text:
Item #
Salem China Primrose Creamer
Backstamped: Salem U.S.A. - **57 ZSize: 2-1/4 inches height, 6-inches length from spout to handle, 4-1/4 inches widthCondition: used, no chipsComments: pattern is green leaves, with a red flower; several on front, smaller version on back.- Has a cute shape!
Manufacturer: Salem China Co., U.S.A.
Yellow Sugar Bowl, White Lid
Marked: USASize: 2-3/4 inches height to rim, 4-inches to tip of lid; 4-inches across rim, 2-1/4 inches across baseCondition: used, no chipsComments: a friendly, bright yellow body, with a white interior and lid
Manufacturer: Royal USA China
Wild Rice, Salem China, Round Platter/Chop Plate 13Inches, 1959
Marked: Salem Shangri La Series ovenproof Wild Rice 59UPattern: Wild Rice, ( discontinued by 1963)Size: 13-3/8 inches across tab handles, 12 inches across, the other directionCondition: Used, no chips, normal use wear and surface scratches
Manufacturer: Salem China Co. U.S.A.
Salem China - Woodhue Cream & Sugar, Lid - Designed by Viktor Schreckengost
Marked: by Salem China Made In U.S.A. - *54xSize Creamer: 2-3/4 inches heightSize Sugar Bowl: 3-inches with lid in placeCondition: used, vintage, no chips, Comments: 1954 pattern is Woodhue Designed by Viktor Schreckengost; green and brown leaves
Manufacturer: Salem China, U.S.A.
U.S.A. Yellow Creamer
Marked: U.S.A.Size: 3-3/8 inches height, 5-1/4 inches length from spout to end of handle, 3-3/8 inches across rim, 2-inches across base.Condition: used, vintage, good, normal manufacturing defects.Comments: bright yellow exterior, white inside
Manufacturer: Made in U.S.A.
Iroquois Harvest Time Sugar Bowl, Cover
Marked: noSize: 5-1/4 inches across rim, 2-1/4 inches height to rim, 2-3/4 inches height with lid in placeCondition: used, shows normal use wear, inside handle has a manufacturing defectComments: Circa 1958-1973 / rust base with a white interior and lid with two Maple leaves and a cute tied bow look handle on top.
Manufacturer: Iroquois China, Syracuse N.Y. U.S.A.
Iroquois Casual Open Sugar Bowl, Off White, Russel Wright
Marked: Iroquois Casual China by Russel WrightSize: 2-1/8 inches height, 3-7/8 inches across rim, 2-1/2 inches across baseCondition: Used, goodComments: has two notches, color is not a bright white sitting on white paper it is more cream, ivory, or off white.
Manufacturer: Iroquois China, Syracuse N.Y. U.S.A.
North Star - Saucer Salem China
Pattern: North Star by Salem China Marked: NoSize Saucer: 6-1/8 inches across rimCondition: used, vintage, no chips or cracks, average use wearComments: cups have a white interior and solid turquoise/blue on outside, handle and base.
Manufacturer: Salem China U.S.A.
Two Metlox - Poppytrail White Coasters
Marked: Poppytrail By Metlox Made In CaliforniaSize: 3-3/4 inches acrossCondition: used, vintage, no chips or stains or crazing.
Manufacturer: Metlox - Poppytrail
Canonsburg - Temporama Cup
Pattern: Temporama by Canonsburg Circa 1960Mid-Century cup is white with the blue, brown and green designs. Unmarked - Size: 2-1/8 inches height, 4-inches across the rim, with a 1-7/8 inch base. Condition: used, good, nice shine. Comments: cute handle shape; should have an all blue saucer. Note: you may also like TE3658, a saucer
Manufacturer: Canonsburg Pottery, Canonsburg PA - U.S.A.
Metlox, Poppytrail Shoreline-Chartreuse Saucer
Marked: Poppy Trail By Metlox Made In CaliforniaSize: 6 by 6 inchesCondition: used, vintage, normal manufacturing kiln marks, no cup available.Comments: Shape is square, Circa 1953
Manufacturer: Metlox, California, U.S.A.
Vintage Blue Creamer
Marked: NoSize: 3-1/2 inches height, 4-3/4 inches length from spout to end of handle, 2-3/4 inches across rim, 2-inches across base.Condition: used, vintage, no chips, normal manufacturing defectsComments: pretty blue exterior, white inside
Manufacturer: Unknown
Vintage George Briard Fruit Cruet
Marked: © George Briard (on front) 14 (on base) 67 (on lid)Size: 6-1/2 inches height to top of lid, 2-inches across baseCondition: used, vintage, some gold trim missing from the pear side, apple side has more trim remaining.Comments: has a mod fruit design pear and apple on each side with leaves Circa 1960s
Manufacturer: Unknown
Steubenville Mid Century - Sugar Bowl & Shaker
Sugar Bowl Marked: by Steubenville - Made In U.S.A.Size Sugar Bowl: 4-1/4 inches height to tip of lid, 3-3/8 inches width, 3-1/4 inches depth, 2-inches across base.Size Shaker: 2-1/8 inches height, 1-1/4 inches across base. Condition: used, vintage, light crazing on lower portion of shaker - a manufacturing defect on sugar bowl of a wrinkle in one pink circle decal on one side, under-side of lid base has a frit, shaker has a few brown age marks; all are shown in photos.Comments: Design of AQUA and PINK CIRCLES with BLACK SPIRALS on front and back of sugar bowl and also on one side of the lid. Pattern is on one side of the shaker only. Shaker has three holes on top and came filled with pepper, so I assume it to be a pepper shaker. It has a rubber stopper on base. A wonderful set, hard to research, so not many are left out there Id think.
Manufacturer: Steubenville China, Steubenville, Ohio U.S.A.
Metlox Colorstax Salad Plate, Yellow
Marked: Metlox - Colorstax Hand Crafted Made In California USA Metlox Potteries Dishwashers Ovens Microwave SafeSize: 7-3/4 inches across rim, 4- inches across base rim.Condition: used, vintage (Circa 1983-1986) no chips, normal use wear, utensil marks.Comments: cheerful pottery plate!
Manufacturer: Metlox Potteries California U.S.A.
This is Page 1 of 4 in this category.
If you are finished shopping, click on the shopping cart button to view your order.
To order an item from tipp-eclectics, just click on the 'Add to Cart' button.
Clicking on the thumbnail picture of any item gives you a larger picture of that item.
Thanks for shopping at tipp-eclectics!
Contact us!
823 Claymore Ct.Tipp City, OH 45371United States
Updated Sunday, October 23 2016Product descriptions copyright© 2016 tipp-eclecticsAll else copyright© 1995-2016 TIAS.com All rights reserved.


text:
Tuesday, 14 Aug 2012
ARM and GlobalFoundries to Collaborate on 20nm SoC Featuring FinFET Technology
ARM and GlobalFoundries have announced their collaboration to produce system-on-chip (SoC) solutions based on the latter's 20-nanometer (nm) fabrication process and FinFET transistors. This will help achieve better system performance and power-efficiency for a range of mobile applications.
iPhone 5 Coming to International Markets in First Week of October?
Apple is said to be holding pre-orders for its upcoming iPhone on the day of its launch, and the second wave of iPhone launches will hit international markets in the first week of October.
Market Share of Plasma Televisions Hits 15-month Low
According to IHS iSuppli's recent report, the market share for all plasma television displays sold by U.S. retailers fell to its lowest level in July since the first quarter of 2011, as rising retail prices proved to be a major disincentive to consumers.
uTorrent Introduces New Monetization Measures
Taking advantage of being the world's most popular bit-torrent clieant, uTorrent has announced that it will be displaying advertisements in its software to generate more revenue along with sponsored links.
Google Acquires Frommer's Travel Guides
Google has just announced the acquisition of Frommer's travel guide business from publishers John Wiley & Sons.
Monday, 13 Aug 2012
Toshiba to Boost HDD Production by 35% to Meet Demand
Toshiba will be increasing production of hard drives by about 35% in the next three years to meet increasing demand from data centers and PC manufacturers.
Samsung Reveals its Exynos 5 Dual, a CortexA15 Dual-Core SoC
Samsung has revealed its new dual-core mobile application processor known as the Exynos 5 Dual. This new system-on-chip (SoC) features a pair of Cortex-A15 CPUs with a Mali T-604 graphics processing unit. Read on to uncover its full specifications.
Intel Banking on Wireless Charging to Improve Mobile Offerings
Intel is turning to wireless charging to improve on the attractiveness of its mobile offerings. Intel hopes to introduce this in Intel-powered Ultrabooks and smartphones by the second half of 2013.
Microsoft to Drop 'Metro' Design Name, Looks to Replace It with 'Modern' (Update)
Microsoft is advising developers (and maybe even OEM partners) to not use the word 'Metro' when they're referring to the interface of Windows Phone or Windows 8. The reason? It's just a code name.
HTC Working on a 5-inch Device with 1080p Display?
Rumors suggest that HTC is working on a 5-inch device with 1080p display to compete against the likes of the Samsung Galaxy Note II and LG Optimus Vu.

subset: commoncrawl


text:
Log in Sign Up
(0 item)
Email address:
Forgot your password?
Birdhouse Cottage Crafts
Store Catalog
Store Categories
Birdhouse Cottage Crafts
Latest Designs
Seaside Wall Hanging
Adorable applique sea creatures bob along on this beautiful underwater scene.
Freemotion Quilting Feathers
Embellish your borders and blocks with the elegant look of Freemotion Quilting.
St Patricks Day Bottle Jackets
Spread the luck o' the Irish with crafty bottle jackets decorated for St. Paddy's Day.
Thread Catchers 3
Keep these handy catchers next to your machine, or take them with you on the go!
Chunky Feather Quilt Designs
A new style of the ever popular quilted feather designed for five or six inch blocks.
Pretty Pony Quilt
This lap quilt is the perfect size for little ones to cuddle with on cool evenings.
Square Charger Plates
Color co-ordinate with your tablecloth or decor by creating your own charger plates!
Ruffled Feathers Placemat
These placemats feature a unique and modern take on the traditional quilted feather.
Ruffled Feather Table Runner
This table runner features a unique and modern take on the traditional quilted feather.
Leaf Table Runner
This quick-stitching table runner features an elegant pattern of quilted leaves.
Feathered Table Runner
This project features a far easier technique to join quilted squares in the hoop.
Falling Leaves Quilt
Usher in the colorful season of autumn with a quilt featuring a dozen applique designs.
Quilted Feather Place Mats
Dress up your dining room for company or special occasions with these washable designs.
Quilted Borders
Add a special touch to home decor and linens with an elegant set of quilted borders.
Quilted Feather Cushion Cover
Freshen up your home decor with a creative set of quilted feather cushion covers.
Babies Butterfly Quilt
Wrap your precious babies and grandchildren in this modern quilt, perfect for a crib.
Seasonal Favorites
Festive Hot Plate Holders
Snowman Hot Plate Holders
Bough, Bow, Berries
Thread Catchers 3
Free Motion Borders
Free Motion Quilted Feathers
Jolly Molly Flower Pots
Chunky Feather Quilt Designs
Flower Pot Placemats
Lavender Dream Pockets
Leaf Table Runner
Applique Roses 1
Best Sellers
Feathered Table Runner
Stylish Note Book Covers
Round Charger Plates
Freemotion Quilting Feathers
The Cottages
Twisted Ribbon Quilt Designs
Sweet Pea Wall Hanging or Quilt
Gift Wraps
Victorian Summer Cushion Cover
Quilted Note Book Covers
Seaside Wall Hanging
Floral Quilt Borders
Pen & Pastel Rose Coasters
Sweet Pea Cushion Cover 3
Quilt Border Stitch Designs
Ruffled Feathers Placemat
© 2016 Copyright secretsof.com Embroidery Designs
Back to top


text:
Long-term l-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in Humans
Jump to
Background—Coronary endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors and coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine. Thus, the present double-blind, randomized study was designed to test the hypothesis that long-term, 6-month supplementation of l-arginine, the precursor of the endothelium-derived vasodilator NO, reverses coronary endothelial dysfunction to acetylcholine in humans with nonobstructive coronary artery disease.
Methods and Results—Twenty-six patients without significant coronary artery disease on coronary angiography and intravascular ultrasound were blindly randomized to either oral l-arginine or placebo, 3 g TID. Endothelium-dependent coronary blood flow reserve to acetylcholine (10−6 to 10−4 mol/L) was assessed at baseline and after 6 months of therapy. There was no difference between the two study groups in clinical characteristics or in the coronary blood flow in the response to acetylcholine at baseline. After 6 months, the coronary blood flow in response to acetylcholine in the subjects who were taking l-arginine increased compared with the placebo group (149±20% versus 6±9%, P<0.05). This was associated with a decrease in plasma endothelin concentrations and an improvement in patients' symptoms scores in the l-arginine treatment group compared with the placebo group.
Conclusions—Long-term oral l-arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for l-arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.
The coronary vascular endothelium modulates vascular tone through release of vasodilating and vasoconstricting substances. The endothelium-derived relaxing factor NO is synthesized from the amino acid l-arginine by a family of enzymes, the NO synthases, through a metabolic route, namely the l-arginine–NO pathway.1 NO mediates vascular smooth muscle cell relaxation and inhibits platelet aggregation and adhesion and smooth muscle cell proliferation.1 2 Endothelin-1, on the other hand, is an endothelium-derived peptide that produces coronary vasoconstriction at pathophysiological concentrations by binding to specific receptors on the vascular smooth muscle.2 Repeated studies have established that coronary endothelial dysfunction is present in early atherosclerosis and is characterized by a coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine.3 4 5 Indeed, Zeiher and colleagues6 have suggested that coronary endothelial dysfunction may be a mechanism of exercise-induced myocardial ischemia in patients with effort angina and normal coronary arteriogram. We recently demonstrated that coronary endothelial dysfunction in humans is characterized by increased coronary and circulating endothelin and decreased production of the second messenger of NO, cGMP.7 These studies underscore that endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors.
Previous studies in experimental animals and humans that used either feeding or intravenous infusion of l-arginine have shown that l-arginine improves peripheral endothelium-dependent dilatation, inhibits platelet aggregation, and may reduce atherosclerosis.8 9 10 11 Moreover, short-term intracoronary administration of l-arginine improves coronary endothelial response to acetylcholine in hypercholesterolemic subjects.12 Supplemental oral l-arginine in patients with heart failure resulted in improvement in symptoms in association with a decrease in plasma endothelin concentrations.13 To date, the effect of long-term administration of l-arginine on coronary endothelial function is unknown. Thus, the present study was designed to test the hypothesis that long-term oral l-arginine supplementation for 6 months reverses coronary endothelial dysfunction in response to acetylcholine in humans with nonobstructive coronary artery disease. Moreover, the effect on plasma endothelin concentrations and symptoms was also assessed.
The study protocol was approved by the Mayo Clinic Institutional Review Board. All patients gave written informed consent to participate in the study and were referred for coronary angiography because of recurrent chest pain. Exclusion criteria included ≥40% diameter stenosis of any coronary artery, prior myocardial infarction, unstable angina pectoris, uncontrolled hypertension, peripheral vascular disease, ejection fraction <55%, left ventricular hypertrophy, active smoking, diabetes mellitus, and significant endocrine, hepatic, renal, or inflammatory disease. None of the patients had a left-dominant system.
Drug Infusion
Patients were brought to the cardiac catheterization laboratory between 8 am and 10 am in the fasting state after all cardiovascular medications had been discontinued for at least 72 hours. None of the patients were receiving lipid-lowering drugs. Diagnostic coronary angiography was performed via the percutaneous femoral approach without prior administration of nitrates or calcium channels blockers. The coronary angiogram was reviewed before the infusion of drugs; severity of stenosis was assessed by on-line quantitative coronary angiography. Patients with significantly obstructive coronary artery disease (≥40% diameter stenosis of any coronary artery) or diffuse disease were excluded from further studies.
The determination of endothelium-dependent and endothelium-independent CFR was performed as previously described.7 14 Additional intravenous heparin (5000 to 7500 U) was administered before instrumentation. Heart rate and mean arterial pressure were continuously monitored. A Doppler guidewire (FloWire, Cardiometrics Inc) 0.014 in. in diameter within a 2.2F coronary infusion catheter (Ultrafuse, SciMed Life System) was advanced and positioned in the middle portion of the LAD, 2 to 3 mm distal to the tip of the infusion catheter. Baseline average peak velocity as measured by Doppler echocardiography was recorded. Intracoronary bolus injections of incremental doses (18 to 36 μg) of adenosine (Fujisawa), an endothelium-independent vasodilator, were administered into the guiding catheter positioned in the ostium of the left main coronary artery until maximal hyperemia was achieved in all of the patients, and the maximal average peak velocity was recorded (in only 4 patients, or 13%, a dose >24 μg was required to achieve maximal hyperemia).14 15 To ensure that the increase in CBF did not merely reflect the forces of intracoronary bolus injection, CFR in response to normal saline (3 to 6 mL) was measured before adenosine injection and served as control.
The assessment of the endothelium-dependent CFR was performed by selective infusion of acetylcholine into the LAD. After a 5-minute equilibration period, baseline average peak velocity was recorded, followed by coronary angiography using nonionic contrast medium (Omnipaque, Winthrop Laboratories). Acetylcholine (Iolab Pharmaceuticals) at concentrations of 10−6, 10−5, and 10−4 mol/L (to achieve estimated final blood concentrations in the coronary bed of 10−8, 10−7, and 10−6 mol/L) was infused with a Harvard pump for 3 minutes at each concentration. Hemodynamic data (heart rate and mean arterial pressure), Doppler measurements, and coronary angiography were obtained after each infusion. The infusion was terminated when the largest dose of acetylcholine (10−4 mol/L) was reached. Nitroglycerin (Abbott Laboratories) was then injected as an intracoronary bolus (200 μg) through the guiding catheter.
At each time interval, average peak velocity was recorded, followed by coronary angiography. The angles, skew rotation, and table height were kept constant during the procedure. In addition, the distances between the patient and the image intensifier and x-ray tube were kept constant. Coronary artery diameter was measured at three sites (proximal, middle, and distal) in three end-diastolic frames and averaged by an independent investigator unaware of the Doppler flow data using a computer-based image analysis system, as previously described.16 For the calculation of CBF, the measurements were performed in a 1-cm segment 5 mm distal to the tip of the Doppler wire. For each time interval, the diameter was measured in the same segment. CBF was calculated from the Doppler-derived time-velocity integral and vessel diameter17,18: CBF=π(average peak velocity/2)(coronary artery diameter/2).2
After the intracoronary infusions, IVUS of the LAD was performed with a Hewlett-Packard imaging system, as described previously,19 to confirm the absence of significant obstructive coronary artery disease. Continuous images were recorded throughout the LAD on a 0.5-in videotape for off-line analysis. A special effort was made to keep the IVUS catheter parallel to the long axis of the vessel lumen. Five or six segments of the LAD were identified in the videotape recording of the IVUS images by the digital counter, and the exact position of the IVUS catheter in relation to the artery was recorded on cine film at each position. The location of the catheter seen on the cine film of each segment was used to correlate the identified IVUS image with the angiographic segment.
An off-line computer-interactive analysis system was used to digitize the intracoronary IVUS video images onto a 256×256-bit matrix. Standard calibration markers obtained directly from the IVUS images were used for calibration of absolute measurements. All measurements were made in end diastole and measured at the media-adventitia interface. Measurements of coronary artery diameters and areas were averaged from two orthogonal planes. All measurements were made by an observer blinded to the Doppler or angiographic findings.
After the procedure, patients with coronary endothelial dysfunction, defined as an attenuated increase (<50%) or a decrease in CBF in response to graded infusion of acetylcholine12 and normal CFR in response to adenosine (CFR >2.5), were recruited into the study and randomized. Oral l-arginine was given at a dose of 1 g TID for week 1, 2 g/d for week 2, and at the target dose of 3 g TID beginning in week 3. Both the active drug and the placebo were prepared as identical capsules and supplied by Triage Pharmaceuticals Inc. This dose has previously been shown to improve endothelial function in hypercholesterolemic subjects.8 10 11 The patients were instructed to avoid taking other medication, over-the-counter vitamins, or amino acids. The patients were thereafter contacted, in a blinded fashion, weekly for month 1 and monthly for the remainder of the 6-month study duration for monitoring of any side effects and to ensure compliance with treatment instructions. During these interviews, the patients were also questioned about their symptoms of chest pain. Their symptoms were scored as follows: 0, no symptoms; 0.5, improvement in their symptoms; and 1.0, no change or worsening of their symptoms.
One week before the repeat angiogram, all medications except for the study drug were discontinued. The study drug was continued until the evening before the repeat study. During the repeat angiogram at 6 months, the entire intracoronary infusion protocol was repeated by the investigator, who was blinded to the randomization. The same angles, skew rotation, and table height as in the baseline study were used. There were no complications at the baseline or follow-up procedures, and all patients tolerated the entire procedures without side effects.
Biochemical Studies
Venous blood samples were collected before the baseline procedure and after the 6 months of treatment. Fasting lipid analyses were performed for total cholesterol, HDL cholesterol, and triglycerides; LDL was measured in the Mayo Clinic Immuno Chemistry Laboratory by use of the Roch reagent, a colorimetric assay on the COBAS Mira System. The concentration of free l-arginine was analyzed with an automated amino acid analyzer by the Mayo Clinic laboratory, the normal range being from 20 to 180 μmol/L. Plasma endothelin was determined by the ET-1,2[125I] assay system (Amersham), as previously described from our laboratory.7 The recovery of the extraction procedure is 81%, as determined by addition of synthetic endothelin to plasma, and interassay and intra-assay variations are 9% and 5%, respectively. The minimal level of detection is 0.5 pg per tube. The cross-reactivities of endothelin-2, endothelin-3, and proendothelin in this assay are <5%, <3%, and <37%, respectively.
Continuous variables are presented as mean±SEM. The effect of acetylcholine infusion is expressed as percent change (mean±SEM) in CBF during the infusion of 10−4 mol/L relative to baseline. The effect of adenosine is expressed as the maximal ratio between the coronary flow velocities after and immediately before the bolus injection. The differences within the groups were analyzed by repeated-measures ANOVA, and the differences between groups were analyzed by ANOVA and Student's unpaired t test and the χ2 test. A value of P<0.05 was accepted as significant.
Of the 52 patients screened, 30 subjects fulfilled the selection criteria and were randomized. However, during the 6-month study, 4 patients discontinued the study. One patient from each group discontinued the study secondary to minor gastrointestinal side effects and 1 from each group secondary to personal preference. The remaining 26 participants completed the study (l-arginine, group 1, n=13, and placebo, group 2, n=13).
Of the remaining patients, 23% from group 1 (l-arginine) and 31% from group 2 (placebo) received calcium channel blockers for treatment of hypertension. None of the patients received nitrates, β-blockers, ACE inhibitors, or cholesterol-lowering drugs. All the patients were referred for the evaluation of stable exertional chest pain suspected to be of cardiac origin. Before the coronary angiogram, 10 patients (77%) from each group underwent a noninvasive functional test, which was positive and consistent with myocardial ischemia in 6 patients from group 1 and 5 patients from group 2.
The demographic and clinical characteristics of the two groups at baseline are outlined in Table 1⇓. There was no difference between the study groups in age, sex, or coronary artery disease risk factors. Nor was there any difference between groups 1 and 2 in the extent of coronary artery atherosclerosis as determined by IVUS (maximal area stenosis, 35±11% and 37±9%, respectively) or in the left ventricular ejection fraction (68±3% and 67±5%, respectively).
At baseline, the two groups also had similar resting CBF, CFR in response to adenosine, and CBF response to graded infusion of acetylcholine (peak response to 10−4 mol/L: group 1, 10±8% versus group 2, 5±6%) (Tables 2⇓ and 3⇓).
In the subjects who were taking l-arginine for 6 months, there was a significant improvement in CBF (149±20% versus 6±9%, P<0.05) and epicardial coronary artery diameter (16±1.4% versus −25.9±1.8%, P<0.05) in response to acetylcholine compared with the placebo group (Table 3⇑, Figure 1⇓). This change was associated in group 1 with a significant decrease in plasma endothelin concentrations (35±5%) and a mild but significant increase in plasma l-arginine levels (33±8%), which remained unaltered in group 2 (Table 2⇑). There was no correlation between the decrease in plasma endothelin concentrations and the CBF response to acetylcholine. There was no difference in the response to l-arginine between the hypertensive and normotensive patients. There was no significant difference between the subjects on l-arginine or placebo in respect to mean arterial pressure, plasma cholesterol, CFR in response to adenosine, and CBF in response to intracoronary nitroglycerin (Table 2⇑). Also, there was no difference between the groups in the extent of coronary artery atherosclerosis at follow-up angiogram.
A significant improvement of the symptoms score was observed in the group that was treated with l-arginine compared with the placebo group (Figure 2⇓) after 1 week and persisted for the 6-month study.
The present study demonstrates that long-term oral l-arginine supplementation for 6 months in humans with nonobstructive coronary artery disease improves coronary small-vessel endothelial function in response to acetylcholine in association with a significant improvement in their symptoms. The group that received l-arginine demonstrated an improvement in endothelial function at the level of both the epicardial and small coronary vessels. This improvement in coronary endothelial function was associated with a decrease in plasma endothelin concentrations. This study proposes a role for l-arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.
The endothelium is an important modulator of coronary vascular tone through the release of endothelium-derived relaxing factors such as NO and endothelium-derived vasoconstrictors such as endothelin.2 Early coronary atherosclerosis is associated with coronary endothelial dysfunction, which is characterized by an attenuated or absent endothelium-dependent vasodilatation, such as the response to intracoronary administration of acetylcholine.3 4 5 The significance of coronary endothelial dysfunction is underscored by its implications as a mechanism of exercise-induced myocardial ischemia6 and by its association with myocardial perfusion defects, as recently observed in our laboratory.20
A growing body of evidence suggests that dietary supplementation of arginine improves endothelial function in experimental animals and in humans. Short-term administration of intracoronary l-arginine restored the impaired endothelium-dependent dilatation in hypercholesterolemic patients.12 Recently, Clarkson and colleagues8 reported that a 4-week regimen of oral l-arginine improved peripheral endothelium-dependent dilation in hypercholesterolemic subjects, and Rector and colleagues13 demonstrated beneficial effects of oral l-arginine in patients with heart failure. The present study extends these previous observations and demonstrates that long-term l-arginine improves coronary endothelial function in humans.
The patients treated with l-arginine demonstrated a significant improvement in symptoms compared with the placebo group. This observation may support the hypothesis that their symptoms were related to their abnormalities in coronary endothelial function. This observation is also in accord with previous studies that demonstrated an improvement in symptoms in patients with heart failure subsequent to l-arginine treatment13 and with a recent report that oral l-arginine supplementation has a beneficial effect on exercise capacity in patients with stable angina.21
The mechanism by which l-arginine improves endothelial function may be multifactorial. l-Arginine is the substrate for NO synthase, the enzyme that catalyzes the production of NO in vascular endothelial cells.1 NO contributes to the resting epicardial and the coronary microvascular tone. Moreover, the acetylcholine-induced increase in CBF is largely due to release of NO from the coronary epicardial and microvascular bed.22 Thus, one possible mechanism for the beneficial effect of l-arginine is the enhanced production of NO from the coronary endothelium. This mechanism was recently challenged because the intracellular concentration of l-arginine far exceeds the Km of the NO synthases,22 23 and l-arginine did not improve relaxation to acetylcholine in aortic rings from hypercholesterolemic rabbits in vitro.24 However, the composition of the buffer solution in the in vitro studies may have contributed to this discrepancy, because when l-glutamine was added to the solution, l-arginine did enhance endothelium-dependent vascular relaxation.22 23 Another hypothetical mechanism whereby l-arginine administration could directly affect the activity of the endothelial NO synthase may be uncovered by a recent observation that an endogenous inhibitor of NO synthase, asymmetric dimethylarginine, accumulates in the serum of cholesterol-fed rabbits and might antagonize the normal intracellular concentrations of l-arginine.25 Although we did not measure the levels of asymmetric dimethylarginine in the present study, it may be speculated that large doses of l-arginine might overcome this effect.
An additional, indirect mechanism by which l-arginine may improve endothelial function is through other vasoactive factors, such as endothelin-1. Indeed, in the present study, plasma endothelin concentration decreased after 6 months of l-arginine supplementation, and this observation is supported by a previous study that demonstrated a beneficial effect of oral l-arginine in patients with heart failure in association with a decrease in plasma endothelin-1 concentrations.13 The increase in NO activity by l-arginine may decrease endothelin production, because endothelium-derived NO inhibits the production of endothelin via a cGMP-dependent pathway.26 Moreover, we recently reported that experimental hypercholesterolemia, which is associated with coronary endothelial dysfunction and a decrease in endogenous coronary NO activity, is characterized by an enhanced coronary vasoconstrictive response to pathophysiological doses of endothelin-1.27 Thus, a decrease in plasma endothelin concentration may both directly and indirectly contribute to the improvement in coronary endothelial function by decreasing the sensitivity of the coronary circulation to other vasoconstrictor factors, such as angiotensin II and norepinephrine.28 29 Indeed, recent studies have demonstrated a clear benefit of pharmacological therapy, such as ACE inhibitors, on coronary endothelial dysfunction.30
We previously reported that plasma and circulating endothelin concentrations are increased in patients with coronary endothelial dysfunction.7 The decrease in circulating endothelin-1 in the present study in association with an improvement in coronary endothelial function further supports the hypothesis that in early coronary atherosclerosis, an imbalance between production and release of NO and endothelin occurs that leads to augmented coronary vasoconstriction. Because endothelin and NO act primarily as local, paracrine/autocrine factors, it seems reasonable to assume that the circulating levels of endothelin underrepresent the local and tissue concentrations in the coronary circulation.
An increasing body of evidence suggests that dietary supplementation of arginine inhibits atherogenesis.31 Aji and colleagues9 recently reported that oral l-arginine for 6 months prevented xanthoma development and inhibited atherosclerosis in LDL cholesterol receptor knockout mice, suggesting that this response may be mediated by NO. Moreover, long-term administration of supplementary dietary arginine markedly inhibits intimal lesion formation in hypercholesterolemic rabbits32 and preserves endothelium-dependent vasodilatation.33 NO can inhibit monocyte adhesion to the endothelium1 31 and may also inhibit the production of superoxide anion by activated neutrophils.34 Thus, it may be speculated that long-term l-arginine administration improves coronary endothelial function by attenuating the progression of coronary atherosclerosis.35 In the present study, a small number of selected patients were studied, and the results may be influenced by altered hemodynamics or other mechanisms. Moreover, we did not measure biochemical markers to evaluate the NO pathways, such as urinary nitrogen oxides or cGMP.36 Thus, a larger, comprehensive study may be required before the therapeutic role for l-arginine and the mechanism of its beneficial effect can be elucidated.
In summary, this study demonstrated that oral l-arginine supplementation for 6 months improves coronary endothelial function in association with improvement in symptoms. This study proposes a therapeutic role for l-arginine in patients with chest pain and coronary endothelial dysfunction.
Selected Abbreviations and Acronyms
|coronary blood flow
|coronary flow reserve
|intravascular ultrasound
|left anterior descending coronary artery
This study was supported by the National Institutes of Health (HL-03180–01), the Miami Heart Research Institute, The Bruce and Ruth Rappaport Vascular Biology Program, and the Mayo Foundation.
- Received October 14, 1997.
- Revision received January 21, 1998.
- Accepted January 23, 1998.
- Copyright © 1998 by American Heart Association
- ↵
- ↵
Lerman A, Burnett JC Jr. Intact and altered endothelium in regulation of vasomotion. Circulation. 1992;86(suppl III):III-12–III-19.
- ↵
Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, Sugimachi M, Suzuki S, Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993;91:29–37.
- ↵
Zeiher AM, Drexler H, Wollschager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991;83:391–401.
- ↵
Quyyumi AA, Cannon RO III, Panza JA, Diodati JG, Epstein SE. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation. 1992;86:1864–1871.
- ↵
Zeiher AM, Krause T, Schächinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995;91:2345–2352.
- ↵
Lerman A, Holmes DR Jr, Bell MR, Garratt KN, Nishimura RA, Burnett JC Jr. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation. 1995;92:2426–2431.
- ↵
Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celemajer DS, Deanfield JE. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;7:1989–1994.
- ↵
Aji W, Ravalli S, Szabolcs M, Jiang X, Sciacca RR, Michler RE, Cannon PJ. l-Arginine prevents xanthoma development and inhibits atherosclerosis in LDL cholesterol receptor knockout mice. Circulation. 1997;95:430–437.
- ↵
Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991;83:1057–1062.
- ↵
Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248–1253.
- ↵
- ↵
Rector TS, Bank AJ, Mullen KA, Tshumperlin LK, Sih R, Pillai K, Kubo SH. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation. 1996;93:2135–2141.
- ↵
- ↵
- ↵
Cannan CR, Higano ST, Holmes DR Jr, Garratt KN, Lerman A. Beyond the coronary angiogram: further evaluation of the coronary vasculature and endothelial function. J Cardiol. 1996;9:153–161.
- ↵
- ↵
Hasdai D, Gibbons RJ, Holmes DR Jr, Higano ST, Lerman A. Coronary endothelial dysfunction is associated with myocardial perfusion defects. Circulation. 1997;96:3390–3395.
- ↵
- ↵
Quyyumi AA, Mulcahy D, Andrews NP, Husain S, Panzy JA, Cannon RO. Coronary vascular nitric oxide activity in hypertension and hypercholesterolemia. Circulation. 1997;95:104–110.
- ↵
Arnal J-F, Münzel T, Venema RC, James NL, Bai CL, Mitch WE, Harrison DG. Interactions between L-arginine and L-glutamine change endothelial NO production: an effect independent of NO synthase substrate availability. J Clin Invest. 1995;95:2565–2572.
- ↵
- ↵
- ↵
Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990;85:587–590.
- ↵
Mathew V, Cannan CR, Miller VM, Barber DA, Hasdai D, Schwaetz RS, Holmes DR Jr, Lerman A. Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia. Circulation. 1997;96:1930–1936.
- ↵
Yoshida K, Yasujima M, Kohzuki M, Kanazawa M, Yoshinaga K, Abe K. Endothelin augments presser response to angiotensin II infusion in rats. Hypertension. 1992;20:292–297.
- ↵
Yang Z, Richard D, Von Segesser L, Bauer E, Stulz P, Turina M, Lüscher TF. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries: a new mechanism of vasospasm? Circulation. 1990;82:188–195.
- ↵
Mancini GBJ, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND study (Trial on Reversing Endothelial Dysfunction). Circulation. 1996;94:258–265.
- ↵
Tsao PS, Lewis NP, Alpert S, Cooke JP. Exposure to shear stress alters endothelial adhesiveness: role of nitric oxide. Circulation. 1995;92:3513–3519.
- ↵
Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992;90:1168–1172.
- ↵
Jeremy RW, McCarron H, Sullivan D. Effects of dietary l-arginine on atherosclerosis and endothelium-dependent vasodilatation in the hypercholesterolemic rabbit: response according to treatment duration, anatomic site, and sex. Circulation. 1996;94:498–506.
- ↵
Clancy RM, Leszczynska P, Piziak J, Abramson SB. Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on NADPH oxidase. J Clin Invest. 1992;90:1116–1121.
- ↵
Cooke JP, Tsao PS. Arginine: a new therapy for atherosclerosis? Circulation. 1997;95:311–312.
- ↵
This Issue
Jump to
Article Tools
- Long-term l-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in HumansAmir Lerman, John C. Burnett, Stuart T. Higano, Linda J. McKinley and David R. HolmesCirculation. 1998;97:2123-2128, originally published June 2, 1998http://dx.doi.org/10.1161/01.CIR.97.21.2123
Citation Manager Formats
Share this Article
- Long-term l-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in HumansAmir Lerman, John C. Burnett, Stuart T. Higano, Linda J. McKinley and David R. HolmesCirculation. 1998;97:2123-2128, originally published June 2, 1998http://dx.doi.org/10.1161/01.CIR.97.21.2123
Related Articles
- No related articles found.
Cited By...
- Safety and performance benefits of arginine supplements for military personnel: a systematic review
- Emergence of Nonobstructive Coronary Artery Disease: A Womans Problem and Need for Change in Definition on Angiography
- Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs
- Coronary Microvascular Dysfunction, Microvascular Angina, and Treatment Strategies
- 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
- 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
- Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease
- The role of the vascular dendritic cell network in atherosclerosis
- Arginase 1 contributes to diminished coronary arteriolar dilation in patients with diabetes
- Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives
- Long-Term Administration of Endothelin Receptor Antagonist Improves Coronary Endothelial Function in Patients With Early Atherosclerosis
- Review Article: L-Arginine as a Nutritional Prophylaxis Against Vascular Endothelial Dysfunction With Aging
- Women and Ischemic Heart Disease: Evolving Knowledge
- Microvascular Angina and the Continuing Dilemma of Chest Pain With Normal Coronary Angiograms
- The effect of l-arginine and creatine on vascular function and homocysteine metabolism
- Defining the potential for cell therapy for vascular disease using animal models
- Sweet and Sour: Unraveling Diabetic Vascular Disease
- Diabetes-induced Coronary Vascular Dysfunction Involves Increased Arginase Activity
- Beneficial effects of a long-term oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients
- Vasculoprotective Effects of Erythropoietin: New Developments and New Alternatives
- A pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease
- Transport of extracellular L-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production
- Effects of L-Arginine on Fibroblast Growth Factor 2-Induced Angiogenesis in a Model of Endothelial Dysfunction
- Therapeutic uses of autologous endothelial cells for vascular disease
- Oral L-Arginine Improves Hemodynamic Responses to Stress and Reduces Plasma Homocysteine in Hypercholesterolemic Men
- Restenosis: Another "Dysfunction" of the Endothelium
- HPLC-Tandem Mass Spectrometric Method for Rapid Quantification of Dimethylarginines in Human Plasma
- Non-invasive assessment of coronary flow reserve in idiopathic dilated cardiomyopathy: hemodynamic correlations
- Impaired L-Arginine Transport and Endothelial Function in Hypertensive and Genetically Predisposed Normotensive Subjects
- L-Arginine and Hypertension
- Arginine and Endothelial and Vascular Health
- In Salt-Sensitive Hypertension, Increased Superoxide Production Is Linked to Functional Upregulation of Angiotensin II
- The clinical implications of endothelial dysfunction
- Inhibition of the Cardiac Angiogenic Response to Surgical FGF-2 Therapy in a Swine Endothelial Dysfunction Model
- Oral L-arginine improves endothelial function in healthy individuals older than 70 years
- Flow, NO, and atherogenesis
- Endothelial Dysfunction: A Marker of Atherosclerotic Risk
- Acute Intravenous l-Arginine Infusion Decreases Endothelin-1 Levels and Improves Endothelial Function in Patients With Angina Pectoris and Normal Coronary Arteriograms: Correlation With Asymmetric Dimethylarginine Levels
- Arginine intake, blood pressure, and the incidence of acute coronary events in men: the Kuopio Ischaemic Heart Disease Risk Factor Study
- L-Arginine in cardiovascular disease: dream or reality?
- Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity
- Oral L-arginine (and other active ingredients) for ischemic heart disease?
- Randomized trial of a medical food for the dietary management of chronic, stable angina
- Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors
- Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: Lack of effect of oral l-arginine on endothelial function, oxidative stress and exercise performance
- L-Arginine in the Management of Cardiovascular Diseases
- Dietary modulation of endothelial function: implications for cardiovascular disease
- Upregulation of the Nitric Oxide-cGMP Pathway in Aged Myocardium : Physiological Response to l-Arginine
- An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes
- In Vivo and In Vitro Evidence for Impaired Arginine Transport in Human Heart Failure
- Arginine Nutrition and Cardiovascular Function
- Does ADMA Cause Endothelial Dysfunction?
- Arginine Intake and Risk of Coronary Heart Disease Mortality in Elderly Men
- Oral L-Arginine in Patients With Coronary Artery Disease on Medical Management
- Blood pressure and metabolic changes during dietary L-arginine supplementation in humans
- Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction
- Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition
- Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar(R)
- Endothelial and metabolic characteristics of patients with angina and angiographically normal coronary arteries: Comparison with subjects with insulin resistance syndrome and normal controls
- Plasma {alpha}-Tocopherol and Coronary Endothelium-Dependent Vasodilator Function
- Novel Mechanism for Endothelial Dysfunction : Dysregulation of Dimethylarginine Dimethylaminohydrolase
- The 1998 Nobel prize in Medicine: clinical implications for 1999 and beyond
This article has not yet been cited by articles in journals that are participating in Crossref Cited-by Linking.


text:
Jerez:Nick Heidfeld was fastest on Tuesday on the opening day of Formula One's final testing session of 2007.
The BMW Sauber driver had a best time of 1 minute, 19.042 seconds from 78 laps around the 4.428-kilometer (2.751-mile) Circuito de Jerez. Honda's Jenson Button was next at 1:19.155, and McLaren test driver Pedro de la Rosa was third fastest in 1:19.712.
World champion Kimi Raikkonen of Ferrari had the fourth best time at 1:19.712 from 48 laps.
The man Raikkonen replaced seven-time champion Michael Schumacher was scheduled to test with the Italian team on Thursday and Friday.
Schumacher was fastest in winter testing at Barcelona last month in the 38-year-old German's first spin behind the wheel of a Ferrari since retiring in 2006.
McLaren driver Lewis Hamilton, who finished second to Raikkonen in the driver's standings after leading for most of his rookie season, is scheduled to drive Wednesday and Thursday.


text:
Dismiss Notice
Missed the live Ask the Expert event?
Not to worry. Check out the archived thread of the Q&A with Ken Hutcheson, President of U.S. Lawns, and the LawnSite community in the Franchising forum .
FS: Lawn Care Package. RTR
Discussion in 'Marketplace' started by rcslawncare, Jun 29, 2011.
Page 3 of 3
Page 3 of 3


text: Motorcade Crash Victim's Family Sues Hillary Clinton Dallas officer's family blame city, Clinton campaign for his death By Rob Quinn, Newser Staff Posted Feb 24, 2010 2:08 AM CST 12 comments Comments Dallas police Sr. Cpl. Victor Lozada-Tirado was killed while escorting a Hillary Clinton campaign motorcade. (AP Photo/The Dallas Police Department) View 2 more images (Newser) – The family of a Dallas motorcycle cop who died escorting Hillary Clinton in a campaign motorcade 2 years ago are suing her, the city, and the makers of the helmet he was wearing. Dallas officials didn't give the officer proper training and the Clinton campaign didn't give enough notice that it would require motorcade assistance, claims the suit by Victor Lozada-Tirado's widow and children. Lozada-Tirado, 49, had been controlling traffic at intersections as Clinton's motorcade rolled through the city. He was killed when he lost control of his bike rounding a curve to perform a "leapfrog" maneuver to pass the motorcade. The lawsuit notes that supervisors had failed to ensure that officers involved in the motorcade had ridden the entire route before the escort. View 2 more images


text:
Oakland University to launch Women's Leadership Institute
Kristin Bull |Negotiation is the theme of a daylong conference planned to launch the effort next month; leaders from business, higher education and nonprofits plan to participate.
Crain's Detroit Business is a metered site. Print and digital subscribers have unlimited access to stories, but registered users are limited to eight stories every 30 days. After viewing three metered stories, you'll be asked to register or log in. After eight more stories in 30 days, you'll be asked to subscribe.
Workphone: 313-446-1608
E-mail: email@example.com
Assistant managing editor


text:
Moraine lake HQ WALLPAPER - (#96626)
Image Stats
- Screen detected:
- Author: none
- Total Views: 3096
- Rating: 0 Votes
- Category: 1151x768
- License: Free for personal desktop use
Wallpaper TagsClick any of the tags to browse for similar wallpapers and desktop backgrounds:
lake nice nature shore crystal slope mirrored peaks clear canada cliggs alberta lovely hills beautiful water mountain moraine reflection
Download WallpaperHD resolutions (16:9): 1366x768 1600x900 1920x1080
Widescreen resolutions (16:10): 1280x800 1440x900 1680x1050 1920x1200
Normal resolutions: 1024x768 1280x1024
Original resolution: 1151x768
Join us on: Google+, Facebook, and Twitter and please share with your friends your favourite wallpapers that can only be found here!
If you like our Moraine lake desktop image vote for it and help it to get to high positions! We also give you the option to share it on social media for everyone of your friends to see and experience the great quality and content.


text:
Jose Gonzalez first divined his way as a solo guy, propagating brushed-string guitar ballads from his home base in the mild wilds of Sweden. But hey, it turns out he's never been just that; he's also been in this band Junip all along and, if the gentle brood doesn't fall far from the pleasantly muted tree, it's still pretty damn enjoyable. On Fields, Junip's first full-length, Gonzalez works his way across a gently prickly surface of hazy keyboard accoutrements and percussion that eases nicely into the turns like a bulbous '79 Saab 900. This is well-appointed, intelligent music that indulges in some stargazing prog exploration. With Lost in the Trees.
Wed., Nov. 24, 7 p.m., 2010
Get the This Week's Top Stories Newsletter
Every week we collect the latest news, music and arts stories — along with film and food reviews and the best things to do this week — so that you'll never miss Village Voice's biggest stories.
Upcoming Events
Sponsor Content


text:
AWSO Mission Statement
The Association of Wisconsin Symphony Orchestras serves as a resource for the growth and appreciation of orchestra music in the state of Wisconsin. The Association promotes and facilitates the exchange of ideas among the various state orchestras and their affiliate organizations by holding periodic educational conferences and by providing a structured network.
Next AWSO Board Meeting - September, 2016 - TBD
Workshop - 2016 Workshop: Friday, April 8, 2016, Blue Harbor Resort, Sheboygan. Hosted by the Sheboyban Symphony Orchestra. Photos...
2015 Workshop: Photos, Summary, Board Meeting Minutes, Annual Meeting Minutes
Become a Member
Our members receive benefits and support by being a part of our statewide network. Become a member or renew your membership by clicking the link below.


text:
Postal: 589 Read Place ALBURY NSW 2640
Telephone: Norm 02 6041 2412
Next Committee Meeting: 8 November 2016
Last Updated: 27 October 2016
Welcome to the Albury Wodonga Orienteering Club. The aim of the club is to provide an opportunity for members of all ages to compete in the growing sport of orienteering.
There are a number of changes to the membership process. To see options for AWOC membership, please CLICK.
Compete Safely!
Participants, particularly novice members should read the details of how to prepare and compete in orienteering events. Beginners will benefit by reading http://www.orienteering.asn.au/newcomers/ .
If you feel that you want to have a say in the running of the club, ordinary members are entitled and welcome to come along to the AWOC Committee meetings. These take place on the second Tuesday of each month from 8pm at various venues. Feel free to come along and have your input into the running of our club.
As you would appreciate, running a club and activities takes a lot of voluntary effort. We are always after volunteers to assist with committee activities, course design, preparation and setting up and administrative tasks. The work can be good fun and a great learning experience. There will always be experienced members to turn to for advice and volunteers will be trained for the various roles. Let the club know if you are able to help and in what particular activities you are interested.
Upcoming Events
The area is in fairly good condition despite the wet period. Lots of single track and complex route choices. Men's event about 18-
Sunday 6 November -
As the weather warms up and everything dries out, why not come out for the AWOC Street and Park Orienteering Series. These events are designed for people with little or no experience as well as mountain bikers and experienced orienteerers. Running/mountain bike courses are offered at various standards. Street and Park Orienteering is an excellent way to gain fitness over summer and have fun at the same time. The series starts on Wednesday evening 9 November. Start times from 5.30pm -
9 November Willow Park Pearce Street, Wodonga followed by a sausage sizzle.
16 November Monument Hill Albury at the Monument car park.
23 November Birallee Silva Drive Wodonga.
30 November Gateway Island car park, The Causeway.
4 December Noreuil Park Mitta Mitta Canoe Club room, Albury including AGM.
(Start time 4pm).
Check Out The Site
Feel free to find out about the sport of Orienteering, the events calendar for the club, local club news and much more by clicking on the menu buttons at the top of the page.


text:
Illinois Public Media News
In-depth reporting from WILL, NPR, the Associated Press, and other sources
Contact WILL News at firstname.lastname@example.com
(AP Photo File)
April 15, 2013
UI Prof: "42" Brings Accurate Story of Racist Abuse Within Baseball
(Jacquelyn Martin/AP)
April 13, 2013
Immigration Debate Puts Farm Workers Union In Spotlight
Page 601 of 1074 pages ‹ First < 599 600 601 602 603 > Last ›
WILL Newscast audio
NPR News
Cleveland Beats Chicago Cubs 6-0 In Game 1 Of World Series
U.N. Says 2016 Will Be Deadliest Year Ever For Migrants Crossing The Mediterranean
Novelist Paul Beatty Is First American To Win Britain's Man Booker Prize
Giants Cut Kicker Josh Brown Over Domestic Abuse Allegations
Researchers Build 'Nightmare Machine'
Indians Or Cubs, The World Series Will Put An End To One Team's Drought
Vatican: Don't Scatter Cremation Ashes, And Don't Keep Them At Home
Judge Approves VW's $14.7 Billion Settlement Over Emissions Scandal
Pope Francis Meets With Venezuelan President To Discuss Country's Crisis
Antarctica's Ice Sheets Are Melting Faster — And From Beneath
More NPR News
WILL Highlights
Generous Estate Gifts
Illinois Public Media receives $2.8 million through The Geneva and R. Linn Belford Fund and the Howard Rutan Endowment.
The Bandwagon
Not your typical sports podcast. Forget the "hot takes" and meet us at the intersection of sports and culture every two weeks.
Classic Mornings
Get more out of your classical music experience and check out Vic Di Geronimo's blog.


text:
5 Bedrooms Detached House for sale
***unique 5 bedroom detached house*** spacious detached home in a great location close to schools, shops and local amenities. an ideal family home with five large bedrooms (one currently…
3 Bedrooms Detached House for sale
A detached property with 3 reception rooms, 3 bedrooms and 2 bathrooms in a most convenient location at moortown corner. epc rating e
3 Bedrooms Semi Detached House for sale
Moor Allerton Crescent, Leeds, West Yorkshire, LS17 6SH
Fantastic family home - newly refurbished - three bedrooms - large rear gardens - semi-detached property - driveway - detached brick built garage - gardens to front - moortown - no…
3 Bedrooms Semi Detached House for sale
Stainburn Crescent, Moortown, Leeds, LS17 6ND
Excellent potential - semi-detached property - three bedrooms - gardens front and rear - driveway - in need of modernisation - detached garage - full double glazed windows - moortown…
Brackenhurst Drive, Moortown, Leeds, LS17
A stylish and well appointed duplex apartment offering very spacious accommodation. epc rating d
1 Bedroom Ground Flat for sale
Kingsway Court, Moortown, Leeds, LS17 6SS
Ground floor apartment - one ensuite bedroom - recently refurbished - gas central heating - garage - communal gardens - moortown - no chain
**a well appointed and improved first floor flat offering spacious accommodation in a great location, just off scott hall road** epc rating c
Free Instant Valuation
Find out if you are charging enough rent or what your property would be worth if you were to sell now
Share with your friends
Marketed by:
Knight Knox - x1 Aire, Leeds
Fifth Floor, Quay West at MediaCityUK
Trafford Wharf Road
Tel: See phone number 0161 772 1370
Website: Go to Agent Website


text:
Direct wafer bonding is a manufacturing process that is used in the fabrication of electronic, optical and mechanical microsystems. The initial step in the process requires that the wafers are sufficiently smooth, flat and compliant such that short-range surface forces can elastically deform the wafers and bring the surfaces into complete contact. Analytical and computational mechanics models of this adhesion process as well as experiments that validate these models are presented in this work. An energy-based analysis is used to develop the models that allow acceptable limits of wafer-scale flatness variations to be predicted. The analytical models provide basic insight into the process while the finite-element-based model reported provides a method to analyse a broad range of realistic cases, including the bonding of wafers with etch patterns and arbitrary geometries. Experiments, in which patterned silicon wafers with different magnitudes of wafer-scale shape variations were bonded, were performed and the results demonstrate that the proposed models can accurately predict the size and shape of the bonded area based on the wafer geometry, elastic properties and work of adhesion.
1. Introduction
Direct wafer bonding is the joining of thin (0.4–1 mm), large diameter (50–300 mm) semiconductor substrates without the use of an intermediate bonding medium. A two-step procedure is used to join the wafers, in which the wafers are initially bonded at room temperature via macroscopically short-range surface forces and then heated to form strong primary bonds at the interface (Tong & Gosele 1999). The process is attractive, as it allows high-strength bonds that are stable at high temperatures to be formed without the introduction of a bonding interlayer or the application of clamping loads during thermal treatment. The numerous attributes of this bonding approach have resulted in it being employed in a range of applications, including the manufacture of semiconductor substrates, advanced micro- and optoelectronic devices and microelectromechanical systems (MEMS).
While direct bonding continues to be adopted in an even wider range of applications, a lack of quantitative models has limited the ability to design and control the process. This has made adoption of direct bonding for new applications a time-consuming and expensive endeavour and has restricted the use of pre-bond metrology. A large fraction of the manufacturing problems that arise result from incomplete bonding in the room-temperature contacting step. If the wafers are sufficiently smooth and flat and there is an adequate density of appropriate bonding species on the surfaces, a bond front will propagate outward from the point of initial contact and pull the wafers together. However, if the wafers have high surface roughness or different shapes due to large flatness variations, bonding may fail. Establishing the acceptable limits of surface roughness and flatness variations is essential to develop robust bonding processes.
Several authors have reported models that examine the role of surface waviness (Tong & Gösele 1995; Yu & Suo 1998) and surface roughness (Gui et al. 1999; Miki & Spearing 2003) in the room-temperature bonding step. The models that describe the effect of surface waviness use an energy-balance approach that compare the elastic strain energy required for the two wafers to deform to a common geometry to the reduction in surface energy that occurs when the bond is formed. The analyses given by Tong & Gösele (1995) and Yu & Suo (1998) provide insight into the importance of wafer geometry and give a first-order criterion for bonding. However, since they compare the reduction in total surface energy to the total gain in strain energy, the models cannot be used to predict the degree to which wafers will bond or the effect of local flatness irregularities or etch patterns. In recent work, Turner & Spearing (2002) proposed a bonding criterion that allows the extent of bond advance to be predicted by considering the energy accumulated in the wafers as the bond propagates. This analysis, which is similar to the familiar Griffith energy balance in fracture mechanics and the approach employed by Johnson et al. (1971) in their work quantifying the role of adhesion in the contact of compliant spheres, allows the size of the bonded area to be predicted and permits bonding difficulty to be evaluated locally across a wafer. Turner & Spearing (2002) presented the basic framework, analytical expressions and two-dimensional finite-element simulations to illustrate the use of this approach for assessing the bonding of bare and patterned wafers in which the out-of-plane shape of the wafers are defined by a simple curvature. The results presented illustrate the essentials of the modelling approach, but did not provide a route for applying the model to realistic wafers with arbitrary geometries or verify the models experimentally.
The current work presents computational mechanics models that extend the models developed in Turner & Spearing (2002) to a wider range of cases and reports experimental results that validate the models. The paper begins with a review of the general energy-based bonding criterion and the analytical models that were developed using this criterion, as they provide background for the development of the computational model and provide insight into the design of the experiments. Next, a finite-element-based model that uses techniques adapted from fracture mechanics to evaluate the bonding criterion and calculate the shape of the bond front in wafer pairs with arbitrary geometries is presented. The model is outlined and its capabilities demonstrated through a set of test cases. Then, experiments, which were conducted to test the validity of the model, are described. Finally, the model and experiments are compared and the results are discussed.
2. Mechanics framework
Wafers typically have a range of flatness variations, from surface roughness at the smallest scale, to surface waviness with millimetre-scale spatial wavelengths, to shape variations that extend across the entire wafer. All of these flatness variations can play a role in bonding and must be controlled in order to realize robust bonding processes. The focus in this work is the effect of wafer-scale shape variations, which are deviations of the midsurface of the wafer from a flat reference plane, as shown in figure 1a. These shape deviations can result from manufacturing variations in wafer production as well as the deposition of residually stressed thin films on the surface. Shape maps of two bare 100 mm diameter silicon wafers that are from the same manufacturing lot are shown in figure 1b and demonstrate the type of shape variations that are commonly observed on prime grade semiconductor wafers. While the wafers shown in figure 1b have moderate flatness variations with a peak-to-valley height of 10 μm, larger variations, up to 100 μm across a 100 mm wafer, are not uncommon on poorly manufactured wafers or wafers with a highly stressed film on one surface.
In order for bonding to be achieved, wafer-scale shape variations, such as those shown in figure 1, must be accommodated during the room-temperature bonding step through elastic deformation. This combination of adhesion and elastic deformation that results in bonding is not relegated to just direct bonding, but is also found in a range of natural and engineered systems. Adhesion that is mediated by short-range surface forces plays a role in the contact between soft solids (Johnson et al. 1971), the ability of certain animals to adhere to walls (Spolenak et al. 2005) and stiction problems in MEMS (de Boer et al. 2000). In all of these examples, an energy-based approach, in which the change in strain energy in the body is compared to the change in surface energy, has been used to model the adhesion processes. This approach, which was first proposed by Johnson et al. (1971), and later demonstrated to be equivalent to the Griffith energy balance in linear elastic fracture mechanics (Maugis & Barquins 1978), is well suited to examine the direct bonding process.
The application of this energy-based approach to direct bonding can be understood by considering the model bonding system illustrated in figure 1a. Two wafers that have different initial shapes must elastically deform to a common shape for bonding to occur. The bonding process is driven by short-range surface forces. The overall driving force may be quantified in terms of the surface energies, γ1 and γ2, and the interface energy, γ12, as the work of adhesion, . As the bonded area increases, the strain energy, U, and total interface energy increases, while the total surface energy decreases. Calculating the total system energy and differentiating to find the equilibrium bond area of the system yields the criterion for bond front advance (Turner & Spearing 2002)(2.1)The term dU/dA, which is a function of the geometry and elastic properties of the wafers, represents the strain energy accumulated in the wafers as the bond advances. While it may be helpful to think about dU/dA as a strain energy accumulation rate, the quantity is equivalent to the strain energy release rate, G, that is commonly used in fracture mechanics. The fact that dU/dA=G is important, as it allows numerous analytical and computational methods that have been developed for fracture mechanics to be employed for adhesion problems.
To employ the criterion given in equation (2.1) to predict success or failure in bonding processes, G must be calculated based on the wafer geometry and elastic properties and then compared to the work of adhesion. Routes for calculating G analytically and numerically to examine the effect of wafer-scale shape variations are demonstrated in §§3 and 4.
3. Analytical model
If the shapes of the initial wafers can be described by simple functions, analytical models can be developed to predict the final shape of the bonded pair and the extent of bond advance. A relevant simple shape to consider, as it is the shape that results when there is a uniform residually stressed film on one surface of a wafer, is a wafer which is parabolic with a shape described by a curvature, κ. The position of the midsurfaces of the two wafers, w, as a function of the radial coordinate, r, is given as(3.1)
The application of the bonding criterion given in §2 to this case was examined in Turner & Spearing (2002). The analysis used classical plate theory and gives the final curvature of the bonded pair,(3.2)and an expression for the strain energy release rate when bonding unpatterned wafers,(3.3)where η is the thickness ratio, η=h1/h2, Σ is the modulus ratio, Σ=E1/E2 and R is the non-dimensional bond front radius, R=c/b (c, bond radius; b, radius of wafer). It is important to note that when the wafers are unpatterned and have a parabolic shape, dG/dR is always negative, suggesting that bond propagation will be unstable if the work of adhesion is constant across the wafer. Thus, wafers will either bond completely or not bond at all. As such, the criterion for bonding may be written by taking R=0(3.4)
In many practical applications, features are etched on the surfaces of the wafers prior to bonding and these features can affect the bond propagation. In Turner & Spearing (2002), the effects of shallow and deep features on bond propagation were considered. Here, the results for bonding with shallow features are reviewed. The simple pattern, shown in figure 2, was considered and is used in the experiments here. The strain energy release rate for a wafer pair with this spoke pattern at the interface is(3.5)
Depending on the pattern, bond propagation in patterned wafers may be stable or unstable. As an example, for the spoke pattern used in the experiments in this work, where R0=0.14 and Ct=0.30, dG/dR>0 for R from R0 to 1, the bond front advance will be stable. Given that the propagation is stable, the bond front will arrest when G=W, which allows the radius of the bonded area to be calculated. For the pattern used in this work and assuming a Poisson ratio of 0.18, which is an in-plane average for a (100) silicon wafer, the bonded radius is(3.6)
Note that the size of the bonded area is a function of the work of adhesion, elastic modulus, wafer thickness and curvature difference.
4. Numerical model
The analytical model in §3 provides insight into the essential scaling in the bonding process and can be used to predict the final shape and bonded areas in pairs in which the wafers are elastically isotropic and have simple geometries and etch patterns. For more complicated cases, where the wafer shapes are not described by simple functions, the wafers are single crystal and have anisotropic elastic properties, or the etch patterns are complex, a more flexible model is required. The challenge in predicting the bonded area in these more complicated cases is that the shape of the bond front is not known a priori and must be determined by finding the bond area where the bonding criterion, G=W, is satisfied along the entire front. This is significantly more challenging than the axisymmetric case in which the bonded area was assumed to be circular and defined by a single bond radius. In order to examine this more general class of problems, a finite-element-based numerical model that implements the bonding criterion outlined in §2 was developed. Finite-element methods were used as they allow complex geometries and material properties to be defined and G to be calculated locally along the bond front. The finite-element model was coupled with a procedure to iterate the bond front position that allowed the size and shape of the bond area to be predicted.
(a) Finite-element model
The wafers used in the experimental work, and hence used to define the geometry and elastic properties in the model, were 100 mm (100) silicon wafers. The mesh employed is shown in figure 3a. The wafer has a 100 mm diameter and a flat (18 mm long) that is oriented parallel to the [110] direction. The spoke pattern used in the experiments (R0=0.14 and Ct=0.30) was incorporated into the mesh. The wafers were modelled as a linear elastic material with anisotropic properties (silicon: C11=165.7 GPa, C12=63.9 GPa, C44=79.6 GPa). The out-of-plane geometry was defined by the wafer thickness and wafer shape (position of the wafer midsurface). For analysis of the experiments, the thickness and shape were imported directly from measurements of the wafers. The model includes both wafers in the bonding pair and the shape and the thickness of each are specified independently.
Figure 3a shows a mesh with a circular bond front, as was often used as the initial condition, while figure 3b shows a mesh after iteration in which the bonding criterion is satisfied along the entire bond front. The basic arrangement of the elements in plane shown in figure 3 was used throughout this study. There are four elements across the width of each spoke and three across the regions between the spokes. The mesh is refined around the bond front in the radial direction. The refined region is 5 mm wide and has four elements perpendicular to the front. The model was meshed with 20-node continuum solid elements with two elements through the thickness of each wafer. The mesh geometry shown was chosen through a series of convergence studies that ensured that the G values calculated were not a function of the mesh density.
The bonding process was modelled by calculating the distance between the two wafer surfaces from the shape and thickness data and then applying an appropriate displacement to close the gap at the interface. The displacements were applied between corresponding nodes on the opposite wafer surfaces and were specified in a way such that the gap was closed while maintaining a constant reaction force on corresponding nodes on each wafer. This is required as only the total displacement that is needed to close the gap is known and the relative deflections of the two wafers is governed by equilibrium considerations. The mesh was generated using a custom Matlab script and was exported to and solved with the commercial finite-element package Abaqus.
(b) Local calculation of G
The quantity dU/dA that is compared to the work of adhesion to assess bonding is equivalent to the strain energy release rate. A host of techniques, including the elemental crack advance method, the J-integral and the virtual crack closure technique (VCCT), have been developed for calculating the strain energy release rate using finite-element methods. While any of these techniques can be adapted for adhesion analyses, the VCCT is used here as the implementation is straightforward and it allows G to be calculated locally along the entire bond front from one finite-element simulation. The basic principle of the VCCT is that the strain energy required to advance a crack may be estimated by calculating the work required to close the crack over a small area immediately ahead of the crack front. The work is calculated from the reaction forces at the crack tip and the displacements immediately behind the crack tip. G was calculated locally along the front using the standard equations for 20-node solid elements (Krueger 2002). The VCCT provides the ability to calculate the mode I and II components of the strain energy release rate. In cases where dissimilar materials are bonded, or the wafers have significantly different thicknesses, the bond will be subject to a mixed mode loading that may affect the behaviour and both components must be considered. However, in the present work, in which both wafers are silicon and have nearly the same thickness, the loading at the interface is nearly pure mode I and the mode II component does not need to be considered.
(c) Iterative scheme
The equilibrium bond position is the position at which G=W is satisfied along the entire bond front. As the shape of the bond front is not known a priori, a bond front position is initially assumed. The finite-element model is solved and it is checked to see if the front is in equilibrium. If the bond shape does not satisfy equilibrium, the position of the bond front is adjusted and equilibrium is checked again. The adjustment to the bond front position is done in a systematic fashion using a quasi-Newton method with a rank-one Broyden update scheme (Hitchings et al. 1996).
The strain energy release rate at any node on the bond front can be considered to be a nonlinear function of the position of all the nodes along the bond front. The mesh is constructed in a manner such that the position of the nodes on the front is defined solely as a function of the radial coordinates of the bond front. This allows the strain energy release rate at any node to be defined as(4.1)where i indicates the node and n represents the total number of nodes along the front. Equilibrium is satisfied along the entire front when the strain energy release rate at every node along the front is equal to the work of adhesion. This condition may be written as a nonlinear set of equations(4.2)
The vector, R, (R=[r1 … rn]T), fully specifies the bond front position. The strain energy release rates at each of the nodes may be calculated for a given R from one finite-element simulation.
The R that satisfies equation (4.2) specifies the bond front position at equilibrium and may be solved iteratively. The approach used here to solve equation (4.2) was adapted from Hitchings et al. (1996) and uses a quasi-Newton method to update the bond shape after each iteration. After each iteration, a new bond front position is calculated:(4.3)where k indicates the iteration number. An approximate Jacobian, B, is updated after each iteration using the rank-one Broyden update formula(4.4)where(4.5)
The iteration scheme calculates the new bond front position based on the previous position of the front, the difference between G and the specified work of adhesion and the approximate Jacobian. Given that G may vary significantly along the bond front and the exact Jacobian is not being used, equation (4.3) may predict a new bond front that is not physically possible (i.e. outside the boundary of the wafer) or would cause significant mesh distortion. To prevent this, the radial shifts, (ΔR=Rk+1−Rk), that are predicted in each iteration, are checked to ensure that they do not exceed a specified value, ΔRlim. Values of 3–5 mm for ΔRlim were used. If any of the calculated shifts along the front did exceed the specified ΔRlim, the shifts along the entire front were scaled by a factor, , such that the maximum shift at any node along the front was ΔRlim. The bond front position was iterated until G was within ±1% of the specified work of adhesion value along the entire front. Convergence was typically achieved in 20–50 iterations. This iterative scheme and its integration with the other parts of the model is summarized in figure 4.
(d) Results
The capabilities of the model were explored by examining the bonding of different combinations of wafers with the shapes shown in figure 5. The bonding of wafers B and E shown in figure 5 illustrates the basic operation of the model well. The shapes shown in the figure were imported into the model and an initial circular front with a radius of 27 mm was assumed (figure 3a). Figure 6 shows the distribution of G along the circular front. The variation in G that is observed results from the asymmetry in the shape of the wafers and the anisotropic elastic properties. The model required 32 iterations to determine the bond front in which G was within ±1% of the target of 25 mJ m−2. The distribution of G along the converged bond front is shown in figure 6 and the shape of the equilibrium bond front is shown in figure 3b.
The bonded area shapes for six different wafer pairs at various values of work of adhesion are shown in figure 7. Each pair shown in figure 7 is labelled by a two-letter combination which indicates the shapes of the two wafers shown in figure 5 that were considered. The predicted fronts for the three pairs shown in the top row of figure 7 illustrate the effect of varying degrees of asymmetry on the bond front shape. Wafer A has the shape with strongest asymmetry and thus the bond front predicted for pair A–E is the most asymmetric in the set. The asymmetry of the underlying wafers decreases from left to right in the top row of figure 7 and a corresponding change in the shape of the bond front is seen. Comparison of the size of the bonded areas at a constant work of adhesion (20 or 25 mJ m−2) across pairs A–E, B–E and C–E shows that the bonded area is smallest in pair C–E. As all the wafers have the same maximum curvature and pair C–E has the least asymmetry, this result suggests that a conservative estimate of the bond area could be made by using the axisymmetric analytical model with the maximum curvature difference.
Comparing pairs B–E and C–E to pairs B–D and C–D illustrates that the shapes of both wafers in the pair influence the shape of the final bonded area. It is seen that in pairs B–E and C–E, where the bottom wafer has an axisymmetric curvature that is comparable to the maximum curvature of the asymmetric wafer, the bonded areas are less asymmetric than when the bottom wafer is flat (pairs B–D and C–D). Pair B–F shows the bonding of two asymmetric wafers with their principal curvatures orthogonal to one another. It is seen that the bonded area is not significantly asymmetric, which can be understood by realizing that the gap at the interface (wB−wF) is axisymmetric. The final point that is illustrated in the predictions shown in figure 7 is the effect of elastic anisotropy. In all the predictions, the bond areas have sides that are slightly flattened as a result of the cubic symmetry of the silicon.
5. Experimental
(a) Approach
The aim of the experiments in this work was to validate the mechanics-based models for wafer bonding presented. Figure 8 shows the basic arrangement used in the experiments. An unpatterned wafer with a tensile residually stressed film on the back surface was bonded to a wafer with a shallow etched spoke pattern on the bonding surface. A spoke pattern with R0=0.14 and Ct=0.30 was used to achieve stable propagation such that the bond front would arrest when G=W and result in a measurable bond area.
The basic premise of the experiments is to bond wafers with different shapes, monitor the propagation and assess the ability of the model to predict the final shape and size of the bond front. While the elastic properties of the wafers are known and the geometry and thickness was measured, the work of adhesion was not known and could not readily be measured. The work of adhesion in this context is a lumped parameter that is a function of the type and density of the bonds formed at the interface as well as smaller-scale flatness variations (waviness and roughness). Given that the work of adhesion could not be measured independently, the approach used in these experiments was to bond multiple pairs with different shapes, calculate the work of adhesion for each pair from the bond position using the model and then compare the work of adhesion across different pairs. Given that the wafers were from the same manufacturing lot and were cleaned in the same manner prior to bonding, the expectation is that the extracted work of adhesion values should be constant across all the pairs if the model properly accounts for the different geometries of the wafers.
All wafers used in the bond propagation study were 100 mm (100) silicon wafers that were nominally 525 μm thick. The wafers were single side polished and were taken from the same manufacturing lot. A tensile residually stressed nitride film was deposited on the back surface of one wafer in the pair to add controlled wafer-scale shape variations. The thickness of the film was varied from 0.2 to 0.6 μm to achieve a range of wafer shapes. These wafers were fabricated by initially growing a 500 nm thermal oxide, then deposition of high stress (σ≈0.7–1.0 GPa) stoichiometric silicon nitride. The silicon nitride was removed from the bonding surface by masking the back with a deposited low-temperature oxide, and etching the nitride from the front in a standard hot-phosphoric etch solution (H3PO4 (85%) at 165 °C). The mask oxide on the back surface and the 500 nm thermal oxide on the bonding surface were removed using a buffered oxide etch (7 : 1 NH4F(40%) : HF(49%)). The spoke patterned wafers were fabricated by first growing a 1000 nm thermal oxide, then patterning the oxide using standard photolithography and a wet oxide etch. The pattern was transferred to the silicon using deep reactive ion etching. The etch depth on all wafers was between 2 and 3 μm, which is deep enough to prevent bonding, but sufficiently shallow not to alter the stiffness of the wafer. Following etching, the oxide mask was removed using a buffered oxide etch. A standard RCA clean was used immediately prior to bonding to ensure a hydrophilic surface and consistent surface chemistry.
During bonding, the wafers were supported at the centre on a 3 mm diameter pin and pressed into contact with another pin to initiate the bond. All experiments were performed at room temperature and pressure in a class 100 clean room at a relative humidity of approximately 37%. The bond front propagation was monitored using infrared (IR) transmission imaging and the bonded areas were measured directly from digitized images. After bonding, the pairs were separated and the geometry of each wafer was measured using an ADE 9900 capacitance gauge (ADE Corporation 2000) that has a 2 mm2 capacitance probe that is scanned across the wafer to obtain full wafer maps of the thickness and shape.
(b) Analysis
The work of adhesion for each bonded pair was calculated based on the wafer geometry, elastic properties, etch pattern and measured bond area using the axisymmetric model described in §3 and the numerical model presented in §4. Employing the axisymmetric model (equation (3.6)) was not straightforward as the shapes of the wafers and the bonded areas for the most part were not axisymmetric. This made it difficult to define a single bond radius and wafer curvature difference for each pair difficult. As a result, for each pair, a minimum, average, and maximum bond radius and curvature difference were determined from the experiments and a minimum, average, and maximum W for each wafer pair were calculated using equation (3.6). The finite-element model presented a more direct route to calculate work of adhesion values for the pairs as their asymmetric geometries could be accounted for properly in the model. For each pair, the measured shapes and thicknesses of the individual wafers were imported into the model and the bonding behaviour was mapped out as a function of work of adhesion.
Figure 9 shows an example of this process for one of the pairs in the experiment. The measured shapes of the individual wafers that are imported into the model are shown in figure 9a,b and the bond fronts predicted using the finite-element model for a range of work of adhesion values are shown in figure 9c. The work of adhesion for each pair may be determined by selecting the predicted bond front that fits the experimentally observed front the best.
(c) Results and discussion
Six wafer pairs were bonded in the study. The shapes of the individual wafers in each pair and the resulting bond radii are summarized in table 1. The wafer shape has been expressed as the peak-to-valley shape difference (P−V) across the centre 90 mm of the wafer. The sign next to the P−V values indicates if the wafer shape was concave up (+) or down (−) during bonding. The signed P−V value clearly does not fully describe the wafer shape, but is given as it provides an understanding of the relative shapes of the wafers in the experiments. Measurements of the wafer thickness showed that the mean thicknesses of the wafers in the set ranged from 523 to 528 μm and that the total thickness variation of each wafer was less than 4 μm.
The bond front position (and hence the work of adhesion) was observed in the experiments to be time dependent. The bond front was observed to advance at a rate of several millimetres per second in the first few seconds after contact and then continue to grow at a much slower rate for hours after contact. This time dependence is presumably associated with the dynamics of bond formation at the interface as well as the adsorption of molecules (i.e. water) on the surface and is likely to be a function of various factors such as temperature and humidity. No attempt was made to characterize this dependence fully or to further understand its origin as it is outside the focus of validating the mechanics models in this work. To minimize the effect of time in the extracted work of adhesion values, all images and measurements of the bond front were recorded 10 min after initial contact of the wafers. A period of 10 min was selected as the rate of bond advance was relatively slow at this point and the time period was short enough such that multiple pairs could be bonded sequentially without the ambient conditions (temperature and humidity) changing significantly.
The IR images of four of the bonded pairs listed in table 1 are shown in figure 10. Also shown in the images are the bond fronts predicted using the finite-element model. In each image there are two predictions, the smaller of the predicted bond areas corresponds to W=35 mJ m−2 and the larger to W=40 mJ m−2. Pair P5 is not shown as the bond front propagated to the edge of the wafer. The sixth pair in the experimental set is not shown either as irregular bond front propagation, which is consistent with surface contamination, was observed.
The work of adhesion values extracted from the pairs in the bond propagation study is summarized in figure 11. Work of adhesion values calculated via the axisymmetric model and the finite-element model are both shown. For the axisymmetric analytical results, the markers in figure 11 correspond to the W calculated from the average bond radii and curvature difference of the pair and the limits of the error bars represent the W calculated from the minimum and maximum bond radii and curvature. Across pairs P1–P4, the average work of adhesion values extracted using the axisymmetric model range from 29 to 43 mJ m−2, while those extracted with the numerical model range from 36 to 40 mJ m−2. The variability in the results extracted with the axisymmetric model is not surprising given that clear asymmetries are present in the wafer shapes and observed bond fronts. Pair P5 is the pair that bonded completely and as such only a lower bound on the work of adhesion may be calculated from the test. The lower bound calculated from P5 is consistent with the work of adhesion values of pairs P1–P4. The irregular propagation observed in pair P6 prevented the model from being employed to compute a work of adhesion.
The results in figures 10 and 11 show that the finite-element model accurately predicts the shape of the bond area and that the work of adhesion values extracted from pairs with different geometries are the same. The magnitude of work of adhesion values extracted is reasonable. The work of adhesion values reported are 'apparent' work of adhesion values in that they include effects of smaller-scale flatness variations as well factors such as humidity. Previous measurements on polycrystalline and single crystal silicon surfaces with a thin native oxide have shown that work of adhesion values can range from 10 to 140 mJ m−2 (e.g. Miki & Spearing 2003; Maboudian & Carraro 2004), depending on the roughness and the relative humidity. The work of adhesion values of 36–40 mJ m−2 measured in this work fall in this range.
6. Conclusions
A comprehensive set of models for predicting bonded area based on the wafer geometry, elastic properties and work of adhesion have been presented and experimentally validated. The analytical model is useful for analysing wafers where the wafer-scale shape variations are parabolic and to make first-order estimates of bonding in asymmetric wafer pairs. The numerical model presented is significantly more flexible and allows the bonding of wafers with complicated shapes and etch patterns to be analysed. The excellent agreement between the predicted and observed bond areas shown in figure 10 and the consistency in extracted work of adhesion values (numerical results) shown in figure 11 indicate that the proposed model accurately captures the mechanics of the bonding process and has the ability to model the effect of wafer-scale shape variations in direct bonding.
The set of models presented here have significant potential to aid in the design and control of direct bonding processes. The analytical model provides a route for quickly estimating the ability to bond two wafers and clearly shows the effect of changing the geometry or material of the wafers in the process. The numerical model allows tolerances to be set on wafer geometry and enables the effect of specific etch patterns on bonding to be studied. Furthermore, the models presented can be used to aid in the design of novel wafer bonding processes, such as the bonding of wafers in a stressed configuration to produce uniaxially strained silicon.
Beyond wafer bonding, this work also demonstrates a unique approach of using computational fracture mechanics techniques to analyse surface-force-driven adhesion problems that arise when soft materials or thin compliant structures make contact. As investigations into contact in biological and micromechanical systems are pushed further, there will undoubtedly be a need to employ computational approaches to adequately understand the mechanics of the systems. The computational techniques demonstrated here are general and provide a set of tools that allow such problems to be addressed.
The authors would like to acknowledge the MIT Microsystems Technology Laboratory (MTL), where all of the microfabrication and experimental work was performed, and the assistance of the ADE Corporation (P. Hester) in obtaining wafer shape measurements. This work was supported by the Cambridge MIT Institute (CMI-059/P-IR(FT) MEMS).
↵* Author and address for correspondence: Department of Mechanical Engineering, University of Wisconsin–Madison, 1513 University Ave, Madison, WI 53719, USA (firstname.lastname@example.com).
↵† Present address: School of Engineering Sciences, University of Southampton, Southampton SO17 1BJ, UK (email@example.com).
- Received April 15, 2005.
- Accepted August 18, 2005.
- © 2005 The Royal Society


text: New at this...just getting started after spending almost a year gathering parts and pieces to start reloading. Successfully reloaded five rounds of 380 which fired and operated action with somewhat less kick than factory ammo - which is what I expected starting at the starting load in my Hornady 8th edition. Here's the kicker: So I reloaded 10 rounds of 45 ACP last night to the Hornady specs (since I am using Hornady #45137 FMJ SWC bullets) of 5.5 gr of Titegroup. A Titegroup load is not listed in my Lyman 49th edition. I just went back to my reloading bench to recheck my data before firing the rounds and I began to compare the two manuals with powders listed in both manuals and now I'm stopped in my tracks. For instance, for the same bullet (185 gr FMJ SWC): Lyman shows a charge range for Bullseye of 3.5 gr to 5.6 gr. Hornady shows a charge range for Bullseye of 5.4 gr to 6.6 gr Lyman shows a charge range for HS-6 of 6.6 gr to 9.1 gr. Hornady shows a charge range for HS-6 of 8.7 gr to 10.1 gr A couple of other powders show a similar spread in recommended loads. Now, I don't know if my 5.5 gr of Titegroup is at the low end or in the middle. If the offset is the same as for Bullseye, then the starting load in the Hornady manual would be very near the max in the Lyman manual. In the middle of this post, I went to the Hodgdon Load Data for this round and it gives a range of 5.0 gr to 5.5 gr = I am at the max!!! So I have now officially learned to check multiple sources first, so I've already beat myself up on that one, so which do I believe? Do I find all possible data and use the lowest? Forum - Help! What must I do do get a warm and fuzzy feeling before pulling the trigger on these rounds? Do I need to pull and restart?