nucleotide polymorphisms associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate single-nucleotide polymorphisms selected from prior genetic analyses of baseline CRP, CRP reduction was associated with
rs2794520
in
CRP
(mean, −3.5% [SE, 2.0%] change in CRP per minor allele;
P
=6.4×10
−4
) and with
rs2847281
in
PTPN2
(mean, 3.7% [SE, 1.9%] change in CRP per minor allele;
P
=7.4×10
−4
). These associations remained significant after multiple testing correction but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin-induced LDL-C reduction or with CRP reduction among 3380 placebo-allocated JUPITER participants.

Conclusions—

The genetic determinants of rosuvastatin-induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy.
Retrospective Analysis of Surgery Versus Endovascular Intervention in Takayasu Arteritis
Authors: Saadoun David , Lambert Marc , Mirault Tristan , Resche-Rigon Mathieu , Koskas Fabien , Cluzel Philippe , Mignot Cécile , Schoindre Yoland , Chiche Laurent , Hatron Pierre-Yves , Emmerich Joseph , Cacoub Patrice
Published: January 2012

Background—

With recent advances in endovascular treatment, percutaneous endoluminal angioplasty has become particularly attractive for arterial lesions of Takayasu arteritis. However, data came from case reports or small series, and the long-term outcome has not been reported. The incidence of potential vascular complications after surgery or endovascular treatment is still to be determined.

Methods and Results—

This retrospective multicenter study analyzed the results and outcomes of 79 consecutive patients with Takayasu arteritis (median age, 39 years; interquartile range [IQR], 25–50 years; 63 women [79.7%]) who underwent 166 vascular procedures (surgery, 104 [62.7%]; endovascular repair, 62 [37.3%]) for the management of arterial complications. After a follow-up of 6.5 years (IQR, 2.2–11.5 years), 70 complications were observed, including restenosis (n=53), thrombosis (n=7), bleeding (n=6), and stroke (n=4). The overall 1-, 3-, 5-, and 10-year arterial complication–free survival rates were 78% (IQR, 69%–88%), 67% (IQR, 57%–78%), 56% (IQR, 46%–70%), and 45% (IQR, 34%–60%), respectively. Among the 104 surgical procedures, 39 (37.5%) presented a complication compared with 31 of the 62 (50%) with endovascular repair. In multivariate analysis, biological inflammation at the time of revascularization (odds ratio, 7.48; 95% confidence interval, 1.42–39.39;
P
=0.04) was independently associated with the occurrence of arterial complications after the vascular procedure. Patients who experienced complications had higher erythrocyte sedimentation rates (
P
<0.001) and C-reactive protein (
P
<0.001) and fibrinogen (
P
<0.005) serum levels compared with those without complications.

Conclusions—

The overall 5-year arterial complication rate was 44%. Biological inflammation increased the likelihood of complications after revascularization in patients with Takayasu arteritis.
Phospholipase A
2
Enzymes, High-Dose Atorvastatin, and Prediction of Ischemic Events After Acute Coronary Syndromes
Authors: Ryu Sung Kee , Mallat Ziad , Benessiano Joelle , Tedgui Alain , Olsson Anders G. , Bao Weihang , Schwartz Gregory G. , Tsimikas Sotirios ,   for the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Trial Investigators
Published: January 2012

Background—

Secretory phospholipase A2 (sPLA
2
) and lipoprotein-associated phospholipase A2 (Lp-PLA
2
) are enzyme biomarkers of increased cardiovascular risk and targets of emerging therapeutic agents. Their relationship to cardiovascular events in the setting of high-dose statin therapy compared with placebo in patients with acute coronary syndrome is not known.

Methods and Results—

sPLA
2
and Lp-PLA
2
mass and activity were measured in 2587 patients in the Myocardial Ischemia Reduction With Acute Cholesterol Lowering (MIRACL) trial at baseline and after 16 weeks of treatment with atorvastatin 80 mg/d or placebo. Baseline levels of sPLA
2
and Lp-PLA
2
mass and activity were not associated with the primary efficacy measure of the trial of death, myocardial infarction, or unstable angina. However, in the overall cohort, baseline sPLA
2
mass predicted risk of death after multivariable adjustment (hazard ratio for 2-fold increase, 1.30; 95% confidence interval, 1.09–1.56;
P
=0.004). This association remained significant when examined separately in the placebo group but not in the atorvastatin group. Compared with placebo, atorvastatin reduced median sPLA
2
mass (−32.1% versus −23.1%), sPLA
2
activity (−29.5% versus −19.2%), Lp-PLA
2
mass (−35.8% versus −6.2%), and Lp-PLA
2
activity (−24.3% versus 5.4%;
P
<0.001 for all). Atorvastatin reduced the hazard of death associated with elevated sPLA
2
mass and activity by ≈50%.

Conclusions—

sPLA
2
mass independently predicts death during a 16-week period after acute coronary syndrome. High-dose atorvastatin significantly reduces sPLA
2
and Lp-PLA
2
mass and activity after acute coronary syndrome and mitigates the risk of death associated with sPLA
2
mass. Atorvastatin may exert antiinflammatory effects on phospholipases that contribute to its therapeutic benefit after acute coronary syndrome.
The impact of depression heterogeneity on inhibitory control
Authors: Quinn Candice R , Harris Anthony , Kemp Andrew H
Published: January 2012

Objective: Major depressive disorder (MDD) is associated with deficits in executive cognitive function, including inhibitory control. However, inconsistencies have been found across studies. Depression is a heterogeneous disorder and these inconsistencies may therefore relate to heterogeneity in relatively small samples.

Method: Here we sought to examine event-related potentials (ERPs) during a cognitive Go/No-Go task in melancholic ( n = 60) and non-melancholic depressed patients ( n = 54) relative to controls ( n = 114).

Results: Behavioural responses indicate that inhibitory control processes are differentially affected by subtypes of depression such that melancholic patients exhibit a greater number of commission errors and more variable response rates in comparison to non-melancholic patients and controls respectively. However, ERPs do not differ during a cognitive Go/No-Go task when ERPs associated with correct responses are examined.

Conclusions: These findings indicate that while patients with melancholia differ from patients without melancholia and controls, no neurophysiological differences are observed when controlling for observable behavioural impairment.
T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells
Authors: Sabbah Shereen , Jagne Ya Jankey , Zuo Jianmin , de Silva Thushan , Ahasan Mohammad M. , Brander Christian , Rowland-Jones Sarah , Flanagan Katie L. , Hislop Andrew D.
Published: January 2012

T-cell immunity is important for controlling Kaposi sarcoma–associated herpesvirus (KSHV) diseases such as the endothelial cell malignancy Kaposi sarcoma, or the B-cell malignancy, primary effusion lymphoma (PEL). However, little is known about KSHV-specific T-cell immunity in healthy donors and immune control of disease. Using PBMCs from healthy KSHV-infected donors, we found weak ex vivo responses to the KSHV latent antigens LANA, vFLIP, vCyclin, and Kaposin, with LANA most frequently recognized. CD4+ T-cell clones specific to LANA, a protein expressed in all KSHV-infected cells and malignancies, were established to determine whether they could recognize LANA-expressing cells. B-cell targets expressing or fed LANA protein were consistently recognized by the clones; however, most PEL cell lines were not. PELs express the KSHV protein vIRF3 that inhibits promoter function of the HLA class II transactivator, decreasing expression of genes controlled by this transactivator. Re-expressing the class II transactivator in the PELs increased expression of downstream targets such as HLA class II and restored recognition but not killing by the LANA-specific clones. We suggest that PELs are poorly controlled in vivo because of inefficient recognition and killing by T cells.
Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma
Authors: Koduru Srinivas , Wong Ellice , Strowig Till , Sundaram Ranjini , Zhang Lin , Strout Matthew P. , Flavell Richard A. , Schatz David G. , Dhodapkar Kavita M. , Dhodapkar Madhav V.
Published: January 2012

Tumor microenvironment (TME) is commonly implicated in regulating the growth of tumors, but whether it can directly alter the genetics of tumors is not known. Genomic instability and dendritic cell (DC) infiltration are common features of several cancers, including multiple myeloma (MM). Mechanisms underlying genomic instability in MM are largely unknown. Here, we show that interaction between myeloma and DCs, but not monocytes, leads to rapid induction of the genomic mutator activation-induced cytidine deaminase (AID) and AID-dependent DNA double-strand breaks (DSBs) in myeloma cell lines as well as primary MM cells. Both myeloid as well as plasmacytoid DCs have the capacity to induce AID in tumor cells. The induction of AID and DSBs in tumor cells by DCs requires DC-tumor contact and is inhibited by blockade of receptor activator of NF-κB/receptor activator of NF-κB ligand (RANKL) interactions. AID-mediated genomic damage led to altered tumorigenicity and indolent behavior of tumor cells in vivo. These data show a novel pathway for the capacity of DCs in the TME to regulate genomic integrity. DC-mediated induction of AID and resultant genomic damage may therefore serve as a double-edged sword and be targeted by approaches such as RANKL inhibition already in the clinic.
Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study
Authors: Manz Michael , Burri Emanuel , Rothen Claude , Tchanguizi Nuschin , Niederberger Christian , Rossi Livio , Beglinger Christoph , Lehmann Frank Serge
Published: January 2012

Background

The evaluation of patients with abdominal discomfort is challenging and patient selection for endoscopy based on symptoms is not reliable. We evaluated the diagnostic value of fecal calprotectin in patients with abdominal discomfort.

Methods

In an observational study, 575 consecutive patients with abdominal discomfort referred for endoscopy to the Department of Gastroenterology & Hepatology at the University Hospital Basel in Switzerland, were enrolled in the study. Calprotectin was measured in stool samples collected within 24 hours before the investigation using an enzyme-linked immunosorbent assay. The presence of a clinically significant finding in the gastrointestinal tract was the primary endpoint of the study. Final diagnoses were adjudicated blinded to calprotectin values.

Results

Median calprotectin levels were higher in patients with significant findings (N = 212, median 97 μg/g, IQR 43-185) than in patients without (N = 326, 10 μg/g, IQR 10-23, P < 0.001). The area under the receiver operating characteristics curve (AUC) to identify a significant finding was 0.877 (95% CI, 0.85-0.90). Using 50 μg/g as cut off yielded a sensitivity of 73% and a specificity of 93% with good positive and negative likelihood ratios (10.8 and 0.29, respectively). Fecal calprotectin was useful as a diagnostic parameter both for findings in the upper intestinal tract (AUC 0.730, 0.66-0.79) and for the colon (AUC 0.912, 0.88-0.94) with higher diagnostic precision for the latter (P < 0.001). In patients > 50 years, the diagnostic precision remained unchanged (AUC 0.889 vs. 0.832, P = 0.165).

Conclusion

In patients with abdominal discomfort, fecal calprotectin is a useful non-invasive marker to identify clinically significant findings of the gastrointestinal tract, irrespective of age.
Detection of group A Streptococcus in tonsils from pediatric patients reveals high rate of asymptomatic streptococcal carriage
Authors: Roberts Amity L , Connolly Kristie L , Kirse Daniel J , Evans Adele K , Poehling Katherine A , Peters Timothy R , Reid Sean D
Published: January 2012

Background

Group AStreptococcus(GAS) causes acute tonsillopharyngitis in children, and approximately 20% of this population are chronic carriers of GAS. Antibacterial therapy has previously been shown to be insufficient at clearing GAS carriage. Bacterial biofilms are a surface-attached bacterial community that is encased in a matrix of extracellular polymeric substances. Biofilms have been shown to provide a protective niche against the immune response and antibiotic treatments, and are often associated with recurrent or chronic bacterial infections. The objective of this study was to test the hypothesis that GAS is present within tonsil tissue at the time of tonsillectomy.

Methods

Blinded immunofluorescent and histological methods were employed to evaluate palatine tonsils from children undergoing routine tonsillectomy for adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis.

Results

Immunofluorescence analysis using anti-GAS antibody was positive in 11/30 (37%) children who had tonsillectomy for adenotonsillar hypertrophy and in 10/30 (33%) children who had tonsillectomy for recurrent GAS pharyngitis. Fluorescent microscopy with anti-GAS and anti-cytokeratin 8 & 18 antibodies revealed GAS was localized to the tonsillar reticulated crypts. Scanning electron microscopy identified 3-dimensional communities of cocci similar in size and morphology to GAS. The characteristics of these communities are similar to GAS biofilms fromin vivoanimal models.

Conclusion

Our study revealed the presence of GAS within the tonsillar reticulated crypts of approximately one-third of children who underwent tonsillectomy for either adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis at the Wake Forest School of Medicine.

Trial Registration

The tissue collected was normally discarded tissue and no patient identifiers were collected. Thus, no subjects were formally enrolled.
MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults
Authors: Qin Xianhui , Li Jianping , Cui Yimin , Liu Zeyuan , Zhao Zhigang , Ge Junbo , Guan Deming , Hu Jian , Wang Yanni , Zhang Fumin , Xu Xin , Wang Xiaobin , Xu Xiping , Huo Yong
Published: January 2012

Background

This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults.

Methods

A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks.

Results

After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989).

Conclusions

This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.
In vitro and in vivo double-enhanced suicide gene therapy mediated by generation 5 polyamidoamine dendrimers for PC-3 cell line
Authors: Chen Yue , Wang Gang , Kong Deling , Zhang Zhihong , Yang Kuo , Liu Ranlu , Zhao Weiming , Xu Yong
Published: January 2012

Background

One of the most frequently used and efficient suicide gene therapies for prostate cancer is HSV-TK/GCV system, but its application has been limited due to lack of favorable gene vector and the reduction of "bystander effect". We investigated the effect of a novel combination of HSV-TK/GCV fused with Cx43 and gemcitabine using non-viral vector generation 5 polyamidoamine dendrimers (G5-PAMAM-D) on PC-3 cells.

Methods

RT-PCR and Western blot were used to detect TK and Cx43 expression. Cell viability and proliferation were measured by using MTT assay. Cell apoptosis was detected with double-staining of Annexin V-FITC and propidium iodide (PI) by flow cytometry. Nude mice models were established to evaluate the therapeutic effect in vivo.

Results

G5-PAMAM-D efficiently delivered recombinant plasmids into PC-3 cells and HSV-TK and Cx43 could be expressed successfully. With gemcitabine, G5-PAMAM-D mediated HSV-TK and Cx43 expression effectively inhibited prostate cancer PC-3 cell proliferation, leading to more cellular apoptosis and inhibiting PC-3 tumor growth in nude mice models.

Conclusions

This study illustrates that this new suicide gene system mediated by G5-PAMAM-D is effective in decreasing PC-3 cell proliferation and inducing cell apoptosis, and inhibiting tumor growth in vivo. In a word, our study could provide a potential approach for gene therapy of prostate cancer.
A mutation in the interferon regulatory element of HBV may influence the response of interferon treatment in chronic hepatitis B patients
Authors: Lu Jia-Jie , Chen En-Qiang , Yang Jia-Hong , Zhou Tao-You , Liu Li , Tang Hong
Published: January 2012

Background

A functional interferon regulatory element (IRE) has been found in the EnhI/X promoter region of hepatitis B virus (HBV) genome. The purpose of this study is to compare the gene order of responder and non-responder to interferon therapy in patients with chronic hepatitis B (CHB), so as to evaluate the relationship between IRE mutation and the response to interferon treatment for CHB patients.

Results

Synthetic therapeutic effect is divided into complete response (CR), partial response (PR) and non-response (NR). Among the 62 cases included in this study, 40 cases (64.5%) were in the response group (CR and PR) and 22 (35.5%) cases were in the NR group. Wild type sequence of HBV IRE TTTCACTTTC were found in 35 cases (56.5%), and five different IRE gene sequences. included TTTtACTTTC, TTTCAtTTTC, TTTtAtTTTC, TTTtACTTTt and cTTtACcTTC, were found in 22 cases (35.5%), 1 case (1.6%), 1 case (1.6%), 2 cases (3.2%) and 1 case (1.6%) respectively. There were 41.9%cases (26/62) with forth base C→T mutation, consisted of 32.5% (13/40) cases in response group and 59.1% (13/22) cases in NR group. Among the 35 cases with IRE sequences, there were 67.5% (27/40) cases in response group and 36.4% (8/22) in NR group, and the difference in IRE sequences between two groups was statistic significantly (P = 0.027). The result suggested that there is likely relationship between the forth base mutation (C→T) of IRE region and the response of HBV to Interferon therapy, and this mutation may partially decrease the inhibition effect of interferon on HBV.

Conclusion

The forth base C→T mutation in IRE element of HBV may partially influence the response of Interferon treatment in CHB patients.
Central coordination as an alternative for local coordination in a multicenter randomized controlled trial: the FAITH trial experience
Authors: Zielinski Stephanie M , Viveiros Helena , Heetveld Martin J , Swiontkowski Marc F , Bhandari Mohit , Patka Peter , Van Lieshout Esther MM
Published: January 2012

Background

Surgeons in the Netherlands, Canada and the US participate in the FAITH trial (Fixation using Alternative Implants for the Treatment of Hip fractures). Dutch sites are managed and visited by a financed central trial coordinator, whereas most Canadian and US sites have local study coordinators and receive per patient payment. This study was aimed to assess how these different trial management strategies affected trial performance.

Methods

Details related to obtaining ethics approval, time to trial start-up, inclusion, and percentage completed follow-ups were collected for each trial site and compared. Pre-trial screening data were compared with actual inclusion rates.

Results

Median trial start-up ranged from 41 days (P25-P75 10-139) in the Netherlands to 232 days (P25-P75 98-423) in Canada (p = 0.027). The inclusion rate was highest in the Netherlands; median 1.03 patients (P25-P75 0.43-2.21) per site per month, representing 34.4% of the total eligible population. It was lowest in Canada; 0.14 inclusions (P25-P75 0.00-0.28), representing 3.9% of eligible patients (p < 0.001). The percentage completed follow-ups was 83% for Canadian and Dutch sites and 70% for US sites (p = 0.217).

Conclusions

In this trial, a central financed trial coordinator to manage all trial related tasks in participating sites resulted in better trial progression and a similar follow-up. It is therefore a suitable alternative for appointing these tasks to local research assistants. The central coordinator approach can enable smaller regional hospitals to participate in multicenter randomized controlled trials. Circumstances such as available budget, sample size, and geographical area should however be taken into account when choosing a management strategy.

Trial Registration

ClinicalTrials.gov: NCT00761813
Opposite effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) over-expression and knockdown on colorectal liver metastases
Authors: Bandapalli Obul R , Paul Eva , Schirmacher Peter , Brand Karsten
Published: January 2012

Background

Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed.

Methods

To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect.

Results

In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden.

Conclusion

These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model.
Enhancers and silencers: an integrated and simple model for their function
Authors: Kolovos Petros , Knoch Tobias A , Grosveld Frank G , Cook Peter R , Papantonis Argyris
Published: January 2012

Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function is proposed. All are transcription units that tether their target promoters close to, or distant from, transcriptional hot spots (or 'factories').
Effect of prostaglandin E2 injection on the structural properties of the rat patellar tendon
Authors: Ferry Scott T , Afshari Hessam M , Lee Justin A , Dahners Laurence E , Weinhold Paul S
Published: January 2012

Background

Increased tendon production of the inflammatory mediator prostaglandin E2 (PGE2) has been suggested to be a potential etiologic agent in the development of tendinopathy. Repeated injection of PGE2 into tendon has been proposed as a potential animal model for studying treatments for tendinopathy. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit PGE2 production and are commonly prescribed in treating tendinopathy have been shown to impair the healing of tendon after acute injury in animal models. The contradictory literature suggests the need to better define the functional effects of PGE2 on tendon. Our objective was to characterize the effects of PGE2 injection on the biomechanical and biochemical properties of tendon and the activity of the animals. Our hypothesis was that weekly PGE2 injection to the rat patellar tendon would lead to inferior biomechanical properties.

Methods

Forty rats were divided equally into four groups. Three groups were followed for 4 weeks with the following peritendinous injection procedures: No injection (control), 4 weekly injections of saline (saline), 4 weekly injections of 800 ng PGE2 (PGE2-4 wks). The fourth group received 4 weekly injections of 800 ng PGE2 initially and was followed for a total of 8 weeks. All animals were injected bilaterally. The main outcome measurements included: the structural and material properties of the patellar tendon under tensile loading to failure, tendon collagen content, and weekly animal activity scores.

Results

The ultimate load of PGE2-4 wks tendons at 4 weeks was significantly greater than control or saline group tendons. The stiffness and elastic modulus of the PGE2 injected tendons at 8 weeks was significantly greater than the control or saline tendons. No differences in animal activity, collagen content, or mean fibril diameter were observed between groups.

Conclusions

Four weekly peritendinous injections of PGE2 to the rat patellar tendon were not found to be an effective model of clinical tendinopathy. In contrast, improved structural and material properties of the patellar tendon were found after PGE2 injection. While PGE2 has been thought to have a contributory role in the development of tendinopathy and anti-inflammatory medications remain a common treatment, our results suggest a positive role of PGE2 in tendon remodeling in some circumstances.
Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer
Authors: Munster Pamela N. , Moore Amy P. , Ismail-Khan Roohi , Cox Charles E. , Lacevic Mensura , Gross-King Margaret , Xu Ping , Carter W. Bradford , Minton Susan E.
Published: January 2012

Purpose

Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.

Patients and Methods

Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.

Results

Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.

Conclusion

When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.
Intersection Cuts with Infinite Split Rank
Authors: Basu Amitabh , Cornuéjols Gérard , Margot François
Published: January 2012

We consider mixed-integer linear programs where free integer variables are expressed in terms of nonnegative continuous variables. When this model only has two integer variables, Dey and Louveaux characterized the intersection cuts that have infinite split rank. We show that, for any number of integer variables, the split rank of an intersection cut generated from a rational lattice-free polytope L is finite if and only if the integer points on the boundary of L satisfy a certain “2-hyperplane property.” The Dey–Louveaux characterization is a consequence of this more general result.
Selenium compounds in selenium-enriched cabbage
Authors: Mechora Špela , Germ Mateja , Stibilj Vekoslava
Published: January 2012

For the study, cabbage (Brassica oleracea var. capitata L.) and red cabbage (Brassica oleracea var. capitata L. f. rubra) were treated with Na selenate. Cabbage was foliarly sprayed twice with 20 mg Se(VI) L–1, while red cabbage was fertilized twice with 0.5 mg Se(VI) L–1. Despite the high dose of Se, no toxic effects were observed on cabbage plants. The total Se concentration in cabbage leaves was 4.80 ± 0.25 μg Se g–1 (DM) and in red cabbage 0.96 ± 0.04 μg Se g–1 (DM). Soluble Se compounds were extracted from parts of cabbage with protease XIV, resulting in 49 % of soluble Se from roots, 59 % from leaves, and 65 % from stems. In red cabbage, the corresponding figures were 28 % of soluble Se in roots, 31 % in stems, and 43 % in leaves. Se species were determined in the enzymatic extracts using ion exchange high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). The main Se species found in all parts of cabbage and red cabbage was selenomethionine (SeMet), which in roots represented 94 and 55 % of the soluble Se content in cabbage and red cabbage, respectively. In stems and leaves of cabbage, SeMet represented only 23 % of the soluble Se content. In stems of red cabbage SeMet represented 80 % and in leaves 41 % of the soluble Se content. We observed that traces of Se(VI) were present in upper parts of both plants.
Determination of inorganic arsenic in seafood: Emphasizing the need for certified reference materials
Authors: Pétursdóttir Ásta Heiðrún , Gunnlaugsdóttir Helga , Jörundsdóttir Hrönn , Raab Andrea , Krupp Eva M. , Feldmann Jörg
Published: January 2012

To evaluate the accuracy and robustness of an extraction method, utilizing an -alkaline-ethanolic solution and microwave heating, the certified reference material (CRM) TORT-2 was subjected to three different instrumental methodologies: high-performance liquid chromatography (HPLC), coupled with and without post-column hydride generation; inductively coupled plasma-mass spectrometry (ICP-MS); and HPLC-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The three methods gave a consistent value of inorganic arsenic (As) which is near the mean value of the reported values in the literature, which, however, range by a factor of 10. Inorganic As, defined here as all As species that do not have an As–C bond, that is, the sum of arsenite and arsenate and any thiol-bound As, was found to be less than 4 % of total As concentration in 12 samples of fish meal when subjected to this extraction method followed by HPLC-ICP-MS. To date, there is no certified value of inorganic As in a seafood-based reference material to compare to in order to validate the findings. This illustrates the difficulties in quantitative determination of inorganic As in seafood and the need for a reference material for inorganic As and proficiency tests in order to introduce legislation for a maximum level of inorganic As in seafood and feed.
Synthesis, quality control and biological evaluation of tris[(1,10-phenanthroline)[153Sm]samarium(III)]trithiocyanate complex as a therapeutic agent
Authors: Naseri Zohreh , Hakimi Amir , Jalilian A. R. , Nemati Kharat A. , Shirvani-Arani Simindokht , Bahrami-Samani A. , Ghannadi-Maragheh M.
Published: January 2012

Therapeutic radiopharmaceuticals are designed to deliver high doses of radiation to selected target organs or tissues with an aim of minimizing unwanted radiation to surrounding healthy tissue. In this work, [tris(1,10-phenanthroline) [153Sm]samarium(III)]trithiocyanate (153Sm-TPTTC) was developed for possible therapeutic properties. The cold compound, i.e.
natSm-TPTTC was prepared and characterized by IR, UV, mass and 1H-NMR spectroscopy. 153Sm-TPTTC was prepared in two steps using [153Sm]SmCl3, obtained by neutron activation of an enriched 152Sm sample. Stability tests, partition coefficient determination, toxicity tests and biodistribution studies of the complex in wild-type and fibrosarcoma-bearing mice were determined. The radiolabeled complex was prepared in high radiochemical purity (> 99% precipitation method) and specific activity of 278 GBq/mmol and demonstrated significant stability at 4, 25 and 37 ºC (in presence of human serum). Initial complex biodistribution data showed significant liver accumulation in wild-type mice and significant tumor accumulation in fibrosarcoma-bearing mice with tumor:blood and tumor:muscle ratios of 3.55 (2 h) and 38.26 (96 h) respectively. 153Sm-TPTTC properties suggest an efficient tumor targeting agent with high tumor-avidity. Further investigation on the therapeutic properties must be conducted.
Coprecipitation of europium with barium sulphate
Authors: Bouhlassa S. , Salhamen F.
Published: January 2012

The distribution behaviour of the trivalent europium ion at a micro-component scale, between barium sulphate and aqueous solution, was studied at ambient temperature. Experiments were carried out using radioactive tracers. Results indicate an enrichment of the micro component in the solid phase relative to the solution. The effects of the concentrations of the micro and macro-elements on the coprecipitation have been examined. Europium distribution coefficient D
Eu increases from 1.1 ± 0.2 to 3.2 ± 0.4 when initial europium concentration decreases from more than 17 × 10−5 to 1.4 × 10−5 M, in sulphuric media with SO4
2− in excess or C
Ba2+
/C
SO4
2−
< 1. The excess of barium in opposite, results in a decreasing D
Eu. The coprecipitation of europium with barium sulphate as a heterovalent solid-solution is described by heterogeneous model obeying the Doerner and Hoskins logarithmic partition law. The weaker partition coefficients lower than unity (λ = 0.25 when C
Eu(III) ≈ 1.4 × 10−5 M and λ = 0.13 when C
Ba2+
/CSO4
2−
< 1 and 17.8 × 10−5 ≤ C
Eu(III) ≤ 153.5 × 10−5 M) lead to crystals increasingly enriched in the trace element.
Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics
Authors: Ghani Mahdi , Pinto Dalila , Lee Joseph H , Grinberg Yakov , Sato Christine , Moreno Danielle , Scherer Stephen W , Mayeux Richard , St. George-Hyslop Peter , Rogaeva Ekaterina
Published: January 2012

Recently genome-wide association studies have identified significant association between Alzheimer’s disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (>100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a ∼470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs.
Use of Cumulative Poisson Probability Distribution as an Estimator of the Recombination Rate in an Expanding Population: Example of theMacaca fascicularisMajor Histocompatibility Complex
Authors: Blancher Antoine , Aarnink Alice , Savy Nicolas , Takahata Naoyuki
Published: January 2012

We describe a method to estimate the rate of recombination per generation from the genotypes of a large individual sample of an expanding population, for which the founding event is dated. The approach is illustrated with an application to estimating the major histocompatibility complex (MHC) recombination rate in the Mauritian macaque population. We genotyped 750 macaques by means of 17 microsatellites across the MHC region and reconstructed the seven most frequent haplotypes assumed to represent the founding haplotypes (Hrec(0)) as well as the 31% recombinant haplotypes (Hrec(h)) resulting from a variable number “h” of recombinations between the founding haplotypes. The relative frequencies of the various classes of haplotypes (Hrec(0) and Hrec(h)) follow a Poisson distribution. By using a maximum likelihood method, we calculated the mean of the Poisson distribution that best fits the data. By dividing this mean by the number of generations (50−100) from the date of the population founding, we deduced that rate of recombination in the MHC is approximately 0.004 to 0.008 in the Mauritian macaque population. When the founding date of the population is precisely known, our method presents a useful alternative to the coalescent method.
Natural Genetic Variation for Growth and Development Revealed by High-Throughput Phenotyping inArabidopsis thaliana
Authors: Zhang Xu , Hause Ronald J , Borevitz Justin O
Published: January 2012

Leaf growth and development determines a plant’s capacity for photosynthesis and carbon fixation. These morphological traits are the integration of genetic and environmental factors through time. Yet fine dissection of the developmental genetic basis of leaf expansion throughout a growing season is difficult, due to the complexity of the trait and the need for real time measurement. In this study, we developed a time-lapse image analysis approach, which traces leaf expansion under seasonal light variation. Three growth traits, rosette leaf area, circular area, and their ratio as compactness, were measured and normalized on a linear timescale to control for developmental heterogeneity. We found high heritability for all growth traits that changed over time. Our study highlights a cost-effective, high-throughput phenotyping approach that facilitates the dissection of genetic basis of plant shoot growth and development under dynamic environmental conditions.
Linkage and Physical Mapping of Sex Region on LG23 of Nile Tilapia (Oreochromis niloticus)
Authors: Eshel O , Shirak A , Weller J I , Hulata G , Ron M
Published: January 2012

Evidence supports that sex determination (SD) in tilapia is controlled by major genetic factors that may interact with minor genetic as well as environmental factors, thus implying that SD should be analyzed as a quantitative trait. Quantitative trait loci (QTL) for SD in Oreochromis niloticus were previously detected on linkage groups (LG) 1 and 23. Twenty-one short single repeats (SSR) of >12 TGs and one single nucleotide polymorphism were identified using the unpublished tilapia genome sequence on LG23. All markers showed two segregating alleles in a mapping family that was obtained by a cross between O. niloticus male (XY) and sex-reversed female (ΔXY) yielding 29 females (XX) and 61 males (XY and YY). Interval mapping analysis mapped the QTL peak between SSR markers ARO172 and ARO177 with a maximum F value of 78.7 (P < 7.6 × 10−14). Twelve adjacent markers found in this region were homozygous in females and either homozygous for the alternative allele or heterozygous in males. This segment was defined as the sex region (SR). The SR encompasses 1.5 Mbp on a single tilapia scaffold (no. 101) harboring 51 annotated genes. Among 10 candidate genes for SD that were tested for gene expression, anti-Müllerian hormone (Amh), which is located in the center of the SR, showed the highest overexpression in male vs. female embryos at 3 to 7 days postfertilization.
Chromosome Y Regulates Survival Following Murine Coxsackievirus B3 Infection
Authors: Case Laure K , Toussaint Leon , Moussawi Mohamad , Roberts Brian , Saligrama Naresha , Brossay Laurent , Huber Sally A , Teuscher Cory
Published: January 2012

Coxsackievirus B3 (CVB3) contributes to the development of myocarditis, an inflammatory heart disease that predominates in males, and infection is a cause of unexpected death in young individuals. Although gonadal hormones contribute significantly to sex differences, sex chromosomes may also influence disease. Increasing evidence indicates that Chromosome Y (ChrY) genetic variants can impact biological functions unrelated to sexual differentiation. Using C57BL/6J (B6)-ChrY consomic mice, we show that genetic variation in ChrY has a direct effect on the survival of CVB3-infected animals. This effect is not due to potential Sry-mediated differences in prenatal testosterone exposure or to differences in adult testosterone levels. Furthermore, we show that ChrY polymorphism influences the percentage of natural killer T cells in B6-ChrY consomic strains but does not underlie CVB3-induced mortality. These data underscore the importance of investigating not only the hormonal regulation but also ChrY genetic regulation of cardiovascular disease and other male-dominant, sexually dimorphic diseases and phenotypes.
Social-Emotional Screening for Infants and Toddlers in Primary Care
Authors: Briggs Rahil D. , Stettler Erin M. , Silver Ellen Johnson , Schrag Rebecca D. A. , Nayak Meghna , Chinitz Susan , Racine Andrew D.
Published: January 2012

BACKGROUND AND OBJECTIVES:

Recommendations in pediatrics call for general developmental screening of young children; however, research suggests social-emotional development, in particular, is important as an initial indicator of general well-being versus risk. We aim to describe a program designed to identify the social-emotional status of young children in the pediatric setting by using the Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) as a universal screening tool, and to assess the effect of interventions by a colocated psychologist on changes in ASQ:SE scores over time.

METHODS:

In a prospective cohort design we analyzed scores on ASQ:SE surveys completed on children 6 to 36 months of age, to determine if children were at risk for problems in social-emotional development. The probability of remaining at risk over time was then compared between subjects receiving intervention by the psychologist, and those who declined intervention. Logit specifications were used in multivariate comparisons to control for a set of covariates.

RESULTS:

Three thousand one hundred and sixty-nine children were screened; 711 (22.4%) scored at or above the risk cutoff. Among the 711 at-risk children, 170 were rescreened. At the time of rescreening, those children who received intervention from the psychologist showed significant improvement on ASQ:SE scores compared with those who declined intervention (P = .01).

CONCLUSIONS:

Universal social-emotional screening in a busy pediatric practice is challenging. Significant percentages of children can be identified as being at risk for social-emotional problems, and colocation of a psychologist promotes the ability to effectively address young children’s social-emotional development within their medical home.
Ethanol Locks to Prevent Catheter-Related Bloodstream Infections in Parenteral Nutrition: A Meta-Analysis
Authors: Oliveira Carol , Nasr Ahmed , Brindle Mary , Wales Paul W.
Published: January 2012

OBJECTIVE:

Patients with pediatric intestinal failure (IF) depend on parenteral nutrition for growth and survival, but are at risk for complications, such as catheter-related bloodstream infections (CRBSIs). CRBSI prevention is crucial, as sepsis is an important cause of IF-associated liver disease and mortality. We aim to estimate the pooled effectiveness and safety of ethanol locks (ELs) in comparison with heparin locks (HLs) with regard to CRBSI rate and catheter replacements for pediatric IF patients with chronic parenteral nutrition dependence.

METHODS:

A systematic review without language restriction was performed on Medline (1948–2010), Embase (1980–2010), and conference programs and trial registries up to December 2010. Search terms included “Catheter-Related Infections,” “Catheter,” “Catheters, Indwelling,” “alcohol,” “ethanol,” and “lock.” Two authors identified 4 retrospective studies for the pediatric IF population. Double, independent data extraction using predefined data fields and risk of bias assessment (Newcastle-Ottawa scale) was performed.

RESULTS:

In comparison with HLs, ELs reduced the CRBSI-rate per 1000 catheter days by 7.67 events and catheter replacements by 5.07. EL therapy decreased the CRBSI rate by 81% and replacements by 72%. One hundred eight to 150 catheter days of EL exposure were necessary to prevent 1 CRBSI and 122 to 689 days of exposure avoided 1 catheter replacement. Adverse events were rare and included thrombotic events.

CONCLUSIONS:

In pediatric patients with IF, EL is a more effective alternative to HL. Adverse events include thrombotic events.