McKay Dee Hospital

This executive summary and recommendations appears in the November 3, 1998, issue of Circulation. The guidelines in their entirety, including the ACC/AHA Class I, II, and III recommen

Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedge pressures (p less than .01), whereas both left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume indexes increased (p less than .01). The increase in LVEDV correlated directly with the percentage of the ventriculographic silhouette that was akinetic or dyskinetic at the initial catheterization (r = .71, p less than .001). To assess regional changes in both infarcted and noninfarcted segments, serial endocardial perimeter lengths of both the akinetic-dyskinetic segments (infarction zone) and of the remainder of the cardiac silhouette (noninfarction zone) were measured in all patients who demonstrated at least a 20% increase in their LVEDV at 2 weeks after myocardial infarction. Notably, there was a mean increase of 13% in the endocardial perimeter length of infarcted segments and a 19% increase in the endocardial perimeter length of noninfarcted segments. Serial M mode echocardiographic studies showed no significant change in the wall thickness of noninfarcted myocardial segments. Hemodynamic changes that occurred in this subgroup of patients included significant decreases in left ventricular end-diastolic and pulmonary capillary wedge pressures (p less than .05) and significant increases in angiographic cardiac index (p less than .01) and LVESV index (p less than .01). We conclude that in patients who manifest cardiac dilatation in the early convalescent period after myocardial infarction, there is remodeling of the entire left ventricle including infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE: "Reference ranges" are developed when it is impossible or inappropriate to establish "normal ranges" by drawing blood on healthy normal volunteers. Reference ranges for the hematocrit and the blood hemoglobin concentration of newborn infants have previously been reported from relatively small sample sizes by using measurement methods that now are considered outmoded. METHODS: We sought to develop reference ranges for hematocrit and hemoglobin during the neonatal period (28 days) by using very large sample sizes and modern hematology analyzers, accounting for gestational and postnatal age and gender. Data were assembled from a multihospital health care system after exclusion of patients with a high likelihood of an abnormal value and those who were receiving blood transfusions. RESULTS: During the interval from 22 to 40 weeks' gestation, the hematocrit and blood hemoglobin concentration increased approximately linearly. For every week advance in gestational age, the hematocrit increased by 0.64% and the hemoglobin concentration increased by 0.21 g/dL. No difference was seen on the basis of gender. During the 4-hour interval after birth, hematocrit/hemoglobin values of late preterm and term neonates (35-42 weeks' gestation) increased by 3.6% +/- 0.5% (mean +/- SD), those of neonates of 29 to 34 weeks' gestation remained unchanged, and those of <29 weeks' gestation decreased by 6.0% +/- 0.3%. During the first 28 days after birth, an approximately linear decrease in hematocrit/hemoglobin occurred. CONCLUSIONS: The figures presented herein describe reference ranges for hematocrit and blood hemoglobin concentration during the neonatal period, accounting for gestational and postnatal age.

Echocardiographic measurements of the left ventricular dimensions and wall thicknesses at end diastole and end systole, aortic root and left atrial dimensions, mitral valve E-F slope, left ventricular ejection fraction, percent fractional shortening of the left ventricular internal dimension, estimated left ventricular mass and percentage systolic thickening of the ventricular septum and left ventricular free wall were obtained in 105 normal subjects ranging from one day to 23 years of age. Each parameter was found to follow a linear regression upon one of three functions of the body surface area. The internal dimensions of left ventricle, the left atrium, and the aortic root, and the mitral valve E-F slope varied in a linear relation to the cube root of the body surface area. Thickness of the ventricular septum and left ventricular free wall varied in a linear relation to the square root of the body surface area. Estimated left ventricular mass varied linearly with the direct measurement of body surface area. Ejection fraction, percent fractional shortening of the left ventricle and percent systolic thickening of the ventricular septum and left ventricular free wall were independent of body surface area despite a marked increase in the size of the left ventricle during normal growth and development.

Both systolic and diastolic dysfunction have been described during pacing-induced ischemia, but the temporal sequence of systolic and diastolic impairment has not been established. Accordingly, 22 patients with coronary artery disease were paced at increasing heart rates and studied with simultaneous hemodynamic monitoring, electrocardiographic recording, and radionuclide ventriculography. In addition, with synchronized left ventricular pressure tracings and radionuclide volume curves, three sequential pressure-volume diagrams were constructed for each patient corresponding to baseline, intermediate, and maximum pacing levels. Eleven patients (group I) demonstrated a nonischemic response to pacing tachycardia without chest pain, significant electrocardiographic changes, or significant rise in left ventricular end-diastolic pressure (LVEDP) in the immediate postpacing period. These patients demonstrated a progressive decrease in LVEDP, end-diastolic volume, and end-systolic volume, no change in cardiac output or left ventricular ejection fraction, and a progressive increase in left ventricular diastolic peak filling rate and the end-systolic pressure-volume ratio. Pressure-volume diagrams shifted progressively leftward and slightly downward, suggesting both an increase in contractility and a mild increase in left ventricular distensibility. The remaining 11 patients (group II) exhibited an ischemic response to pacing tachycardia, with each patient experiencing angina pectoris, demonstrating greater than 1 mm ST segment depression on the electrocardiogram, and exhibiting greater than 5 mm Hg rise in LVEDP immediately after pacing. LVEDP, end-diastolic volume, and end-systolic volume in these patients initially decreased and then subsequently increased during angina, with no change in cardiac output but a decrease in ejection fraction. Left ventricular peak diastolic filling rate and the left ventricular end-systolic pressure-volume ratio both increased at the intermediate pacing rate but fell at maximum pacing. Pressure-volume diagrams for these patients shifted leftward initially, then back to the right, during intermediate and peak pacing levels, often with an upward shift in the diastolic pressure-volume relationship. LVEDP in group II was significantly higher than that in group I at the intermediate pacing level with no difference in end-diastolic or end-systolic volumes, suggesting decreased left ventricular distensibility in these patients before the onset of systolic dysfunction at the maximum pacing level.(ABSTRACT TRUNCATED AT 400 WORDS)

To assess the safety and efficacy of percutaneous balloon valvuloplasty in calcific aortic stenosis, balloon dilatation of critically stenosed, calcified aortic valves was performed in five postmortem hearts, in five patients intraoperatively before aortic valve replacement, and in two elderly patients percutaneously at the time of diagnostic catheterization. The etiology of aortic stenosis in the 12 cases was rheumatic in two, congenital bicuspid calcific stenosis in one, and senile calcific degenerative stenosis in the remaining nine. Prevalvuloplasty examination in the 10 postmortem and intraoperative cases revealed rigid valve leaflets with commissural fusion in three valves and extensive nodular calcification in seven. Subsequent balloon dilatation with 15 to 18 mm valvuloplasty balloons resulted in decreased cusp rigidity and increased mobility of valve leaflets in all cases, without evidence of tearing of valve leaflets, disruption of the valvular ring, or liberation of calcific or valvular debris. In the three valve specimens with commissural fusion, balloon dilatation resulted in partial or complete separation of leaflets along fused commissures. In two cases with extensive nodular calcification, balloon dilatation resulted in a fracture of a calcified leaflet that was evident on both gross and radiologic examination. After postmortem and intraoperative studies, percutaneous catheter valvuloplasty was performed at the time of diagnostic catheterization in two elderly patients (93- and 85-year-old women) with long-standing calcific aortic stenosis. Balloon dilatation with 12 to 18 mm balloons resulted in significant decreases in aortic gradients and significant increases in cardiac index and aortic valve area in both patients. Percutaneous valvuloplasty in both patients resulted in a mild increase in aortic insufficiency and no evidence of embolic phenomena.

This is the first guideline describing the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI). This guideline should be used as an adjunct to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) including the ASIA Impairment Scale (AIS), which documents the neurological examination of individuals with SCI. The Autonomic Standards Assessment Form is recommended to be completed during the evaluation of individuals with SCI, but is not a part of the ISNCSCI. A web-based training course (Autonomic Standards Training E Program (ASTeP)) is available to assist clinicians with understanding autonomic dysfunctions following SCI and with completion of the Autonomic Standards Assessment Form (www.ASIAlearningcenter.com).

Bone morphogenetic proteins (BMPs) have been the subject of considerable research for several decades. The academic chronicle began in 1965 with Dr. Marshall Urist’s discovery of osteoinductive activity within demineralized bone protein extracts, and continued with his later identification of the active molecules as bone morphogenetic proteins. 23,24 This was followed in 1988 by the isolation of an individual protein, BMP-2, from a purified extract and its recombinant production. 25 The long-awaited clinical use and commercial availability of BMPs have only recently approached reality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the only BMP for which a prospective randomized pivotal clinical trial for a spine fusion indication has been completed. It has demonstrated equivalence to autogenous iliac bone graft with regard to both fusion rate and clinical outcome. 7 On the basis of this study, the Food and Drug Administration (FDA) has advised that rhBMP-2 be approved for commercialization as the first complete bone graft substitute for spinal fusion indication. At this writing, all other FDA-cleared bone-grafting products are only osteoconductive scaffolds incapable of solely initiating bone formation under the classic definition of osteoinduction: the ability to induce de novo bone formation at a nonbony site. A significant body of data on the use of rhBMP-2 in spinal fusion surgery has been collected. Both the potential uses of rhBMP-2 and its limitations in spinal fusion applications have become clear through this extensive series of preclinical and clinical investigations. It was determined that an application-specific carrier was required to release the rhBMP-2 protein over an adequate period and at a sufficient concentration. Different fusion techniques such as intervertebral arthrodesis and posterolateral intertransverse process arthrodesis presented their own specific challenges, which required specific carrier–rhBMP-2 combinations. The relevant preclinical and clinical research that provided data regarding site-specific product configurations is presented in this article. The first part of the article reviews some of the preclinical efficacy data and lessons learned from these animal studies. The second part describes FDA-approved investigational device exempted (IDE) clinical human trials and their results involving rhBMP-2 for human spinal fusions. Product Development Considerations Early work with rhBMP-2 demonstrated that the carrier had a profound effect on the efficacy of the molecule for specific applications. It was determined that the carrier serves three very important functions: It acts as a three-dimensional space occupier and scaffolding across which de novo bone formation can occur. It maintains a critical threshold concentration of BMP at the site of implantation for the desired period. It contains the BMP at the site of application to prevent extraneous bone formation. Several carriers for rhBMP-2 have been evaluated including collagen sponges, calcium phosphate ceramics, and degradable synthetic and natural polymers. Each of these vehicles offers its own unique advantages and disadvantages. The efficacy of the carrier–growth factor composite was evaluated largely through preclinical research, which requires a long iterative trial and error process. Ideally, a carrier is a resorbable material with a resorption profile that generally matches the rate of de novo bone formation. If the carrier resorbs before adequate osteodeposition, misdirected bone formation and pseudarthrosis may be the ultimate result. If the carrier resorbs too slowly, bridging bone formation and remodeling may be impeded. Preclinical research is complicated by the fact that rhBMP-2 efficacy is species dependent (i.e., higher concentrations of the molecule are required in more evolved animals). Thus, a valid determination of the efficacy of the carrier–rhBMP-2 composite, before initiation of human clinical trials, ultimately is dependent on findings in primate studies using clinically relevant models. Two of the more common spinal fusion procedures are interbody fusion using load-bearing cages and posterolateral intertransverse process fusion. Because these two distinct spine fusion techniques involve different mechanical and biologic demands, specific carrier–rhBMP-2 composite configurations were indicated for each technique. Therefore, preclinical findings with interbody and posterolateral fusion techniques were reviewed separately. Preclinical Studies by Site of Application Interbody Spinal Fusion The intention of interbody spinal fusion is to achieve a bony arthrodesis across a degenerated and usually narrowed disc space. In the process of achieving fusion, the intervertebral space is distracted to a reasonable approximation of its original height with the intent of restoring sagittal plane alignment. At the time of this writing, no carrier material could be identified that could deliver the molecule biologically to the site of fusion while sustaining the loads for disc distraction and motion resistance. Therefore, preclinical attention was directed at rhBMP-2 with a nonstructural carrier housed in an intervertebral fusion construct such as a cylindrical metallic cage or in cylindrical allograft bone dowels. Normally, these hollow-chamber constructs are packed with autogenous bone graft and provide the osteoinductive stimulus for intervertebral fusion. Because the loads are borne by the construct itself, the autogenous bone graft or any other filling material is not subject to normal physiologic load. One of the most effective nonstructural carriers for rhBMP-2 proved to be the Type I bovine absorbable collagen sponge (ACS). The cohesive ACS is hydrated with rhBMP-2 solution at the time of surgery. The collagen sponge, which efficiently binds the rhBMP-2, then is packed into the fusion construct (Figure 1). This particular collagen sponge has been used commercially over the past 20 years as a hemostatic agent (Helistat). The ACS is a fibular collagen with a slow resorption profile well suited for the delivery of the growth factor. The minimum intraoperative soak time at surgery for adequate binding of the molecule to the sponge before its implantation has been determined to be 15 minutes. After implantation, the ACS undergoes resorption over a 2- to 4-week period via cell-mediated degradation. The collagen also provides a favorable surface for cell attachment during early osteoid formation. The half-life for local delivery of rhBMP-2 is approximately 2 to 3 days. The molecule then is undetectable beyond 4 weeks after implantation.Figure 1: Collagen sponge carrier is soaked with recombinant human bone morphogenetic protein-2 solution at the time of surgery (A), then rolled and placed into an interbody fusion cage (B).The first preclinical interbody cage study using rhBMP-2 was reported by Sandhu et In this study, interbody were in the using the and fusion cages were with autogenous iliac bone graft or rhBMP-2 on a collagen sponge The were after surgery. was determined and to all the had fusion by the were both and the with fusion after the with had fusion at the in In the by rhBMP-2 had the of the cage the by autogenous bone graft (Figure In to the efficacy of rhBMP-2 in this fusion this study also demonstrated the of to the of spinal fusion through metallic intervertebral and and and of interbody cages with iliac and or recombinant human bone morphogenetic protein-2 (rhBMP-2) on a collagen sponge and was the of cages more other preclinical interbody fusion studies using cages and rhBMP-2 demonstrated et used a fusion cage in a was with the use of rhBMP-2 on a collagen The findings that of the cages with were with spinal fusion, as with of the cages with the of the fusion not with the of the fusion. On the basis of the results in these animal intervertebral were in the primate et 2 the use of rhBMP-2 on the collagen sponge in a interbody fusion cage in The cages were with two concentrations of rhBMP-2 and and with a The implantation of a collagen sponge growth factor and a fusion of the with the spinal fusion after the with concentration of the rhBMP-2 on to fusion. The higher concentration was with a and bone formation the concentration any (Figure On the basis of these the concentration was as the for the human clinical of collagen (A), concentration of recombinant human bone morphogenetic protein-2 (rhBMP-2) and concentration of rhBMP-2 study using allograft bone of cages also was with the et reported that after interbody fusion, all with allograft bone with rhBMP-2 on a collagen sponge fusion. of three with allograft bone with autogenous bone graft fusion. the allograft bone in the of recombinant rhBMP-2 had complete resorption and remodeling during the study period. This was distinct from the in which the of the allograft was after (Figure This study that the of rhBMP-2 not only bone also was no of intervertebral or early of the bone in investigational all of the preclinical studies of sponge in interbody fusion and and and of allograft bone with iliac and or recombinant human bone morphogenetic protein-2 on a collagen sponge and 1: of Interbody Fusion Preclinical Studies Fusion The mechanical and biologic for posterolateral spine fusion is more that for interbody spinal fusion. The of rhBMP-2 for posterolateral applications was more Preclinical studies in higher indicated that the Type collagen sponge was an carrier for rhBMP-2 in a posterolateral fusion In this such as that provided by an interbody fusion cage not be several animal studies with and demonstrated the ability of the collagen sponge to deliver rhBMP-2 in an intertransverse process fusion, this was not the in higher such as et reported a fusion rate for rhBMP-2 in a posterolateral fusion 4 weeks after In this only of the both and rhBMP-2 and more bone and remodeling autogenous bone Fusion with rhBMP-2 was and (Figure the of to and of at 4 as with recombinant human bone morphogenetic protein-2 and collagen carrier at the time et 15 reported a fusion rate of in a posterolateral fusion within weeks after the implantation of rhBMP-2 on a collagen In this of the In a trial in which the were not the were to induce process fusion in the of et evaluated the use of rhBMP-2 as an for autogenous bone by to the the as the or by on a collagen sponge that then was to the autogenous fusion were with in which rhBMP-2 was to the autogenous bone The fusion were with rhBMP-2 on the collagen sponge to autogenous bone et also evaluated rhBMP-2 as an in the posterolateral fusion demonstrated that the fusion in the of rhBMP-2 after surgery (Figure of with or and recombinant human bone morphogenetic protein-2 (rhBMP-2) the in the fusion from that of at weeks with and rhBMP-2 at the time This was significant findings in were not in the primate In a series of by et rhBMP-2 concentrations to be effective in were not effective in posterolateral in It was that mechanical of the collagen sponge was the sponge and bone formation. In a a was and placed over the collagen sponge carrier across the to from (Figure this a rhBMP-2 concentration a fusion. fusion also were the On the basis of these is that a carrier had to be for the posterolateral fusion of a spine with across used to the recombinant human bone morphogenetic collagen of a spine after surgery of bone formation the with use of a and to no bone the use of a et reported on of the first carriers to achieve posterolateral fusion with in this The carrier was a calcium phosphate of and phosphate Both and have a long of clinical undergoes very slow and undergoes The calcium phosphate was to for a part of the composite to resorption while a of was for the of phosphate are well to This carrier requires only a intraoperative soak time to adequate rhBMP-2 binding before The of rhBMP-2 release from the has been in a posterolateral fusion The half-life was to be approximately days. et reported that all three rhBMP-2 concentrations evaluated in this primate study and in of the with autogenous bone graft a fusion (Figure This trial was the first preclinical of rhBMP-2 efficacy for posterolateral spinal fusion in a primate and of fusion from weeks after arthrodesis with and phosphate and and with recombinant human bone morphogenetic protein-2 (rhBMP-2) and bone and are in the fusion with bone in the fusion with and carriers with have been for use in the posterolateral fusion A composite of and into the collagen The of these the provides to by in the posterolateral fusion (Figure This as the can be and into the desired and before with rhBMP-2 solution using an The rhBMP-2 solution then is the using a to that used with the ACS The soak time in this is a minimum of minutes. The of to was to resorption of the carrier and of bone formation. It was that resorbs too to bone formation. A with a of undergoes significant resorption in approximately 3 to 4 and is by bone that is after the carrier is via cell-mediated and The of rhBMP-2 release from the carrier was in a posterolateral fusion The half-life was approximately to that of the The composite sponge is of resorbable calcium phosphate in a collagen This sponge is to in a posterolateral fusion as is across the their et demonstrated that all with as with the fusion rate in iliac autogenous bone graft of fusion and that these were and in and to with carriers such as the ACS collagen sponge and the with rhBMP-2 (Figure the of to of at as with using recombinant human bone morphogenetic protein-2 (rhBMP-2) and collagen sponge carrier and rhBMP-2 on the carrier at the time carrier then was evaluated in the primate In all the with posterolateral fusion et to the effect of delivery in the posterolateral the effect of to the ACS collagen Two such of allograft or resorbable to the ACS collagen sponge some resistance. The allograft or resorbable of ACS collagen or in the collagen sponge (Figure of such as allograft or to the collagen sponge used in the primate study, and both of these posterolateral of the time in the In only of three with autogenous bone graft in this had fusion, and that fusion was by bone (Figure of the posterolateral fusion with and that with recombinant human bone morphogenetic absorbable collagen sponge, and resorbable or allograft at 2 all the preclinical studies of sponge and carriers in posterolateral fusion models. On the basis of these preclinical in the results of primate several human clinical trials were under Food and Drug Administration investigational device The describes the clinical results to from the use of rhBMP-2 in some of these spinal fusion of Fusion Preclinical Studies the of rhBMP-2 for Spinal At this writing, more have in clinical trials human spinal fusion. In more have been in these studies for The composite device of rhBMP-2 by the absorbable collagen sponge has been Bone The studies and in a study on the use of Bone in a cage for interbody fusion, a pivotal study on the use of Bone in a cylindrical cage for interbody fusion, a study on the use of Bone in a cylindrical allograft bone for interbody fusion, a pivotal study on the of a cage with Bone for interbody fusion, a study on intervertebral with a cylindrical fusion cage with Bone a study on the use of Bone within a allograft for and and fusion, and a study on the use of an composite for posterolateral spinal fusion. The the clinical data at this for these clinical studies. of Bone Fusion On an investigational device (IDE) was with the to study the use of rhBMP-2 in with disc The rhBMP-2 was with the absorbable collagen sponge as the This composite then was placed into a interbody fusion device The application was approved in and the first surgery was in the approved and by investigational were with rhBMP-2, and 3 were in the The were with a cage with autogenous bone graft from the iliac was in On the basis of the results from the primate study in which the sponge composite also was in a cage for interbody fusion, a of rhBMP-2 at on the collagen sponge was for the The of the study were to the investigational and for fusion efficacy on the basis of and to the of rhBMP-2 in The was to a of with attention to and The study was as a prospective randomized of the investigational and all three of the were using an to the spinal of the investigational the fusion through a the in the study were 3 and after surgery. The and were by at the time with rhBMP-2 on to fusion, as determined by Two of the three also on to fusion. One with pseudarthrosis required a and fusion approximately after the surgery. and as by the are for each of the time in Bone clinical investigational at each of the time Because of the the were not was on each of the before then weeks and 3 after surgery. were for the of specific to rhBMP-2 and bovine collagen Type I the collagen sponge is from bovine of the study had rhBMP-2 after implantation of the had collagen Type I The clinical not to be by the of collagen Type I three these were determined to have had spinal fusions. of at and after surgery the are in of at the time the with Bone are in for 7 and Bone for and of Bone The and efficacy data from the clinical study Bone placed within a for interbody fusion was used to the initiation of a pivotal 7 The pivotal clinical trial from the on and on began on and the study had surgery on A of investigational and were in this the in the study an to the spinal with this study, the also to a to this The results of the are reported in the This pivotal clinical study was as a randomized The investigational the with Bone for interbody fusion. 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At this writing, of the in the study have been evaluated at the time are in and data are presented in The time was 2 and the was days. This with the of 3 reported in a clinical study of interbody using with Bone Bone and is presented in the of to of the with Bone and through a had a and Bone pivotal clinical and as on an are in in for both of these was at each of the time Bone pivotal clinical and fusion results to the are reported in The fusion data are with from a study of of the with iliac autogenous bone The fusion in both the Bone and at both and after surgery. to the fusion were that the of equivalence investigational and was Bone pivotal clinical Fusion is presented in a of in both the investigational and to a of in the investigational to work in the Bone pivotal clinical was on the investigational 3 after surgery. 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At this writing, all the have had a at a minimum of after surgery. In of were by after as with of In fusion was at by the a of at 15 in and a in The data from this study the efficacy of the composite as a substitute for autogenous bone graft for posterolateral intertransverse process fusion. This the preclinical and clinical at this regarding the use of rhBMP-2 for spinal fusion. The preclinical studies were important for the and limitations of rhBMP-2 used with different spine fusion only from preclinical animal that higher fusion in interbody fusion cages with bone use of the ACS in a posterolateral application required the of to adequate space for bone formation. rhBMP-2 carriers such as the and the sponge were to be to autogenous bone graft in posterolateral At this writing, the primate studies also to into results in human clinical trials, in animal models. 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To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased (+ 18%; p less than .01) and T decreased (-30%; p less than .01), while heart rate increased by only 8% (87 +/- 12 to 94 +/- 15 beats/min; p less than .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p less than .01). Left ventricular peak filling rate increased (1.2 +/- 0.6 to 1.7 +/- 0.7 end-diastolic volumes/sec; p less than or equal to .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 +/- 7 to 18 +/- 9 mm Hg; p less than .01). There was a fall in left ventricular end-diastolic pressure (28.6 +/- 6 to 19 +/- 7 mm Hg; p less than or equal to .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Necrotizing enterocolitis (NEC) sometimes occurs after a transfusion, but it is unclear whether this is a chance association or cause and effect. STUDY DESIGN AND METHODS: We compared features of neonates that developed surgical NEC within 48 hours after transfusion with others that developed NEC not preceded by transfusion. We assessed the blood used for transfusion and feeding practices among NEC cases and controls. RESULTS: Forty neonates developed surgical NEC after a transfusion and 72 developed NEC unrelated to a transfusion. Those with NEC after transfusion were born at earlier gestation (mean 27 weeks, 90% confidence interval [CI] 26-28 years vs. mean 30, 90% CI 29-31; p < 0.001) and were of lower birth weight (mean 981 g, 90% CI 835-1128 g vs. mean 1371 g, 90% CI 1245-1496; p < 0.001) and developed NEC later during their neonatal intensive care unit course (day of life: mean 23, 90% CI 20-27 vs. mean 16, 90% CI 13-19; p < 0.001). Transfusions were more prevalent among those that developed NEC (p < 0.001). The blood transfused to those that developed NEC was not older, but those who developed NEC had been fed larger volumes of milk in the 24 hours before and during transfusion (p = 0.04) and were more likely to have been fed a bovine product during that period (p = 0.004). CONCLUSION: Approximately one-third of surgical NEC cases in our system occurred after a transfusion. We speculate that a target area for reducing the prevalence of posttransfusion NEC involves feeding practices immediately before and during RBC transfusion.

OBJECTIVE: Severe thrombocytopenia (platelets <or= 50000/microL) in a NICU patient can have significant consequences; however, previous reports have not focused exclusively on NICU patients with counts this low. METHODS: We identified all patients with severe thrombocytopenia who were cared for in the Intermountain Healthcare level III NICUs from 2003-2007. RESULTS: Among 11281 NICU admissions, severe thrombocytopenia was identified in 273 (2.4%). Just over 30% of these presented in the first three days of life. Half presented by day 10, 75% by day 27, and 95% by day 100. The prevalence was inversely related to birth weight. Cutaneous bleeding was more common in patients with platelet counts of <20000/microL; however, no statistically significant correlation was found between platelet counts and pulmonary, gastrointestinal, or intraventricular bleeding. The most common explanations for severe thrombocytopenia were acquired varieties of consumptive thrombocytopenia. Platelet transfusions (median 5, range 0-76) were administered to 86% of the patients. No deaths were ascribed to exsanguinations. The mortality rate did not correlate with the lowest platelet count but was proportionate to the number of platelet transfusions. CONCLUSION: The prevalence of severe thrombocytopenia in the NICU is inversely proportional to birth weight and most cases are acquired consumptive thrombocytopenias. We speculate that very low platelet counts are a causal factor in cutaneous bleeding, but pulmonary, gastrointestinal, and intraventricular bleeding are less influenced by the platelet count and occur primarily from causes other than severe thrombocytopenia. The lowest platelet count does not predict the mortality rate but the number of platelet transfusions received does.

To study the mechanism of increase in the mitral valve area (MVA) and the anatomic features of the mitral valve that may affect the results of catheter double-balloon valvuloplasty (CBV) in adult patients with mitral stenosis, Doppler and two-dimensional echocardiography was performed in 12 patients before and immediately after CBV. Immediately after CBV, there was an increase in the transverse diameter of the mitral valve orifice from 18 +/- 1.6 to 25 +/- 2.8 mm (mean +/- SD, p less than .001). The anterior angles at the commissure increased from 33 +/- 6 to 57 +/- 20 degrees (p less than .05) and the posterior angles from 36 +/- 9 to 54 +/- 14 degrees (p less than .05). The MVA was greater after CBV in patients with pliable mitral valves (2.6 +/- 0.7 cm2) compared with those with rigid mitral valves (1.9 +/- 0.8 cm2; p = .08). After CBV, MVA was smaller in patients with calcification (2.1 +/- 0.2 cm2) compared with those without (2.7 +/- 0.5 cm2; p = .10) and in those with subvalvular disease (2.0 +/- 0.6 cm2) compared with those without (2.9 +/- 0.9 cm2;p = .03). The MVA by Doppler ultrasound before CBV (1.0 +/- 0.2 cm2) correlated well with MVA by cardiac catheterization (1.0 +/- 0.3 cm2; r = .8, SEE = 0.2 cm2). After CBV, the correlation of MVA by Doppler ultrasound (2.0 +/- 0.5 cm2) with MVA by cardiac catheterization (2.4 +/- 0.8 cm2) was poor (r = .3, SEE = 0.44 cm2).(ABSTRACT TRUNCATED AT 250 WORDS)

The feasibility of using continuous on-line recording of intraventricular electrical impedance to measure ventricular stroke volume was assessed in 12 patients at cardiac catheterization with a multielectrode impedance catheter and a 1.3 kHz measuring current of 4 microA. Stroke volumes determined by electrical impedance were compared with stroke volumes determined by the thermodilution technique in 10 patients and correlated with an r value of .95. Directional changes in impedance recordings throughout the cardiac cycle were also compared with volume curves obtained from six patients by radionuclide ventriculography, and in all instances the agreement between the two volume recordings was excellent. For all patients, on-line measurements of impedance showed a beat-by-beat decrease in stroke volume with the Valsalva maneuver and the administration of amyl nitrite, as well as an immediate increase in stroke volume in the contraction following an extra-systolic beat. Similar directional changes in stroke volume were recorded in both left and right ventricles. Left ventricular pressure-volume relationships were assessed with simultaneous left ventricular pressure recordings and volume signals recorded from the impedance catheter to determine if impedance measurements of volume can be used clinically. Pressure-volume diagrams were subsequently plotted, and for all patients these diagrams showed characteristic isovolumetric contraction and relaxation phases as well as typical ejection and filling periods. Moreover, beat-by-beat sequential pressure-volume diagrams constructed for patients during the administration of amyl nitrite revealed a linear end-systolic pressure-volume relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Preliminary reports have documented the utility of balloon aortic valvuloplasty as a palliative treatment for high-risk patients with critical aortic stenosis, but the effect of this procedure on cardiac performance has not been studied in detail. Accordingly, 32 patients (mean age 79 years) with long-standing, calcific aortic stenosis were treated at the time of cardiac catheterization with balloon dilatation of the aortic valve, and serial changes in left ventricular and valvular function were followed before and after valvuloplasty by radionuclide ventriculography, determination of systolic time intervals, and Doppler echocardiography. Prevalvuloplasty examination revealed heavily calcified aortic valves in all patients, a mean peak-to-peak aortic valve gradient of 77 +/- 27 mm Hg, a mean Fick cardiac output of 4.6 +/- 1.4 liters/min, and a mean calculated aortic valve area of 0.6 +/- 0.2 cm2. Subsequent balloon dilatation with 12 to 23 mm valvuloplasty balloons resulted in a fall in aortic valve gradient to 39 +/- 15 mm Hg, an increase in cardiac output to 5.2 +/- 1.8 liters/min, and an increase in calculated aortic valve area to 0.9 +/- 0.3 cm2. Individual hemodynamic responses varied considerably, with some patients showing major increases in valve area, while others demonstrated only small increases. In no case was balloon dilatation accompanied by evidence of embolic phenomena. Supravalvular aortography obtained in 13 patients demonstrated no or a mild (less than or equal to 1+) increase in aortic insufficiency. Serial radionuclide ventriculography in patients with a depressed left ventricular ejection fraction (i.e., that less than or equal to 55%) revealed a small increase in ejection fraction from 40 +/- 13% to 46 +/- 12% (p less than .03). In addition, for the study group as a whole there was a decrease in left ventricular end-diastolic volume index (113 +/- 38 to 101 +/- 37 ml/m2, p less than .003), a fall in stroke-volume ratio (1.49 +/- 0.44 to 1.35 +/- 0.33, p less than .04), and no immediate change in left ventricular peak filling rate (2.05 +/- 0.77 to 2.21 +/- 0.65 end-diastolic counts/sec, p = NS). Serial M mode echocardiography and phonocardiography showed an increase in aortic valve excursion (0.5 +/- 0.2 to 0.8 +/- 0.2 cm, p less than .001), a decrease in time to one-half carotid upstroke (80 +/- 30 to 60 +/- 10 msec, p less than .001), and a small decrease in left ventricular ejection time (0.44 +/- 0.03 to 0.42 +/- 0.02 sec, p less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)

Previous studies have shown that licochalcone A, an oxygenated chalcone, exhibits antileishmanial and antimalarial activities. The present study was designed to examine the antimalarial activity of an analog of licochalcone A, 2,4-dimethoxy-4'-butoxychalcone (2,4mbc). 2,4mbc inhibited the in vitro growth of both a chloroquine-susceptible (3D7) and a chloroquine-resistant (Dd2) strain of Plasmodium falciparum in a [3H]hypoxanthine uptake assay. The in vivo activity of 2,4mbc was tested in mice infected with Plasmodium berghei or Plasmodium yoelii and in rats infected with P. berghei. 2,4mbc administered either orally, intraperitoneally, or subcutaneously for 5 days protected the mice from otherwise lethal infections of these parasites. 2,4mbc administered orally for 5 days reduced parasitemia in the rats infected with P. berghei. These results demonstrate that 2,4mbc exhibits potent antimalarial activity and might be developed into a new antimalarial drug.

BACKGROUND: We previously reported that in the year 2006, approximately 35% of the transfusions administered in the Intermountain Healthcare neonatal intensive care units (NICU) were noncompliant with our transfusion guidelines. In January 2009 we instituted an electronic NICU transfusion ordering and monitoring system as part of a new program to improve compliance with transfusion guidelines. STUDY DESIGN AND METHODS: In the four largest NICUs of Intermountain Healthcare, we performed a pre-post analysis of compliance with transfusion guidelines and transfusion usage. RESULTS: After beginning the new transfusion compliance program all four NICUs had an increase in compliance from 65% to 90%. Accompanying the improved compliance, all four NICUs had a reduction in transfusions administered. Specifically, compared with 2007 and 2008, there were 984 fewer NICU transfusions given in 2009. This included 554 fewer red blood cell (RBC) transfusions, 174 fewer platelet transfusions, and 256 fewer frozen plasma infusions. We calculate that in 2009, a total of 200 NICU patients who in previous years would have received one or more transfusions instead received none. Applying specific Intermountain Healthcare billing data to the observed transfusion reductions, this new program resulted in an annual decrease of $780,074 in blood bank charges (blood administration charges were not included). During the 3-year period, January 2007 through December 2009, we detected no change in NICU demographics, major morbidities, length of hospital stay, or mortality rate. CONCLUSION: Implementing a systemwide NICU program to improve compliance with already-established transfusion guidelines increased compliance from 65% to 90%. Improved compliance with transfusion guidelines was accompanied by a significant reduction in transfusions given, with no increase in NICU length of stay or mortality rate.

Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region.

Recent work on adult thought has focused on the emergence of relativistic, dialectic, or integrative assumptions about knowledge. In 1981, Kitchener and King developed a model of reflective judgment that describes seven sets of assumptions about reality and knowledge and corresponding concepts of intellectual justification. This article reports a 2-year longitudinal study of three groups of adolescents and young adults (n = 59) who were tested on the Reflective Judgment Interview and on the Concept Mastery Test, a measure of verbal aptitude. Significant group (p &lt; 0.01) and time (p &lt; 0.01) main effects were found on both measures, with older subjects scoring higher than younger subjects, and all groups showing increases in scores over the 2-year period. Observed differences in reflective judgment persisted when verbal ability was statistically controlled. A significant (p &lt; 0.05) sex effect favoring males was found when the effects of verbal aptitude were statistically removed. Thus, the sequentiality of the reflective judgment stages was empirically tested, with results indicating support for the seven hypothesized shifts in epistemic assumptions over time.

BACKGROUND: Fresh-frozen plasma (FFP) is sometimes administered to nonbleeding preterm neonates who are judged to be at risk for bleeding because they have abnormal coagulation tests. The benefits/risks of this practice are not well defined. One limitation to progress is lack of reference intervals for the common coagulation tests, thus limiting precision about whether coagulation tests are indeed abnormal. STUDY DESIGN AND METHODS: In a sequential observational study, fetal blood was drawn at preterm birth (≤ 34 weeks) from the umbilical vein near the placenta. Fibrinogen, prothrombin time, activated partial thromboplastin time, D-dimer, platelet (PLT) count, and mean PLT volume were measured. Reference intervals were constructed using 5th and 95th percentile values. Associations were then sought between abnormal coagulation values at birth and bleeding problems identified during the first week. RESULTS: Coagulation tests were drawn at 175 preterm deliveries and the results were organized into reference intervals by gestational age. No abnormal coagulation value, either alone or in combination, predicted hemorrhage (intraventricular, gastrointestinal, or pulmonary) during the first week. However, fibrinogen exceeding the 95th percentile was associated with evidence of in utero infection/inflammation (correlations with elevated C-reactive protein, p<0.01, and elevated immature to total neutrophil ratio, p<0.001). CONCLUSIONS: Abnormal coagulation values at preterm birth do not predict bleeding during the first week. This suggests to us that bleeding in the days after preterm birth is not generally the result of in utero coagulopathy. These findings bring into question the value of coagulation screening of nonbleeding preterm infants and prophylactic FFP administration to those with abnormal values.

BACKGROUND: A severe intraventricular hemorrhage (IVH) in a preterm neonate can result in life-long disabilities or death. Pathogenic mechanisms responsible for IVH are incompletely understood. We postulated that if the timing of a severe IVH could be approximated by serial ultrasound, potentially relevant antecedents could be identified. STUDY DESIGN AND METHODS: We retrospectively identified all very-low-birth-weight (VLBW) neonates in our health system, over a 5-year period, with an initial head ultrasound showing no hemorrhage but a subsequent ultrasound showing a Grade 3 or 4. Controls that did not develop an IVH were matched with cases using demographic features and degree of illness measures. RESULTS: Fifty-four cases were matched (1:2) with controls. No differences were found between cases and controls in initial pH, sepsis, ventilation, coagulation studies, or proportion with severe thrombocytopenia. However, during the period when the head ultrasound was normal, cases were more likely to have had a red blood cell (RBC) transfusion (p < 0.001). In 94% of the cases the sequence was 1) no IVH, 2) RBC transfusion, and 3) severe IVH. With the use of logistic regression, each subsequent RBC transfusion during the first week was determined to double the risk of a severe IVH (each transfusion increases relative risk, 2.02; 95% confidence interval, 1.54-3.33). Sensitivity analysis indicated a high likelihood that RBC transfusion, independent of hemoglobin level or other factors, increases the risk of developing a severe IVH. CONCLUSION: These findings suggest a new hypothesis. Namely, RBC transfusions given before the development of an IVH are an independent risk factor for developing a severe IVH.