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Circulating Tumor Cells (CTCs) represent a biomarker which is also potentially involved in development of metastasis, thus their identification and characterization may bring hope for improved follow up in patients with cancer. However, despite a relevant number of studies and investments aimed to change the clinical practice and improve patients’ follow up through the use of this new marker, the clinical benefit of CTC is still under debate. A major role in this setting is played by the method used to extract CTC from blood, as we know now that CTC are not only extremely rare but also heterogeneous, including CTC with epithelial markers, with mesenchymal markers, and CTC in epithelial to mesenchymal transition (EMT) having both types of markers. Thus, it is conceivable that methods using CTC capture based on epithelial markers, such as cytokeratins (CKs) and EpCAM, may lose the most malignant mesenchymal CTCs thus decreasing the clinical value of the whole test. In this context, we have assessed two different approaches for CTC detection, one “CK-based” and the other antigen-independent “cell size-based”, according to the clinical follow up in a patient with metastatic lung cancer.
Lung cancer is a common cause of cancer death worldwide, expected to account for 26% of all female cancer deaths and 29% of all male cancer deaths (1). Despite advances in early detection and treatment, non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage and has a poor prognosis. In this context, a reliable test for counting and analysis of CTCs, believed to be crucial in cancer dissemination and metastasis, could represent a tool with prognostic and predictive significance, also providing a “liquid” biopsy for personalized anticancer therapy.
The aim of this work was to perform a kinetic study of CTCs in a patient with metastatic undifferentiated NSCLC, assessing two non-automated techniques for CTC detection according to the patient’s follow up and cancer evolution.
Materials and methods
For CTC analysis, blood samples (2×8 mL) were collected from a patient with metastatic undifferentiated NSCLC at the A.C. Camargo Cancer Hospital in São Paulo, Brazil, after written, informed consent from patient and approval by the Local Research Ethics Committee (protocol number: 1367-10). Patient clinical-pathological parameters were obtained from the medical records.
Samples were collected in EDTA tubes following time schedule shown in Table 1. After blood collection, tubes were stored at room temperature for subsequent analysis by Carcinoma Cell Enrichment and Detection kit with MACS technology (MiltenyiBiotec, BergischGladbach, Germany) within 24 hours, according to information on data sheet (Miltenyi Biotec, catalog number 030-060-101) (8 mL of blood) and by isolation by size of epithelial tumor cells (ISET) (Rarecell Diagnostics, Paris, France) according to manufacturer instructions (8 mL of blood).
CTC ENRICHMENT The Carcinoma Cell Enrichment and Detection kit with MACS technology selects CTCs by immunomagnetic separation with anti-pan CK antibody that recognizes CK 7, 8, 18 and 19, according to manufacturer procedures and methodology described by Nadal et al. (2). CTCs were defined by the following criteria: CK+ cell with high nucleo-cytoplasmic ratio and larger than leukocytes (3).
ISET methodology isolates intact CTCs from blood through direct filtration without using antibodies, thus exploiting the larger size of CTC as compared with leukocytes, and uses polycarbonate membrane with 8-μm-diameter cylindrical pores. We used procedures of this platform and CTC definition criteria according to previous detailed reports (4). Circulating tumor microemboli (CTM) were defined as groups or clusters of tumor cells containing three or more distinct nuclei and previously identified in metastatic cancer patients (5).
Images of results obtained with the two techniques were taken using a light microscope (Axioskop 40-Carl Zeiss, Germany) coupled to a digital camera (Sony Cyber-shot DSC-S75) at 100× magnification.
Both methods used here are for research use only. However, ISET underwent technical (6,7), and clinical validation (8) in particular, showing the prognostic value of ISET in patients with early and late stage Non Small Cells Lung Cancer.
Immunohistochemistry studies were feasible only on CTC isolated by ISET. ISET membrane spots were cut out and used for single or dual-color immunocytochemistry for CTC identification and characterization according to the manufacturer’s instructions.
To evaluate and distinguish CTCs from White Blood Cells (WBCs) contaminants, besides morphology analysis, dual-color immunocytochemistry (DAB+/Permanent Red; DakoTM) was carried out using the following antibodies: anti-CK7 (1:50; clone OV-TL 12/30, DakoTM) and anti-CD45 (1:100; clone 2B11+ PD7/26, DakoTM), a WBC surface marker; and anti-CK8 (1:50; clone NCL-L-CK8-TS1, NovocastraTM). A dual-color immunocytochemistry approach was also used to evaluate EMT on CTCs. The antibodies used were anti- Pan CK (1:1,000; clone AE1/AE3, Dako), anti-E-cadherin (1:100; clone 36, BD Bioscience) and anti-vimentin (1:1,500; clone V9, Dako).
Single immunocytochemistry (DAB+/DakoTM) was performed to evaluate N-Cadherin expression (1:50; clone 6G11; DakoTM), a marker of EMT and CD34 expression, a marker of endothelial cells (1:100; clone QBEnd 10, DakoTM).
These tests were performed at baseline blood collection (before first cycle of chemotherapy) and before the third cycle of chemotherapy. For CTCs counting, eight spots were used (corresponding to 8 mL of blood) including 4 stained with hematoxylin-eosin and the others stained by ICC as described by Krebs et al. (7).
A 68-year-old woman presented in August 2012 with a history of persistent chest pain in the right hemithorax and a lump measuring about 3 cm in the right inframammary region.
Computed Tomography (CT) scan of the chest showed a cavitated mass approximately 8.7 cm × 7 cm, in the right lower lung lobe, with pleural effusion and nodular thickening in the mid-basal portion of the pleura, and infiltration of 6th right anterior rib. Furthermore, enlarged paratracheal and infracarinal lymph nodes (approximately 1.6 cm), paraseptal and centrilobular emphysema as well as basal ground-glass opacities were found.
Subsequently, a biopsy of the chest wall was carried out and revealed undifferentiated NSCLC. Immunostaining was positive for Pan CK AE1/AE3, CK7 and p63 (focally) and negative for CK20, TTF-1, calretinin, napsin A, CD31, CD34, S-100 and FLI-1. Positron emission tomography-CT (PET-CT) revealed stage IV disease (T4, N2, M1; metastasis in non-regional lymph nodes). It showed paratracheal, fracarinal and periesofagic lymphadenopathy.
Concerning the blood samples collected before the first cycle of chemotherapy (See Methods), the immunomagnetic separation (Miltenyi kit) showed 26.7 CTC/mL (total 214 in 8 mL) with high expression of CK (Figure 1); while the ISET approach showed 735/mL CTC (total estimated: 588 in 8 mL).
Carboplatin and paclitaxel treatment were initiated. After one cycle of chemotherapy, a new CTCs analysis was performed, but the blood sample for ISET was not suitable for analysis (because of coagulation due to lack of blood agitation after collection), thus we could perform the immunomagnetic separation (Miltenyi kit) method only which showed 13.7 CTC/mL (total 110 in 8 mL) with high expression of CK and morphology as in the first analysis, possibly suggesting a response to treatment. However, the number of CTCs was still high and could represent a potential minimal residual disease (9,10); Events that were observed during the time course of patient disease.
Despite the decreased number of CTC detected by Miltenyi, the imaging studies showed a progression of the disease. Figure 1A,B, shows that, although there was no significant difference in tumor size in a 4-month interval between diagnosis and the end of the third cycle of chemotherapy, a new lung lesion measuring 8 mm and pleural progression were identified, demonstrating disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST) (11). This CT scan performed after the third cycle of chemotherapy (4-month interval since the discovery of the lung disease) also revealed progression of disease to liver (multiple nodules up to 3 cm) and retroperitoneal lymph nodes.
Before the third cycle of chemotherapy, we performed another CTCs analysis using the ISET platform, as well as with the immunomagnetic Miltenyi method. The immunomagnetic separation (Miltenyi kit) showed 0.65 CTC/mL (total 5 CTC in 8 mL) with heterogeneous expression of CK and a different expression pattern than the previous analysis (Figure 1D); While the ISET approach showed 128/mL CTC (total estimated 1,024 CTC in 8 mL) which was consistent with the clinical worsening of the disease (imaging progression). CTC morphology was similar by using both methods, although the counts per 8 mL of blood collection were different, the counts by ISET being consistently higher than the counts by immunomagnetic labeling (Miltenyi).
Results obtained by ISET before the third cycle of chemotherapy also demonstrated the presence of CTM (Figure 2). These CTMs have been reported to be associated with potential advantages for CTC survival and proliferation and to be responsible for micrometastatic lesions in distant organs (12). This finding was in accordance with the patient’s disease progression. As circulating endothelial cells can be present in patients with cancer and can be isolated by ISET creating a bias in CTCs counting, we performed a staining with anti-endothelial marker (CD34). No signal was detectable with the CD34 marker on the filters obtained from the patient while the positive and negative controls were satisfactory (data not shown). We thus concluded that the counting of CTCs obtained by ISET is accurate.
Figure 3A shows cells isolated by ISET, stained with hematoxylin-eosin on the membrane, whereas panels B and C show the distinction between CTCs and WBCs which were identified by a positive red CD45 staining. However, CTCs did not present immunopositivity for specific anti-CKs labelling, showing a different pattern of protein expression as compared with the patient primary tumor that was positive for CK7 and Pan CK (clone AE1/AE3). Furthermore, this result is in accordance with low number and heterogeneous CK+ CTCs found by the immunomagnetic Milteny’s methodology.
The pattern of CKs expression observed could be explained by a partial or incomplete EMT process, in which cells lose cell-to-cell adhesion and adopt some mesenchymal features, such as expression of vimentin and N-Cadherin, related to their increasing potential of invasion (13). For this reason, immunocytochemistry for N-Cadherin was performed and a weak staining was observed in the majority of CTCs isolated by ISET before the third cycle of chemotherapy (Figure 4A,B) pointing out the presence of a CTC population with mesenchymal features. We decided to look for other markers of EMT (E-cadherin and Vimentin) both in the first (before the first cycle of chemotherapy) and third (before the third cycle of chemotherapy) blood samples which were treated by ISET. E-cadherin expression was never found while vimentin expression was observed in double-staining with pan CK. Vimentin was highly expressed in the majority of CTCs from the first blood collection (Figure 4C,D), but there were some CTCs without any expression of this marker. Vimentin was moderately expressed in all CTCs isolated from the third blood collection. On the other hand, Pan CK expression, an epithelial marker, was negative in CTC isolated by ISET (first and third blood samples).
After three cycles of ineffective chemotherapy, the patient’s disease gradually progressed and she was initiated on palliative second-line chemotherapy with pemetrexed. This evolution was in agreement with CTC results (increased number and EMT) obtained by the antigen independent CTC isolation performed using ISET but not with CTC results (decreased number) obtained by the CK-based CTC isolation performed using Miltenyi.
In the field of CTC, the issue of “CTC heterogeneity” is critical. It is well known that CTC may lose epithelial antigens and undergo EMT and that tumor cells in EMT are thought to have more “stem” characteristics including more invasive potential and self-renewal capacity (14). It is also known that tumor cells in EMT represent a relevant part of the CTC population in patients with lung cancer (7). Surprisingly, methods which only detect and count epithelial tumor cells and cannot identify CTC in EMT have been shown as having a prognostic value. In fact, Cell SearchTM analysis showed that 21% of evaluated 101 NSCLC patients were positive for CTCs (≥2 CTCs/7.5 mL blood, range, 0-149) and patients with 5 or more CTCs per 7.5 mL blood exhibited significantly worse overall survival (OS) compared to those patients with less than 5 CTCs (median OS, 4.3 versus 8.1 months respectively, P<0.001) (7). However, only 9 out of 101 patients, including 60 with metastases, had 5 or more CTCs per 7.5 mL and the mean survival time difference was of few months. Thus, practically, there is no at present clinical prognostic use of CTC enumeration, with an established cut-off level, for lung cancer patients.
In this setting, we planned to follow a single patient with metastatic lung cancer and compare CTC enumeration with both an “epithelial-antigen dependent” and an “epithelial-antigen independent” method to count CTC and analyzing the change in CTC number according to the clinical follow up. To our knowledge, this is the first study which has been designed to use clinical follow up and kinetic variation of the number of CTCs studied by two different approaches in order to obtain clues to identify the most accurate CTC method to be used in the follow up of patients with lung cancer.
Our results obtained using the “epithelial-antigen dependent” detection and counting of CTC showed a decrease in number of CTC during the disease course, suggesting a possible positive response to treatment. However, the patient’s clinical conditions worsened in paralleled. Of note is the fact that the last analysis by this technique showed CTC with different pattern of CK expression besides cells morphologically similar to CTC not expressing CK (Figure 1D).
In contrast, our results obtained using the “epithelial-antigen independent” ISET methodology, which was performed in parallel, showed an increasing number of CTC which was consistent with the observed worsening of clinical conditions and absence of response to treatment. According to previous reports using ISET we thought that these discrepancy could be related to CTC with EMT phenotype which are not detected by a technique based on CK expression, since progressive loss of epithelial and gain of mesenchymal markers are characteristics of the EMT process (14).
EMT has been associated with self-renewal and survival of CTCs with higher metastatic potential (15). Our results obtained with the ISET platform demonstrated a population of CTC with weak expression of N-Cadherin, a protein that contributes to EMT by stimulating invasive signaling in tumor cells (16). We also observed non-expression of E-cadherin in CTC collected by ISET at two different time-points. Qi et al. (17) showed N-Cadherin as a key protein in transendothelial migration of melanoma cells. In human prostate carcinoma, the overexpression of N-cadherin was associated with loss of E-cadherin and correlated with high Gleason score as well as with systemic and metastatic recurrence after surgery (18).
Hou et al. (12) demonstrated heterogeneous expression of N-Cadherin in CTC and CTM isolated by ISET platform from lung cancer patients which was described as a partial EMT phenotype. In our study, besides expression of N-Cadherin, another evidence for EMT was the fact that CTCs did not show CK7 or CK8 expression. This finding is in agreement with Krebs et al. (7) who found epithelial marker negative subpopulation of CTC isolated by ISET from chemo-naive, (stages IIIA to IV) NSCLC patients. Vimentin expression in CTC found in this study is in agreement with findings published by other authors (19), who also observed CTC expressing only vimentin or co-expressing it with keratin antigens at a very low or undetectable level in CTC from 6 patients with NSCLC. Bonnomet et al. (20) observed, using an experimental tumor model, that tumor cells in vascular tumoral emboli all expressed vimentin as also tumoral emboli in the lungs. However, macrometastases displayed heterogenous vimentin expression, as seen in the primary xenografts.
These findings strongly suggest that a relevant number of CTC in our patient were in EMT and detected by ISET but not detected by the method based on CK expression (Miltenyi).
In our study, the invasive potential of CTC was also shown by the presence of CTM detected by the ISET platform, but not by the immunomagnetic Miltenyi method. Presence of CTM in lung cancer patients was also mentioned by Hou et al. (12): ISET method showed heterogeneous expression of epithelial and mesenchymal markers in the evaluated CTM whereas Cell SearchTM technique found no evidence of CTM.
The relation between CTCs and tumor progression is supported by CTC dissemination and genetic mutations in CTC related to resistance to treatment (15). Maheswaran et al. (21) isolated CTCs from metastatic NSCLC patient carrying a resistance mutation to EGFR inhibitors, and demonstrated the presence of the mutation in pretreatment tumor-biopsy specimens which correlated with a reduced progression-free survival (7.7 vs. 16.5 months, P<0.001).
To summarize, in our case, the number of CTC detected by immunomagnetic labeling (Miltenyi) decreased and the number of CTC counted by ISET increased while the patient clinical conditions evolved to unfavorable prognosis. This may suggest that CTC in EMT were resistant to chemotherapy and continued to expand under therapy while the “epithelial” more differentiated CTC were sensitive to the therapy as their number decreased.
We concluded that the method which only identifies epithelial cells does not allow to assess the effect of the therapy and brings a CTC counting bias. At least for patients with lung cancer, counting CTC with a methodology only based on epithelial antigens and drawing conclusions on the response of patients to therapy seems unreliable.
In conclusion, by studying a single case of a patient with lung cancer and few months of survival after cancer diagnosis, we have obtained data suggesting that an unbiased enumeration of CTC taking into account their heterogeneity and variable expression of epithelial markers is more susceptible to be consistent with the clinical follow up. The method ISET for CTC detection allows to isolate CTCs independently from their expression of epithelial antigens. Our data are in agreement with previous reports (8) and suggest that ISET could provide relevant results when used for CTC counting in follow up of patients with lung cancer. More studies are now clearly needed providing validation of our data in larger clinical cohorts studies.
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for financial support.
Disclosure: The authors declare no conflict of interest.
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It’s been awhile since I have been able to get behind the camera and make a video for ya’ll. Aside from having a 4 month old keeping me on my toes, the biggest thing standing in-between me and making a video for my channel is washing my hair. I know that sounds funny, but it’s true. While a makeup-less face and greasy hair may be the reality of postpartum for many, I would prefer to at least look halfway decent in front of the camera. So, while my hair certainly wasn’t styled, and the makeup on my face a bare minimum, I thought the perfect way to take a break from studying biology and chemistry would be to make a video, so here it is (finally). If this Is your first time tuning in, be sure to check out my previous posts on Chronic Lyme & pregnancy here.
As mentioned in the video, our little girl was stubbornly breached (more like stuck), and we had a bit of a health scare with her weight and heart. However, everything seemed to resolve itself and at 39 weeks we chose to try an external cephalic version. After the procedure failed I went right into a c-section. While this was not my hope and desire, Allie was born very healthy and in the end, that is what truly matters. Fast forwarding a bit, we did have our bout with an unsuspecting tongue tie that we decided to get revised due to the severity of how it was affecting Allie’s overall wellbeing. We caught it soon enough she did not have any issue gaining weight, however, the reflux, sleep deprivation, and visible pain she was going through on the daily basis was easily enough to convince us the procedure was necessary. While laser was an option, we opted for getting it done the traditional way at our practitioner’s office due to cost and needing to get it done as soon as possible. Overall, Allie only had a slight re-adhesion and nurses much much better to this day. It was a process for her to relearn how to properly eat again, and I’ll definitely be going into more detail about our journey with a tongue tie in a separate video post. Overall, Allie is doing great and has turned into a total chunk. As of now, the only supplements that she is taking is Seeking Health’s ProBiota infant probiotic powder and Biotic’s Research vitamin-K drops. Since 3 months (So far Allie seems to be hitting most all her developmental milestones a tad early) we’ve been dealing with teething and the joy that comes with that. Again, I’d love to discuss what we’ve been doing to help her through this process in a separate post (if you’re interested in weekly updates, follow me on my instagram here)
So how is mama doing? Well, while a c-section wasn’t my preferred choice of delivery (for baby or mama if we’re being honest), however, major abdominal surgery (thanks, compressed celiac artery) is something I am very familiar with and thus I rebounded very quickly. The worst part of it all was trying to nurse a squirming baby next to my incision site. As far as surgery wise goes, I’ve been been very pro-active in releasing the scar tissue associated with my incision site. Built up scar tissue can do a myriad of negative things to your body in ways you’d never even think of (more on this in a later post). As far as my overall health goes, everything seems to be hanging in there. I check my thyroid labs every couple months (or more if desired), and everything has remained stable. I’ve continued my bartonella treatment as I did throughout pregnancy. Keeping my detox pathways open and flowing is still the most important thing for me. I do this through routine colonics, activated charcoal, infrared sauna sessions (short, as a precautionary to make sure nothing gets released into my milk supply), and coffee enemas (the caffeine didn’t affect me or Allie during pregnancy and does not affect my milk postpartum). I’d like to say my allergies and related symptoms remained as great as they were during pregnancy, but unfortunately they have slowly reappeared (thought not as bad as before). Come December I will be trying a new treatment for my allergies, which I’ll go into more detail in future posts. Overall, my body handled pregnancy quite well and seems to be handling postpartum equally as well. Of course, I have my days where I struggle to get through (as any human would), but overall I wouldn’t trade it for the world.
2 Corinthians 13:14 “May the grace of the Lord Jesus Christ, and the love of God, and the fellowship of the Holy Spirit be with you all.”

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On 5-21, 8:46 PM, Governor Run Rd., Port Republic, while assisting a motorist, Maryland State Police TFC Slifer observed Matthew Aaron Robertson, 41, of Lusby, operating a motor vehicle on a revoked license. TFC Slifer activated his lights and siren and followed the suspect to Parkers Creek Rd., where he finally stopped and exited the vehicle. When TFC Slifer approached the vehicle, he observed Leona Charlene Hearn, 37, (Robertsons wife) seated in the drivers seat, with the motor running and her hands on the steering wheel. TFC Slifer also detected the strong odor of alcohol emitting from both subjects.
While trying to place Mr. Robertson under arrest, he attempted to strike TFC Slifer. A struggle ensued and both men fell to the ground. At this time, Ms. Hearn exited the vehicle, kicked TFC Slifer, and attempted to hit him with her fist. After a 9-1-1 call by a passing motorist, several officers arrived on the scene and Mr. Robertson and Ms. Hearn were taken into custody.
Mr. Robertson was transported to CMH and treated for minor injuries he sustained in the struggle with TFC Slifer. After his release, he was transported to the CCDC for processing and to await a commissioners hearing. Mr. Robertson was charged with assault, resisting arrest, and DUI.
Ms. Hearn was charged with assault, hindering, and DUI. A secondary search of Ms. Hearn revealed a baggie of suspected marijuana on her person. She was then additionally charged with possession of marijuana. After processing, she was also transported to the CCDC to await a commissioners hearing.

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Minizag is a new compact folding electric bike available to back via Indiegogo from $599 offering the convenience of a folding bike and the power of an electric bike in a compact small form factor design. Equipped with double fork support technology together with a performance Akema torque motor together with Samsung high energy lithium batteries the electric bike can provide a range of up to 30 km and the top speed of 25 km an hour and is fully compliant with EU speed regulations.
Minizag folding electric bike features
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MiniZag Ultra only weighs 15KG, which is the limit of global electric bicycles. That’s thanks to the bodywork being mostly made of magnesium alloy materials. he proportion of aluminum is 2.8:1, and the ratio of magnesium is only 1.8:1. The weight is only 65% of the same aluminum alloy frame, making the body lighter and more portable. “
Assuming that the Minizag funding campaign successfully raises its required pledge goal and production progresses smoothly, worldwide shipping is expected to take place sometime around February 2022. To learn more about the Minizag folding electric bike project checkout the promotional video below.
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Over the past few months, the Department of Defense has been surveying service members and their families, asking them their opinions about serving with openly gay comrades. Some of the questions leaked and they were condemned by certain gay rights groups. Then, some of the results were leaked and they were lauded by certain gay rights groups. Though I have not seen an advance copy, it appears that a vast majority of surveyed service members that responded think that lifting the ban on openly gay service would either improve unit cohesion, morale and readiness or not change anything. Many do not seem to care. And, that makes sense. Many of our service members have served alongside gay comrades knowing full well who was next to them.
A word of caution, though. The full report — several hundred pages long — is likely to give fodder for arguments on both sides. Only 28% of those surveyed actually responded, so the report cannot be said to reflect the entire force. There are sizable numbers of respondents who do not want the ban lifted, and many of them are in the Marine Corp. A former marine and current instructor at Quantico explains why here.
Also, let's keep in mind what the Senate is actually doing. The Senate Armed Services Committee is holding hearings on repealing DADT as part of the 2010 Defense Re-authorization Bill. The amendment does not repeal DADT immediately. It gives the President and Secretary Gates the power to end the policy some time in the future, once the military has had sufficient time to implement repeal in an orderly fashion. So, this week, we will not see an end to DADT. We won't even see a vote. The Senate is beginning its debate. To the administration's credit, DADT discharges have stopped and military leaders have expressed their support for repeal. President Obama has pledged significant involvement in this vote and his new DADT discharge policy, together with his approach to build political support within the military, may prove to be the best approach.
When the report comes to Congress and Senator Carl Levin (D-Mich.) opens the hearings, we should expect near unanimous support for repeal from the Democratic senators on the Armed Services Committee and virulent opposition from Senator John McCain (R-Ariz.). Senator McCain's pretzel twisting and inexplicable daftness on this topic is upsetting, but not entirely unexpected. His "maverick" label was always a misnomer, hiding a highly conservative Senate voting record.
Don't Ask, Don't Tell repeal will hinge on a group of ten so-called moderate senators who are either waiting for the report or who have signaled they would vote to repeal if a full debate were allowed. Sens. Dick Lugar (R-Ind.) and Susan Collins (R-Maine) have already signaled support, while Olympia Snowe (R-Maine), John Ensign (R-Nev.), James Webb(D-Va.) and others may join repeal efforts after reading the report. There are a few wild cards out there. The newly minted Independent senator from Alaska, Lisa Murkowski, has indicated that she would not hold up the Defense Re-authorization Bill simply to keep the ban on openly gay service. Senator Mark Pryor (D-Ark.) has already signaled his opposition to repeal, but look for his erstwhile colleague, the outgoing Blanche Lincoln (D-Ark.) to vote for repeal. She has nothing to lose at this point. Scott Brown (R-Mass.), once the darling of Tea Party right, will likely vote for repeal. He is up for re-election shortly and Massachusetts is overwhelmingly in support of openly gay service. To his credit, Senator Brown is doing is best to appeal to the center of Massachusetts politics, and a vote to end DADT will go a long way to solidify that support.
That leaves us with a few new senators — Mark Kirk (R-Ill.), Joe Manchin (D.-W.Va.) — and a few old senators — George Voinovich (R-Ohio), Kit Bond (R-Mo.) and Judd Gregg (R-N.H.). The senate freshmen are wild cards: they don't have to worry about voters for six years, but both just survived brutal campaigns. Senator Kirk staked out some moderate positions during the campaign and Senator Manchin famously shot the health care bill with a shotgun. I admit that I am not sure where that leaves us with them. However, expect Senator Voinovich to vote the Bill through with a DADT repeal. He is an old-time moderate who believes that the Senate has to function well. Senator Bond is a conservative through and through, so I expect him to support Senator McCain's filibuster. Senator Gregg is a wild card. New Hampshire just elected an overwhelming majority of Republicans to its state legislature, so I am inclined to think his conservative bona fides will be burnished on this vote.
By my count, seven of those senators will vote to repeal DADT, three will support the filibuster and three are wild cards. Stay tuned…
Ari Ezra Waldman is a 2002 graduate of Harvard College and a 2005 graduate of Harvard Law School. After practicing in New York for five years and clerking at a federal appellate court in Washington, D.C., Ari is now on the faculty at California Western School of Law in San Diego, California. His areas of expertise are criminal law, criminal procedure, LGBT law and law and economics. Ari will be writing biweekly posts on law and various LGBT issues.
Follow Ari on Twitter at @ariezrawaldman.
Emerging from our Thanksgiving food comas, we sit, waiting. We wait for the Pentagon's report on "Don't Ask, Don't Tell," due out today, November 30 (one day ahead of schedule — in about an hour). And, we also wait for oral arguments in Perry v. Schwarzenegger, the Prop 8 case, on December 6. It's a big couple of days. Therefore, I'd like to take this opportunity to summarize what we might see come out of the DADT hearings. In a second post on December 6, I will discuss what might come out of the oral argument. In a follow up post, I would like to raise one compelling question that bridges these two topics together – What, if any, is the role of popular opinion in the recognition of gay rights?
Here's the briefer: The Senate Armed Services Committee will soon begin debate on repealing DADT as part of the Defense Re-authorization Bill. It has waited for this report to be released to do so. And, leaks from the report seem to indicate that most service members would either welcome open service or simply would not care. I expect repeal.
A more detailed summary, some analysis and some questions AFTER THE JUMP…


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Objective To analyse whether levels of high-sensitivity cardiac troponin (hs-cTn) below their respective 99th percentile can be used as a single parameter to rule out acute myocardial infarction (AMI) at presentation.
Design Prospective, multicentre study.
Main outcome measures We measured hs-cTn using four different methods (hs-cTnT Roche, hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting to the emergency department with acute chest pain. Two independent cardiologists adjudicated the final diagnosis. Patients were followed for death or AMI during a mean period of 24 months.
Results Among 2072 consecutive patients with hs-cTnT measurements available, 21.4% had an adjudicated diagnosis of AMI (sensitivity 89.6%, 95% CI 86.4% to 92.3%, negative predictive value (NPV): 96.5%, 95% CI 95.4% to 97.4%). Among 1180 consecutive patients with hs-cTnI Siemens measurements available, 20.0% had AMI (sensitivity 94.1%, 95% CI 90.3% to 96.7%, NPV: 98.0%, 95% CI: 96.6% to 98.9%). Among 1151 consecutive patients with hs-cTnI Beckman Coulter measurements available, 19.7% had AMI (sensitivity 92.1%, 95% CI 87.8% to 95.2%, NPV: 97.5%, 95% CI 96.0% to 98.5%). Among 1567 consecutive patients with hs-cTnI Abbott measurements available, 20.0% had AMI (sensitivity 77.2%, 95% CI 72.1% to 81.7%, NPV: 94.3%, 95% CI 92.8% to 95.5%).
Conclusions Normal hs-cTn levels at presentation should not be used as a single parameter to rule out AMI as 6%–23% of adjudicated AMI cases had normal levels of hs-cTn levels at presentation. Our data highlight the lack of standardisation among hs-cTnI assays resulting in substantial differences in sensitivity and NPV at the 99th percentile.
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Coronary artery disease (CAD) is the most common manifestation of cardiovascular disease and it is associated with high morbidity and mortality.1 There are different clinical manifestations of CAD including silent ischemia, stable angina pectoris, unstable angina pectoris, acute myocardial infarction (AMI), sudden death and heart failure.1 In Europe and in the USA, almost 15 million patients per year present to the emergency department (ED) with chest pain or other symptoms suggestive of AMI.2 As in most patients acute chest pain is caused by benign disorders and not by AMI, rapid rule out of AMI is fundamental.3 Delayed rule out of AMI increases resource use and time spent in the ED, patient anxiety and the problem of overcrowding in the ED, which itself is associated with increased mortality and morbidity.3
Since the late 1980s, when cardiac troponins (cTns) were first described as biochemical markers for cardiomyocyte damage, there have been important advances in cTn assay technology, which have led to an improvement in the clinical ability to detect and quantify cardiomyocyte damage.4 According to current guidelines, a test with a high ability to diagnose and rule out AMI has to meet two basic criteria: First, it has to detect increased cTn levels in blood that surpass the 99th percentile of cTn levels in a normal reference population, with an imprecision corresponding to ≤10% coefficient of variation (CV) at the upper reference limit.1 ,5–7 Second, a high-sensitivity assay should be able to measure in at least 50% of healthy individuals concentration levels over the assay's limit of detection (LOD) but below the 99th percentile.6 ,7 None of the earlier generation cTn assays, still in clinical use in many institutions, does fulfil these requirements.8 High-sensitivity cardiac troponin (hs-cTn) assays have a 10-fold to 100-fold lower LOD and meet the demand of analytical precision.1 This enables physicians to detect AMI earlier and more frequently in patients presenting with chest pain.2 ,7 The aim of our study was to determine whether hs-cTn values below the 99th percentile can be used as a single parameter to rule out the diagnosis of AMI at presentation.
Study design and population
Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) is an ongoing prospective, international, multicentre study coordinated and designed by the University Hospital Basel (ClinicalTrials.gov number, NCT00470587).2 Consecutive adult patients were enrolled from April 2006 to August 2011 if presenting to the ED with symptoms suggestive of AMI such as acute chest pain, angina pectoris at rest or other thoracic sensations presumably caused by myocardial ischemia with an onset or peak within the last 12 h. Patients were excluded if presenting with terminal kidney failure requiring dialysis. Patients were excluded from analysis if (1) hs-cTnT, hs-cTnI (Siemens), hs-cTnI (Beckman Coulter) or hs-cTnI (Abbott) values were not available in the respective data-files or if (2) the final diagnosis remained unclear after adjudication. All patients provided written informed consent. The study was performed according to the principles of the Declaration of Helsinki and approved by the local ethics committees.
Routine clinical assessment
The initial clinical assessment included clinical history, physical examination, 12-lead electrocardiography (ECG), continuous ECG monitoring, pulse oximetry, standard blood tests and chest radiography.2 Measurements of cTn levels were performed at presentation and 6–9 h later or as long as clinically indicated.9 Timing and treatment of patients were left to the discretion of the attending physician.
Adjudication of final diagnosis
Adjudication of final diagnosis was performed twice for all patients in the core lab (University Hospital Basel) by two independent cardiologists. In the initial analyses, the adjudication of final diagnoses was performed according to the conventional cTn levels used locally to assess the performance of hs-cTn assays.2 ,10–13 In order to also identify patients with small AMIs that were missed by the conventional assays, patients were readjudicated using hs-cTnT values in addition to the conventional cTn values.
Measurements of hs-cTn
hs-cTnT (Roche) was measured on the Elecsys 2010 analyser (Roche Diagnostics) with a LOD determined to be 5 ng/l, an imprecision corresponding to 10% CV reported at 13 ng/l and the 99th percentile of a healthy reference population at 14 ng/l.5 For this assay, normal hs-cTnT levels were defined as those below 14 ng/l and elevated levels as ≥14 ng/l. The measurements of the last 876 recruited patients (patient 1196–2072) were performed with lots that needed a revision of the calibration curve. Thus, they were corrected using non-linear regression correction.14–16
Measurement of Beckman Coulter hs-cTnI was performed on the Access 2 analyser using an investigational prototype assay with—according to the manufacturer—a LOD of 2 ng/l, a 99th percentile at 9 ng/l, with a CV of less than 10%. For this assay, normal hs-cTnI levels were defined as below 9 ng/l and elevated levels as ≥9 ng/l.
For hs-cTnI (Siemens) Dimension Vista 1500 immunoassay system was used, which has—according to the manufacturer—an LOD of 0.5 ng/l, a 99th percentile at 9 ng/l, and a CV of less than 10% at 3 ng/l.6 Normal hs-cTnI levels were defined as below 9 ng/l and elevated levels as ≥9 ng/l.
Measurement of hs-cTnI (Abbott) was performed with a final precommercial release version of the ARCHITECT High Sensitive STAT Troponin I (hsTnI) assay (Abbott Laboratories, Abbott Park, IL) with a 99th percentile concentration of 26.2 ng/l, a corresponding CV of <5% and a LOD of 1.9 ng/l.6 ,17 For this assay, normal hs-cTnI levels were defined as below 26.2 ng/l and elevated levels as ≥26.2 ng/l. Long-term stability of TnI has been demonstrated previously.18 Good correlation between plasma and serum has been demonstrated.19 Furtherinformation to the adjudication of the final diagnosis and to measurements of hs-cTn are described in the online supplementary material.
The primary endpoint was all cause-mortality and AMI rate during follow-up. Further information is described in the online supplementary material.
Categorical variables are presented as percentages and continuous variables are presented as median and interquartile range (IQR). Continuous, skewed distributed variables were compared with the Mann–Whitney U test and categorical variables were compared using the Pearson χ2-square test. Kaplan–Meier analysis was performed for the endpoint of death during follow-up and for the AMI rate during follow-up. Statistical significance was determined with the log-rank test. All hypothesis testing was two-tailed and p value<0.05 was described as statistically significant. All statistical tests were performed using SPSS for Windows 21.0 (SPSS Inc., Chicago, Illinois) and MedCalc 22.214.171.124 (MedCalc Software).
Figure 1 displays the detailed flow of patients. A total of 2245 patients consented to inclusion in this multicentre study, of whom 2072 were available for inclusion in the analysis of hs-cTnT levels, 1180 were included for analysis of hs-cTnI (Siemens), 1151 for analysis of hs-cTnI (Beckman Coulter) and 1567 for the analysis of hs-cTnI (Abbott). Table 1 provides baseline characteristics of all included patients with hs-cTnT measurements. Baseline characteristics of the patients with hs-cTnI measurements were similar to the ones with hs-cTnT (data not shown).
The diagnosis of AMI was adjudicated in 444 (21.4%) patients with hs-cTnT measurements, in 236 (20.0%) with hs-cTnI (Siemens), in 227 (19.7%) with hs-cTnI (Beckman Coulter) and in 311 (19.8%) with hs-cTnI measurments (Abbott).
At presentation, all four hs-cTn assays showed significantly higher levels in patients with AMI compared with patients without AMI. These results, the results of the second adjudication of the final diagnosis based on hs-cTn values and the results of the subgroup analysis of patients with non-ST-elevation myocardial infarction (NSTEMI) are shown in the online supplementary material.
Normal levels of hs-cTnT at presentation were measured in 63.3% of patients, 58.3% of patients presented with normal levels of hs-cTnI (Siemens), 61.8% presented with normal levels of hs-cTnI (Beckman Coulter) and 78.7% presented with normal levels of hs-cTnI (Abbott).
Normal levels of hs-cTn at presentation for rule out of AMI
In patients with hs-cTnT measurements and diagnosed AMI, 398 (89.6%) presented with elevated levels of hs-cTnT and 46 (10.4%) had normal levels at presentation. As shown in table 2, the sensitivity of hs-cTnT at the time of presentation using the conventional 99th percentile at 14 ng/l was 89.6% (95% CI 86.4% to 92.3%) and the negative predictive value (NPV) was 96.5% (95% CI 95.4% to 97.4%). In patients with hs-cTnI (Siemens) measurements at presentation and the diagnosis of AMI, 222 (94.1%) had initially elevated hs-cTnI levels (≥9 ng/l) and 14 (5.9%) showed normal levels, resulting in a sensitivity of 94.1% (95% CI 90.3% to 96.7%) and a NPV of 98.0% (95% CI 96.6% to 98.9%). In patients with hs-cTnI measurements (Beckman Coulter) at presentation and diagnosed AMI, 209 (92.1%) showed initially elevated hs-cTnI levels (≥9 ng/l) and 18 patients (7.9%) had normal levels. Thus, the sensitivity for AMI with this assay was 92.1% (95% CI 87.8% to 95.2%) and the NPV was 97.5% (95% CI 96.0% to 98.5%). In patients with hs-cTnI (Abbott) measurements at presentation and the diagnosis of AMI, 240 (77.2%) had initially elevated hs-cTnI levels (≥26.2 ng/l) and 71 (22.8%) showed normal levels, resulting in a sensitivity of 77.2% (95% CI 72.1% to 81.7%) and a NPV of 94.3% (95% CI 92.8% to 95.5%).
All four hs-cTn assays showed their highest sensitivity and their highest NPV in patients presenting after 6 h from symptom onset (Roche, n=999; Siemens, n=572; Beckman Coulter, n=561; Abbott, n=775). Further details of patients presenting after 6 h and the results of subgroup analysis of patients with measurements available for all four hs-cTn assays are described in the online supplementary material.
The majority (60.9%, 28 of 46) of patients with AMI who had normal levels of hs-cTnT at presentation were early presenters (<3 h from symptom onset). As shown in table 2, early presenters showed lower values in sensitivity for the cut-off value 14 ng/l (73.8%, 95% CI 64.5% to 81.9%) and in NPV (92.3%, 95% CI 89.0% to 94.8%) compared to late presenters (≥3 h). There sensitivity is 94.7% (95% CI 91.7% to 96.8%) and NPV is 98.1% (95% CI 97.0% to 98.9%).
Death and AMI rate during the follow-up period
As outlined in figure 2 and figure 3, during the first 30 days of follow-up, mortality rate and AMI rate were significantly higher in patients with elevated hs-cTn at presentation than in patients with normal hs-cTn at presentation. Further details are described in the online supplementary material.
We performed a prospective, international, multicentre study enrolling unselected patients presenting to the ED with acute chest pain. The aim of this analysis was to evaluate four different hs-cTn assays and to assess whether hs-cTn values below their respective 99th percentile can be used as a single parameter to rule out the diagnosis of AMI at presentation. We report five major findings:
First, the percentage of AMI patients having normal levels of hs-cTn at presentation varied substantially among the four different hs-cTn assays used and ranged from 6% to 23%. These differences among hs-cTn assays may be related to analytical details of the specific assays, differences among the reference population chosen to define the respective 99th percentiles of each assay as well as potential pathophysiological differences including release kinetics between cTnT and cTnI. The incidence of normal hs-cTn levels in this cohort of unselected acute chest pain patients was similar as the incidence reported in the previous studies recruiting unselected patients.2 ,7 ,20 Second, the vast majority of patients with acute chest pain and normal levels of hs-cTn did not have an AMI. The NPV of the hs-cTn assays examined for normal levels of hs-cTn ranged from 94% to 98%. Third, for all four assays, sensitivity and NPV were higher in patients presenting after 6 h from symptom onset. These results indicate that the rule out of AMI could possibly be performed with a single hs-cTn measurement in conjunction with the 12-lead ECG and a full clinical assessment in patients presenting within 6 h from symptom onset. However, all four assays showed a lower sensitivity in patients presenting within 3 h from symptom onset. This observation confirmed the time-dependent release of cTn from the injured myocardium. It also highlights the need for particular caution regarding the rule out of AMI with hs-cTn in early presenters, especially regarding the high difference in sensitivity of hs-cTnI assays in early presenters. Fourth, differences in NPV and PPV at the 99th percentile among the different hs-cTnI assays were substantial and did not seem to be adequately explained by differences in assay sensitivities. We consider the lack of standardisation, including the use of different reference populations to define the respective 99th percentiles, the most likely explanation for these substantial differences among hs-cTnI assays.21 For example, more than three times as many patients with AMI had hs-cTnI levels in the normal range with the Abbott assay as compared with the Siemens or Beckman Coulter assay.
One of the basic criteria that must be met to diagnose AMI is the detection of a rise and/or fall of cTn that surpass the 99th percentile of cTn levels in a normal reference population.1 ,22 As there is no universally accepted standard of the composition of the reference population that results in important differences in age as well as work-up performed in order to ensure that the healthy reference population is really healthy, most of 99th percentile values reported by manufacturers and in the literature are deduced from different study populations.21 For the hs-cTn assays used in our analysis the 99th percentiles range from 9 to 26.2 ng/l. In case of hs-cTnI (Abbott), choosing a higher 99th percentile resulted in a higher specificity and PPV at the 99th percentile, with the cost of having the highest percentage of patients with AMI and ‘normal’ levels of hs-cTnI at presentation, and therefore, lowest values for sensitivity and NPV.
Fifth, during 30 days follow-up, mortality rate was 17 times higher in patients with elevated hs-cTnT at presentation than in patients with normal hs-cTnT at presentation. Mortality in patients with elevated measurements of hs-cTnI was about 10 times higher than in patients with normal levels. Similarly, the rate of AMI during 30 days follow-up was significantly higher in patients with elevated hs-cTn levels compared to patients with normal hs-cTn levels at presentation, irrespective of the hs-cTn assay used. Our results support previous findings, which showed that the implementation of hs-cTn assays identifies patients at high risk of death or recurrent AMI.23 ,24
A test with a high ability to rule out ACS, that is, a test with a high NPV is of paramount importance for clinicians because it improves the diagnostic triage and facilitates discharge from the ED.1 ,25 Results from two multicentre studies, in which the conventional 4th generation cTnT assay was compared with sensitive and hs-cTn assays, showed that the diagnostic accuracy of the new hs-cTn assays is significantly higher compared with the standard assays, especially in early presenters.2 ,20 One of them, Keller et al, reported a NPV of 84.1% for a single sensitive troponin I assay, when measured in patients presenting within 3 h of chest pain onset.20 Recently, the same study group presented data about hs-cTnI measurements at admission and reported a NPV of 94.7% and a sensitivity of 82.3%.7 Our results support these findings, as all four hs-cTn assays showed comparable NPVs.
One of the particular strengths of this analysis is the adjudication of the final diagnosis using hs-cTnT levels in conjunction with all other information becoming available during work-up. This also allows the accurate detection of small AMIs, which might have been missed in previous studies that relied on conventional cTn levels for the adjudication. Thereby, this analysis extends and corroborates recent findings regarding the utility of normal hs-cTnT levels and the diagnosis of an acute coronary syndrome (AMI and unstable angina) in general.13
Our findings may help to highlight that hs-cTn values should only be used in conjunction with the 12-lead ECG and full clinical assessment. Although normal hs-cTn levels at presentation argue in favour of a diagnosis other than AMI and are associated with a very low risk of death and AMI during follow-up, other clinical information including the second hs-cTn level obtained after 3–6 h—especially in early presenters—have a critical role to definitely rule out AMI as the index event.1
Several potential limitations of this study should be mentioned. First, we assessed the performance of normal levels of four different hs-cTn assays. Although we obtained consistent results in all four assays and consequently suppose that it can be generalised to all hs-cTn assays, further studies need to confirm this assumption. Second, we cannot comment on patients with terminal kidney failure requiring dialysis as these patients were excluded from analysis. Third, as it is a prospective, observational study, we cannot determine the exact clinical benefit associated with risk stratification and improved diagnosis. Fourth, we underlined that one of the strengths of our study was the adjudication of diagnosis using the values of hs-cTnT. Although it could theoretically bias a direct comparison of the diagnostic accuracy of hs-cTnT versus hs-cTnI, we do not expect an alteration of the key message of our study.
Among consecutive patients with acute chest pain, depending on the hs-cTn assay used, 6% to 23% of adjudicated AMI cases had normal levels of hs-cTn levels at presentation. Therefore, although the majority of acute chest pain patients with normal levels of hs-cTn will be found to have causes other than AMI, normal hs-cTn levels at presentation should not be used as a single parameter to rule out AMI. This caveat applies particularly to early presenters. In addition, our data highlight the lack of standardisation among hs-cTnI assays resulting in substantial differences in NPV and PPV at the 99th percentile.
We are indebted to the patients who took part in the trial, to the ED staff, the laboratory technicians, and in particular to Irina Klimmeck, Melanie Wieland, Esther Garrido, Kirsten Hochholzer, Janine Voegele, Ina-Maria Ferel and Fausta Chiaverio for their most valuable support. We also thank Pascal Benkert for his advices in statistics.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
RH and MRG have contributed equally and should be considered first author.
Contributors Guarantors: RH, CM. Study concept, design and supervision: CM. Conduct of the study: all authors. Analysis and interpretation of data: RH, MR, CM. Drafting of the manuscript: RH, MR, CM. Critical revision of the manuscript for important intellectual content and approvement of the final version of the manuscript: all authors.
Funding This work was supported by the Swiss National Science Foundation, the Swiss Heart Foundation, 8sense, Abbott, Brahms, Nanosphere, Roche, Siemens, and the Department of Internal Medicine of the University Hospital Basel.
Competing interests Prof. Mueller has received research grants from the Swiss National Science Foundation [PP00B-102853] and the Swiss Heart Foundation, the Stiftung für kardiovaskuläre Forschung Basel, 8sense, Abbott, ALERE, Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, and the Department of Internal Medicine, of the University Hospital Basel, as well as speaker honoraria from Abbott, ALERE, Brahms, Novartis, Roche, and Siemens. All other authors declare that they have no conflict of interest with this study. The hs-cTn assays were donated by their respective manufacturers. The funding sources were not involved in the design of the trial, the gathering, analysis and interpretation of data, the writing of the manuscript or the decision to publish the paper.
Patient consent Obtained.
Ethics approval Swissethics.
Provenance and peer review Not commissioned; externally peer reviewed.


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What is time Chain?The time chain is a simple device, yet it plays an essential role in the role of her car’s engine. A timing chain is an upgraded version of a time belt, and also it’s helpful to think that it like the belt the holds your pants up. That looks nondescript, but if you take it it off, everything falls apart.So, here’s exactly how it works. Her car’s crankshaft is linked directly come the pistons. It provides the power created by the engine to revolve the car’s wheels. The camshaft (or camshafts), ~ above the various other hand, is responsible for opening and also closing the intake and exhaust valves. This valves manage the flow of waiting (and sometimes fuel) right into the cylinders and permit exhaust gases to exit.It’s critical that the crankshaft and camshaft have actually their timing down right, so that the valves open and close at the appropriate time. Otherwise, the air and also fuel won’t enter the combustion chamber at the correct time, and the operation will fail.So, that’s where the timing chain comes into play. The time chain connects the crankshaft come the camshaft, ensuring that the whole system is synchronized. The valves open and also close at the right time, the cylinders obtain the air and also gasoline that they need, and also everyone is happy.Until the time chain fails, which can happen over time. Then nobody is happy, and also the chain will need to be replaced. That said, timing chains are very durable, and also designed to critical the full lifetime of her car.
symptoms of a failing time Chain
inspect engine warning light comes onOtherwise recognized as the pesky tiny light that you choose to pretend doesn’t exist.Look, I get that ignorance is bliss and also all, yet the inspect engine warning irradiate exists to, well, warn you once something is off with your engine.A time chain the is start to failure will result in one engine that isn’t running fairly right, and that will create the inspect engine warning light.
If you urge on ignoring warning lights, have the right to you at the very least admit the weird noises coming from your vehicle are necessary warning indications that do not do it be ignored?A timing chain the is loose or damaged will often make a whirring or rattling noise. Noises space your auto trying come tell friend something. Be a good friend and listen.
poor engine performance
once the crankshaft and also camshaft aren’t appropriately synchronized, the engine will endure incomplete combustion. That will certainly make the motor run a tiny funny, and also you’ll feel it in your appropriate foot. Acceleration may hesitate, and the auto may stutter. Girlfriend may find yourself without as lot power together you’re typically accustomed to, and it may be because of a funky time chain.
Engine won’t operation
i shouldn’t have to tell girlfriend this, but if her engine won’t run, it’s frequently a sign that other is wrong v your car. And also by “often” I median “always.”If the timing chain snaps, the crankshaft and camshafts i will not ~ be synchronized. When that happens, the engine merely won’t run at all.Not ideal, if you’re trying to, girlfriend know, drive somewhere.gain a Quote
1-Year | 12,000-Mile vouch
exactly how urgent is a timing Chain replacement?Well, let’s start with the obvious. If your car’s engine won’t run, climate a timing chain instead of is nice urgent, assuming you desire to actually use your car.
But if your vehicle does run…well, that still very urgent. If the timing chain breaks, that can reason the valves to call the pistons, result in comprehensive engine damage. So, ns think you recognize the price here. Obtain it changed as quickly as possible.
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HP Integrity rx6600
HP Integrity rx6600 servers offer support for four operating systems: HP UX; Windows Server; Linux; and OpenVMS. Integrity rx6600 servers support up to four 64-bit Itanium 2 dual core processors and up to 384GB system memory. Integrity rx6600s from Global IT are affordable and versatile server platforms, offering a choice of six different dual core processors, up to sixteen 2.5″ SAS hard disk drives, a choice of PCI-X or PCIe I/O technologies, and a second hot-swap power supply affording N+1 redundancy. HP Integrity rx6600 servers are easy to manage, featuring built in Integrity Lights Out 2 Management Processor and HP Systems Insight Manager tools. Integrity rx6600s from Global IT are completely refurbished, rigorously tested, and configured to meet your specifications.


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Phew! That was a close one!
Former flames Nicholas Hoult and Jennifer Lawrence barely missed running into each other on the Met Gala red carpet last night.
Or maybe they did that on purpose so they could have another super secret rendezvous afterwards? We hope so!
Whatever the case may be, we DO know the Warm Bodies actor looked absolutely scrumptious in his electric blue Tom Ford suit jacket, which he paired with a large black bowtie and black trousers.
That color really brings out those baby blues, doesn't it?
We'd say J-Law would be a fool for turning this piece of meat down, but then again, she is the hottest actress in town and can get whomever she wants!
[Image via Getty Images.]
Tags: jennifer lawrence, met gala, met gala 2013, nicholas hoult, red carpet, tom ford

domain: celebrity


AKRON, Ohio - A former police captain accused of altering payroll documents to increase her pay by $21,194 intends to make restitution, case lawyers said.
Elizabeth Wright, who managed the midnight shift, resigned Jan. 2. She is charged with grand theft, tampering with evidence and theft in office. Prosecutors accuse her of changing records to show she was working when she did not.
Wright, 48, pleaded not guilty Tuesday and remained free on a $10,000 signature bond. Summit County Common Pleas Judge Patricia Cosgrove set her trial for June 15.
Mary Ann Kovach, chief of the Summit County prosecutor's criminal division, said on Wednesday that she expects Wright to change her plea. Whether the case goes to trial will depend on if Wright makes restitution, Kovach said.
Wright earned about $74,000 a year as police captain. Her lawyer, Don Malarcik, said Wright has agreed to cooperate with the investigation and has asked for time to arrange paying back what she allegedly owes.


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Indianapolis, INÂ â€“ Westward Road is celebrating the debut of their new music video, â€œGonna Take a Ride.â€ This song is the title track on their current album, and was rearranged and recorded for their newest project,Â Amen Like Thunderat Chapel Valley on their Sanctuary Label. â€œGonna Take a Rideâ€ is a fun and energetic song celebrating that grand homecoming day when we will see our loved ones again and meet our Savior face-to-face. Westward Road thanks those who sent pictures of their loved ones to be a part of the video. â€œWe hope that in some way, we were able to honor their memories,â€ shared Scott Roberts.
Westward road is comprised of Scott and Kelli Roberts, along with their son, Garrett. They have traveled as a family, singing at revivals, concerts and special events since 2014. There is something special about family harmony. Scott writes and arranges many of the songs they sing, and that gives them a unique southern gospel sound with a country flair. Garrett stated, â€œI really enjoy traveling and singing with my family. It is always a great adventure, and I love seeing people dedicate their lives to Christ when we sing.â€
â€œOur prayer is that our songs, our testimonies, and our lives embody the only true and lasting hope for the world, the hope of Christ, and that we will always be faithful in sharing it with everyone we meet,â€ shared Scott. Spoken from a music ministerâ€™s heart, that perfectly describes what Westward Road is all about!
Visit Westward Roadâ€™s website to learn more.
Media contact:Â Â Marcie Gray

domain: artistic


I've reloaded for a few years but recently began working towards maximizing accuracy in several rifles. As part of this effort I recently rotated out all of my old and mixed 7mmRem Mag brass and bought brand new Winchester brass for it. I've weighed each casing and sorted them accordingly, and will be shooting through a chronograph.
In order to get a tight chamber fit in my Ruger M77, I partial resize instead of full-length resizing. But of course partial resizing unfired brass is pointless so...
My question is this: Should I load up some cheap bullets in the all of the new brass and once-fire it before I begin working up test loads with it? My intuition tells me that since the case volume will be slightly larger and chamber fit will be slightly tighter, that might have an effect on the best bullet/powder/powder volume combination. Is it likely that the best load with fired and partially resized brass will be different than the best load with new brass? Or will the difference be so small that the best load will rise to the top regardless, in which case loading and firing 50 rounds beforehand would be pointless.
Anybody have any experience to share concerning the difference in loads or accuracy between once-fired brass vs. new brass?


Simulations in parallel
iGas Technologies is an engineering company whose main profile is connected to the vehicle industry. They design and build electric car chargers with a focus on supplying international markets. iGas Technologies provides its product to customers who want to charge his/ her electric car autonomously or want to provide this privilege to their customers in a fast, easy, and beneficial way
The team at iGas Technologies discovered a problem with one of their products. There was too much heat being created within the device, having too great an influence on the secure workings. In order to solve this problem, the team designed a cooling system that needed to be tested prior to being manufactured. The company needed to know whether or not the system would work in their products before physical prototyping, or if more design iterations were needed.
What we wanted to see the exact numbers depending on the simulated parts and compare them with our calculations and standards. All in all, we wanted to see if we could make our solution work and that it was the simplest it could be.
The team wanted to find a simulation software that didn’t restrict them. Yet, they did not have enough computing power in-house to have a localized simulation platform. With SimScale, lack of computing power wasn’t an issue, as processing takes place in the cloud. Moreover, SimScale is easily accessible from any web browser, giving iGas Technologies access to it anywhere. The team expected that cloud-based simulation would decrease the design and development time per product, ultimately saving costs.
The team was met with a small learning curve at the beginning of their SimScale experience but quickly overcame it. They first needed to test how the meshing worked within SimScale, and how to input the proper parameters for their needs. When they began using the platform initially, they were able to start simulations almost instantly and quickly learn from the results. They also found with the many configurations, settings, and simulation preferences that if someone gets the time, he or she can make a very precise simulation.
iGas Technologies designed a cooling system consisting of 2 heat sinks and two Peltier modules. The simulation was divided into 2 parts; inner heat sink and outer heat sink. They wanted to see if the ‘product box’ reached 60 °C, how much heat was transported to the outer side, and how much the temperature dropped. The workflow for their investigation followed the flow chart depicted below:
The team started with a base calculation, which included what values were in the ‘box’ and what values they wanted to achieve, etc. After selecting the appropriate heatsink and Peltier module, the CAD was created in SolidWorks and then uploaded to SimScale.
The mesh was then created using default settings, except changing the finess to ‘moderate.’ When it came time to pick an analysis type, ‘convective heat transfer’ and ‘conjugate heat transfer’ were used. ‘Convective heat transfer’ was utilized to see how the heat “spread” in the heatsink and the heatsink fins, and ‘conjugate heat transfer’ was used to see how the temperature changed between the Peltier module and the heatsink.
In the beginning, the team needed help meshing with SimScale, and found the support team of application engineers very helpful.
“Anytime we had a problem or didn’t know what to do, we wrote to support via the chat panel. In a short time we got back the answer and started to work through the problem together.”
The iGas team also found, during the conjugate heat transfer analysis, it was a little challenging to see how the boundary conditions work and to find the needed conditions. iGas Technologies turned to SimScale’s library of public projects where they could see how other engineers set up boundary conditions for similar applications to overcome this.
In total, the team ran over 10 simulations with some in parallel. They found the ‘convective heat transfer’ simulations were faster than the conjugate, with 64 processors taking an average of 5 minutes per run. The ‘conjugate heat transfer,’ on the other hand, was run on 96 processors and was an average of 77 minutes per run.
“Overall, SimScale really saved us time, not only in this project but even in mechanical analysis, such as if we want to examine a steel part to determine if it will be strong enough. We just upload to SimScale and start the simulation.”
Since their collaboration with SimScale, iGas Technologies have experienced shortened development time with the ability to easily point out errors and make fewer design mistakes.
“SimScale is a very versatile simulation platform. It has a core advantage with the smooth and fast simulation runs and has a support team that is fast, kind, and helpful.”
When they need to develop and create another cooling system, they will use the results already obtained from SimScale. Along with this, they look forward to using the platform in the future, as they have now learned how to use the features and expect a quicker time from CAD import to results.
The team at iGas Technologies has since ventured into new product design in a new market; a desk that can be lifted to any position to give access for any type of healthy work. As for the current project, the cooling system is now manufactured and going through real-world testing.


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Delta Center | Salt Lake City, Utah
EVENT CANCELLED. Please contact your ticket point of purchase to claim a refund on your tickets.
Mark your calendars and set the date, because on Thursday 24th June 2021 the phenomenal Vivint Smart Home Arena is excited to host Utah Jazz. Fans are already rushing the ticket stands to ensure they don’t miss out on what is sure to be an unmissable basketball experience as these two awesome teams go head-to-head. If you love awesome basketball action, then you can’t afford to miss out on this match-of-the-season contender. Two great teams, led by two of the most experienced coaches in the league will enter, but only one will leave victorious. Don’t miss out on this event! Click the Buy Tickets button now to book your tickets.
If you’re a basketball fan – buckle up! This June the most anticipated game of the season will finally hit the arena of the most iconic basketball stadium in Salt Lake City. That’s right, Vivint Smart Home Arena will showcase the unmissable Utah Jazz, and the tickets are selling out fast! But the action-packed fixture is not the only reason to secure a seat. Each ticket includes a full pack of second to none offerings that will enhance your authentic basketball experience. From the neat facilities, superb sightlines, sizable seats and A-star event staff, to the endless amounts of drinks and snacks to boot – you name it, Vivint Smart Home Arena will deliver it. What better way to enjoy a world-class game unfolding right before your eyes? Order one of the greatest seats today and get a front-row view of the action!

domain: hobby


After waiting 15 minutes, I restarted it and the reservoir tank completely emptied into the radiator but I noticed the upper radiator hose was being sucked/collapsed closed unitl I shut her off. The hose was not collapsed when I originally opened the hood and noticed the coolant was all the way to the top of the reservoir. Any ideas besides the thermostat stuck closed? THANKS!
Tuesday, August 28th, 2007 AT 4:58 PM


|“||An explosive flask used for melting enemy armour. This carefully designed liquid bomb explodes into a dazzling flash of molten debris upon impact.||„|
|— In-game description|
It is one of the few AT weapons not to require Refined Materials.
It appears to resemble a Hawkins Grenade / Hawkins Mine.


LOUISVILLE, Ky. (AP) - Now that Shug McGaughey has won the Kentucky Derby, it's time for the 62-year-old trainer to go after another race missing from his Hall of Fame resume.
CHARLOTTE, N.C. (AP) - One phone call changed his plans. One shot changed a whole lot more for Derek Ernst.
WILLIAMSBURG, Va. (AP) - Cristie Kerr made a short par putt on the second hole of a sudden-death playoff with Suzann Pettersen on Sunday to win the Kingsmill Championship for the third time.
OKLAHOMA CITY (AP) - Down by one in the final minute, the Oklahoma City's Derek Fisher turned a tough situation for the Thunder into the worst-case scenario for the Grizzlies.
MIAMI (AP) - LeBron James was at his best this season, and the voters tasked with selecting the NBA's Most Valuable Player took notice.
ISCHIA, Italy (AP) - Bradley Wiggins is already in control of the Giro d'Italia.
SANTA CLARA (AP) - Sam Cronin scored in the first minute of second-half injury time to give the San Jose Earthquakes a 2-2 tie against the Montreal Impact on Saturday.
TALLADEGA, Ala. (AP) - Rain and wrecks pushed NASCAR to the edge of darkness Sunday at Talladega Superspeedway, where three of the biggest names in the sport led the field to final flag.
MADRID (AP) - Top-ranked Serena Williams won her opening match on the red clay of the Madrid Open on Sunday.
SAO PAULO (AP) - On the final turn of the final lap, James Hinchcliffe finally saw an opening - and made sure he squeezed into it.
OAKLAND (AP) - Draymond Green threw his arms in the air and ran to Golden State Warriors coach Mark Jackson for an emotional hug. Jarrett Jack squatted down, put his right hand on his head and closed his eyes. Stephen Curry wanted to see it all - teammates parading around the court, gold confetti in the air, smiles all around the announced sellout crowd of 19,596.
VANCOUVER, British Columbia (AP) - After a loss in Game 1, coach Alain Vigneault is looking for more offense from the Canucks.
ATLANTA (AP) - Dan Haren pitched eight sharp innings, Denard Span hit a two-run double and the Washington Nationals beat the Atlanta Braves 3-1 Thursday night.
OAKLAND, Calif. (AP) - Stephen Curry had 22 points and eight assists, Andrew Bogut broke out with the best performance of his injury-saddled season and the Golden State Warriors eliminated the Denver Nuggets with a 92-88 victory in Game 6 on Thursday.
ANAHEIM, Calif. (AP) - Alex Ovechkin's franchise-record 31st career playoff goal got the Capitals started before less-heralded teammates Marcus Johansson and Jason Chimera scored 46 seconds apart, and Washington beat the New York Rangers 3-1 Thursday night in Game 1 of their first-round series.
BENTON HARBOR, Mich. (AP) - Colin Montgomerie learned something about playing major championship golf at the age of 51 in the Senior PGA Championship at Harbor Shores.
MONTECAMPIONE, Italy (AP) - Fabio Aru of Italy claimed a solo victory on the tough uphill finish to Montecampione in the 15th stage of the Giro d'Italia on Saturday for his first Grand Tour victory.
NEW YORK (AP) - Triple Crown hopeful California Chrome galloped two miles around Belmont Park as part of his preparations for the Belmont Stakes on June 7.
CARSON (AP) - Landon Donovan broke the Major League Soccer goal record Sunday night, scoring his 135th and 136th regular-season goals in the Los Angeles Galaxy's 4-1 victory over the Philadelphia Union.
CONCORD, N.C. (AP) - Defending Sprint Cup champion Jimmie Johnson passed Matt Kenseth with nine laps to go and won the Coca-Cola 600 on Sunday night for his first victory of the season.
CONCORD, N.C. (AP) - Kurt Busch's attempt at completing "The Double" ended Sunday night after his car blew an engine late in the Coca-Cola 600.


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Results from the Childhood Cancer Survivor Study (CCSS) show that current advances in treatment and follow-up have led to improved survival of childhood cancers, including lymphoma, especially by reducing deaths due to lingering effects of cancer treatment. The study, performed at St. Jude Children’s Research Hospital, was published in the online edition of the New England Journal of Medicine.
The extensive study looked at 34,033 children and adolescents diagnosed with cancer between 1970 and 1999. All participants were considered long-term survivors, living at least five years following diagnosis.
The results show that the death rate — particularly the 15-year death rate — among young cancer patients has decreased significantly since 1970, partly because of a reduction in treatment-related health complications. Data from 1970-74 and 1990-94 showed a decline from 12.6 percent to 6 percent among patients. Deaths due to secondary complications of treatment also decreased, from 3.5 percent to 2.1, percent during those time periods.
Since 1970, pediatric cancer care and follow-up treatment went through important changes. Reduction in exposure to anthracycline chemotherapy, and reduced use and dose of radiation therapy for the treatment of acute lymphoblastic leukemia (ALL) and Hodgkin lymphoma also led to a decreased rate of complications, such as secondary cancers and heart failure.
The percentage of ALL survivors treated by brain irradiation over the study’s 29 years decreased from 86 percent to 22 percent.
In a press release, the principal investigator of the CCSS study, Gregory Armstrong, said: “This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives. The results are a testament to the physicians and scientists who in the past 30 years took a calculated risk of developing new protocols that used less intense therapies that reduced the risk of late effects and maintained excellent five-year survival.”
The biggest difference in death rates were observed for patients diagnosed with standard-risk ALL, Hodgkin lymphoma or Wilms tumor (a kidney cancer) as their primary cancer. According to the American Cancer Society, five-year survival for pediatric patients with these cancers is now 90 percent or better.
Heart disease-related death decreased for survivors of ALL and Hodgkin lymphoma. These patients were also less likely to be treated with radiation therapy or anthracyclines.
According to the release, St. Jude published evidence in 2009 that pediatric ALL is curable without brain irradiation, and the hospital no longer uses such radiation treatment. It reports that 94 percent of its ALL patients now live at least five years post-diagnosis.
The percentage of Hodgkin lymphoma patients treated with radiation fell from 96 percent to 77 percent — a change also accompanied by a decrease in the mean cumulative anthracycline dose given these pediatric cancer patients. “For CCSS, the next question is what is the quality of life and health that childhood cancer survivors enjoy during their extended life span,” Dr. Armstrong said.
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19 May, 11:13
There are six uncapped players in the Ireland squad for the summer tour to North America that was named this morning. An Emerging Ireland squad has also been selected for the Tblisi Cup in Georgia.
"Paul was injured in the act of scoring a try for Ulster during last Saturday's RaboDirect PRO12 match against Connacht at the Sportsground in Galway.
"It is hoped that Paul could be available for Ulster's Heineken Cup semi-final against Edinburgh on April 28. However, at this stage, it is a case of 'wait and see', with treatment and reassessment ongoing."


Girl flawlessly recreates Kriti Sanon’s dance moves from Mimi song Param Sundari. Watch
There are certain videos on the Internet that almost instantly lift your mood and leave you with a huge smile. This video of a girl flawlessly recreating Kriti Sanon’s dance moves from the song Param Sundari featured in the movie Mimi is one such example. The video is such that it will win you over.
“Yes, dancing makes me look more beautiful,” reads the caption shared along with the video. The clip shows the girl dressed in a similar outfit as Kriti Sanon wears in the song. It is her flawless recreation of the actor’s dance moves that makes the video a delightful watch.
Take a look at the clip:
Since being shared, the video has gathered more than 6,200 likes and counting. It has also received tons of appreciative comments.
“Today’s best video on the Internet,” wrote an Instagram user. “Cutest,” shared another. “So sweet,” expressed a third.
Another video showing the girl posing in the outfit she wore for the dance was also shared:
Here’s the song Param Sundari featuring Kriti Sanon from film Mimi:
What are your thoughts on the video?


text: Background: Glycated haemoglobin is produced by a ketoamine reaction between glucose and the N-terminal valine of both ß-chains of the haemoglobin molecule. The major form of glycated haemoglobin is haemoglobin A1c (HbA1c) .The HbA1c fraction is abnormally elevated in chronic hyperglycaemic diabetic patients and it correlates positively with the glycaemic control. However, increased glycated haemoglobin levels have been documented in iron deficiency anaemic patients without any history of diabetes. Aims and Objectives: The aim of this study was to determine the effect of IDA on the HbA1c levels in nondiabetic patients. Methods: 60 non-diabetic, anaemic patients and 60 age-matched healthy subjects were involve in this study. Haematologic investigations were done and the fasting and postprandial glucose and HbA1c levels were measured in all the subjects. Results: The mean HbA1c (8.9 ± 1.8%) level in the patients with IDA was higher than that in the control group (5.4% ± 0.8) (p < 0.05). There were no differences in the levels of fasting and postprandial glucose between the IDA and the control groups (p > 0.05). Conclusion: HbA1c is not affected by the blood sugar levels alone, and there are various confounding factors when HbA1c is measured, especially that of iron deficiency, which is the commonest of the deficiency diseases worldwide. It is hence important to rule out IDA before making a therapeutic decision, based on the HbA1c levels.

domain: health


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Odyssey Bone rug
Odyssey is where old world charm and modern styling meet. Beautifully ornate traditional designs are set off with an explosion of heart warming hues, ranging from peaches, purples and rusts to calming blues and creams. Power loomed in soft polypropylene yarn, this collection requires minimal maintenance and won’t shed.
Size: 230 x 160 cm
Construction - 100% Polypropylene| Power loomed
Made in Egypt