Volume 88, Issue 6, Pages 751-757 (June 2007)

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A Guideline-Driven Assessment of Need for Cardiovascular Disease Risk Intervention in Persons With Chronic Paraplegia

Abstract

Nash MS, Mendez AJ. A guideline-driven assessment of need for cardiovascular disease risk intervention in persons with chronic paraplegia.

Objective

To examine percentages of persons with chronic paraplegia who qualify for lipid-lowering therapeutic lifestyle intervention (TLI) as assessed by authoritative guidelines.

Design

Cross-sectional.

Setting

Academic medical center.

Participants

Forty-one subjects (mean age ± standard deviation, 34±11y) with motor-complete paraplegia (American Spinal Injury Association grade A or B) at T6-L1 levels for greater than 2 years.

Interventions

Not applicable.

Main Outcome Measures

Percentages of subjects qualifying for TLI were independently assessed and then compared using National Cholesterol Education Project Adult Treatment Panel (ATP) II (1994) and ATP III (2002) Guidelines.

Results

A total of 34.1% of subjects qualified for intervention based on the ATP II Guidelines and 63.4% based on ATP III (χ12 test=4.53; 2-tailed, P=.003). Seventy-six percent (31/41) of study participants had high-density lipoprotein cholesterol levels below the high-risk criterion of 40mg/dL established by ATP III. Almost one third of subjects had hypertension, and 34.1% satisfied criteria for diagnosis of the metabolic syndrome.

Conclusions

A high percentage of young, apparently healthy people with chronic paraplegia are at risk for cardiovascular disease and qualify for lipid-lowering TLI. Updated guidelines of the ATP III have increased the urgency for early risk assessment and intervention.

Key Words: Cardiovascular diseases, Lipids, Paraplegia, Rehabilitation, Risk

Article Outline

• Abstract

• Methods

• Participants

• Lipid Profiles

• Risk Assessment

• Data Analysis

• Results

• Discussion

• Conclusions

• References

• Copyright

STUDIES CONDUCTED in the early 1980s forewarned of all-cause cardiovascular diseases (CVDs) as an emerging health hazard for persons with spinal cord injuries (SCIs). Although urosepsis and renal complications after SCI accounted for 43% of deaths in the 1940s and 1950s, mortality from these causes was reduced to 10% of cases in the 1980s and 1990s.1, 2, 3 All-cause CVD is now a frequent cause of death among persons surviving 30 years postinjury and those older than 60 years.3, 4 CVD also occurs earlier in life after SCI, and because of altered sensory patterns might be expressed through atypical symptoms that fail to warn a person of an impending cardiac episode.5, 6 These risks make primary prevention of CVD essential if lifestyle decay and diminished longevity are to be avoided for those with chronic SCI.7, 8

One apparent explanation for accelerated CVD after SCI is a widely reported dyslipidemia,4, 9, 10, 11, 12, 13, 14 whose most consistent feature is a depressed blood plasma concentration of the high-density lipoprotein cholesterol (HDL-C).9, 10, 12, 13, 14, 15, 16 Epidemiologic and clinical trial data have consistently reported an inverse association between HDL-C and CVD risk,17, 18, 19, 20, 21, 22, 23 and affirmed that risks imposed by low HDL-C are lessened by even small increments of improvement in its blood concentration.24, 25, 26 The Framingham Heart Study18, 19, 20, 22, 23 reported that low HDL-C predicts an increased incidence of CVD independent of other risks including high low-density lipoprotein cholesterol (LDL-C) levels, and other clinical trials have found that HDL-C concentrations influence risks for developing CVD irrespective of normal or elevated LDL-C levels.27, 28

The measurement of lipid and lipoprotein levels is a staple of CVD risk assessment, as well as a clinical tool that defines the urgency for therapeutic lifestyle intervention (TLI). CVD risk and need for TLI have been assessed by various methods, although the primary source for dictating lipid and lipoprotein targets has been the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults.29 Three NCEP Adult Treatment Panels (ATP) convened since 198830, 31, 32, 33, 34 have each undertaken extensive review of clinical trials and have used evidence-based approaches for establishing CVD risk. The panels have then adopted these assessments to define clinical pathways for CVD management through recommended diet, activity, and drug interventions. Although ATP I (1988)31 and ATP II (1993)30 recommended an intensive approach to disease management though primary lowering of LDL-C, they still noted important contributions to disease prevention by HDL-C. This position was strengthened by several actions of ATP III35 which have relevance to risk assessment for those with SCI. These included raising the criterion score for “low” HDL-C from 35 to 40mg/dL and designating low HDL-C as a major risk factor that would directly modify LDL-C targets. Unlike its predecessors, ATP III also identified persons with metabolic syndrome36 as candidates for intensive TLI. Many people with SCI have symptoms or diagnosis of this high-risk condition.36, 37, 38, 39

Although various studies have classified persons with SCI at elevated CVD risk based on determinants of health-related states, dyslipidemia, and evidence of accelerated disease, a systematic assessment of CVD risks using NCEP ATP III Guidelines has not been reported. Without use of guideline-driven assessment, the extent to which intervention is needed can only be conjectured. Because the algorithm for these assessments became more conservative with publication of ATP III Guidelines,34 these changes will likely worsen risk prognoses for those with SCI. In the process they may also qualify a higher percentage of the population for TLI. Thus, the current study compared CVD risks and indications for TLI using ATP II and ATP III Guidelines in the same homogenous cohort of persons with chronic paraplegia.

Methods

Participants

In this cross-sectional study, we enrolled 30 men and 11 women between 20 and 54 years with motor-complete (American Spinal Injury Association grade A or B) paraplegia at the T6 to L1 spinal levels for greater than 2 years. Study participants were in good health and free of infection or illness at the time of testing. They consented to participate in the study with the approval of the Medical Sciences Committee for the Protection of Human Subjects. Descriptive characteristics of the study participants are shown in table 1.

Table 1.

Descriptive Characteristics of the Study Subjects


	Characteristics	Values
	Participants (n)	41
	Male	30
	Female	11
	Levels of injury	T6-L1
	ASIA grade	A and B
	Mean age ± SD (y)	34.6±11
	Duration of injury ± SD (y)	6.2±3.7

Abbreviations: ASIA, American Spinal Injury Association; SD, standard deviation.

Lipid Profiles

We obtained blood samples on a single occasion. Participants were instructed to refrain from caffeine and alcohol intake for 24 hours before testing. Antecubital venous blood samples were taken under antiseptic conditions in the postabsorptive state after an overnight (10h) fast. Ten milliliters whole blood was drawn into ethylenediaminetetraacetic acid and gel and lysis activator tubes between 8:00 and 10:00 am. Tubes were centrifuged at 3000rpm for 30 minutes to isolate platelet poor plasma. Fasting glucose was determined on an auto-analyzera using the glucose oxidase method. Total cholesterol (TC), HDL-C, and triglycerides (TG) were assayed by automated methods utilizing commercially available kits according to manufacturer’s instructions and run procedures.40 Precipitation of the apoB-containing lipoproteins using polyanion precipitation was undertaken before HDL-C assay.41 LDL-C was calculated using the method of Friedewald et al42:

Risk Assessment

We assigned risk factors independently for each subject in accordance with both ATP II30 and ATP III34 Guidelines. Risks that modified LDL-C targets irrespective of rating system included cigarette smoking (defined as any cigarette smoking in the previous month), hypertension (blood pressure >140/90mmHg), family history of premature coronary disease in male first-degree relative (<55y) or female first-degree relative (<65y), and age (men <45y, women <55y) (table 2).

Table 2.

Major Risk Factors (exclusive of LDL-C) That Modify LDL Goals and Earn a Risk Point


	Risk	Risk Criterion
	Cigarette smoking	Any smoking in the previous month
	Hypertension	Blood pressure ≥140/90mmHg or taking antihypertensive medication
	Low HDL-C	<40mg/dL⁎†
	Family history	Premature coronary heart disease (coronary heart disease in male first degree relative <55y; coronary heart disease in female first degree relative <65y)
	Age	Men ≥45y; women ≥55y
	Diabetes or metabolic syndrome	Abdominal obesity, elevated triglycerides, low HDL, hypertension, elevated fasting blood glucose‡

⁎

HDL-C ≥60mg/dL counts as a “negative” risk factor; its presence removes 1 risk factor from the total count.

†

Low HDL is defined as <35mg/dL in ATP II.

‡

These risks are rated in ATP III but not ATP II. Critical values are described in the text.

A major risk was assigned by ATP II for HDL less than 35mL/dL, and in ATP III for HDL less than 40mg/dL. Diabetes was rated a risk in ATP III only, but metabolic syndrome was rated a risk equivalent in ATP III (alone) if the following conditions were satisfied: abdominal obesity (>101.6cm for men, >88.9cm for women), TG levels greater than 150mg/dL, HDL less than 40mg/dL in men and 50mg/dL in women, blood pressure greater than 130/85, and fasting glucose greater than 110mg/dL. Presence of clinical atherosclerotic disease that confers high risk for coronary heart disease events (coronary heart disease risk equivalents) were queried from patient history. These included clinical coronary heart disease, symptomatic carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm (table 3). In cases where 2 or more risks factors were present, ATP III alone used a sum of scores on the Framingham Rating System to examine an absolute disease 10-year risk greater than 20% as a risk factor. Risk contributors to the Framingham ranking included age, sex, TC, HDL-C, smoking status, systolic blood pressure, and current medications used to treat hypertension. When all major risks were assessed, 3 categories of factors set the LDL-C goals (table 4): 0 to 1 risk factors set the LDL goal at greater than 160mg/dL; multiple (2+) risk factors at LDL less than 130mg/dL; and CVD or CVD risk equivalents at LDL less than 100mg/dL. A dichotomous ranking was then established to determine whether each study participant had either “met” or “failed to meet” their LDL-C target. By NCEP convention, those failing to satisfy their LDL-C targets require intervention.

Table 3.

Presence of Clinical Atherosclerotic Disease that Confers High Risk for Coronary Heart Disease Events


	Risk Equivalents	Risk Point Score
	Clinical coronary heart disease	1
	Symptomatic carotid artery disease	1
	Peripheral arterial disease	1
	Abdominal aortic aneurysm	1

Table 4.

LDL-C Goals and Cutpoints for TLI in Different Risk Categories


Risk Category	LDL Goal (mg/dL)	LDL Level at Which to Intervene (mg/dL)
Coronary heart disease or risk equivalents (10-y risk >20%)	<100	≥100
2+ risk factors (10-y risk ≤20%)	<130	≥130
0−1 risk factor⁎	<160	≥160

⁎

Almost all people with 0 to 1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with 0 to 1 risk factor is not necessary.

Data Analysis

We computed means, standard deviations, and ranges for all data. The number of major risk factors were rated and compared according to both ATP II and ATP III Guidelines. Frequencies of subjects who “met” or “failed to meet” their LDL-C target using ATP II and ATP III algorithms were compared using the Pearson chi-square test with a Yates correction for continuity. Significance was established at α less than or equal to .05.

Results

Summary data for the lipid profiles are shown in table 5, and the frequency distributions of the data about key lipid and lipoprotein targets in figure 1. Average total cholesterol was 176mg/dL, with 14 of 41 subjects classified on this single outcome as having moderate risk, and 2 of 41 at high risk. Triglyceride levels of 200mg/dL and higher were observed in 14 study subjects. Thirty-one subjects were classified at risk due to low HDL-C with 17 of 41 falling at or below 35mg/dL. More than half of those studied (21/41) had TC:HDL ratios above the criterion score for high risk at 4.5. Almost 30% of subjects studied satisfied criteria for diagnosis of hypertension and about one third for the metabolic syndrome (table 6). When stratified according to qualifications for intervention status, 34.1% of subjects qualified for intervention using NCEP ATP II Guidelines and 63.4% using ATP III (table 7). This difference was significant (χ12 test=4.5; 2-tailed, P=.033) (table 8).

Table 5.

Summary Data From Lipid, Cholesterol, and Lipoprotein Cholesterol Assays (N=41)


Parameter (mg/dL)	TC (mg/dL)	Triglycerides (mg/dL)	HDL-C (mg/dL)	LDL-C	TC/HDL
Mean	176	153	44	102	4.3
SD	40	66	14	38	1.0
Median	175	164	40	101	4.4
Minimum	97	27	23	40	1.9
Maximum	276	300	89	212	8.9

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Fig 1. Frequency distributions referencing criterion risk scores for (A) TC, (B) HDL-C, (C) TG, and (D) the TC:HDL-C ratio. Each graph represents the number of participants in the study population classified by level of risk based on cut-scores used for defining (A–C) acceptable and unacceptable lipid scores and (D) their interplay.

Table 6.

Frequency of Comorbid CVD Risks


Risks	No. of Subjects	Percentage of Subjects
Hypertension	12/41	29.2
Metabolic X	14/41	34.1
Tobacco use	5/41	12.2

Table 7.

Intervention Status as a Function of NCEP Guidelines Classification


Guidelines	Status
Guidelines	Intervention	Nonintervention	Total
NCEP II
Count	14	27	41
Frequency (%)	34.1	65.9	100
NCEP III
Count	26	15	41
Frequency (%)	63.4	36.6	100

Table 8.

Chi-Square Analysis of “Intervention Status” When Analyzed Using NCEP ATP II and ATP III Guidelines


Tests	Value	df	P (2-tailed)
Pearson chi-square	5.475	1	.019
Continuity correction	4.525	1	.033

Discussion

The findings of this study build on previous reports of elevated CVD risks in persons with chronic SCI.10, 43, 44 We further find that TLI is warranted in a high percentage of young, healthy, community-dwelling people with paraplegia. The proportion of subjects qualifying for intervention was significantly higher when applying the analysis strategy recommended by NCEP ATP III, which increased the criterion score for low HDL from 35 to 40mg/dL and designated low HDL-C as an independent risk factor that ultimately influences designation of patient-specific LDL-C targets. Although elevated TC is a common risk factor in adults without disability, the current study population was consistent with those of previous reports that document lower TC in persons with SCI. Notwithstanding, in most lipid profiles the added risk of low HDL-C lowered the LDL-C intervention target from 130 to 100mg/dL, which could not be met by LDL-C levels determined by direct sampling. The health hazards of diabetes and the metabolic syndrome reported as common after SCI15, 37, 45 also credited points toward the risk score, which lowered LDL-C targets for nearly 2 of every 3 persons studied.

In addition to risk assessment undertaken by ATP Guidelines, other benchmark characteristics of CVD risk identified a need for lifestyle intervention, and support findings of risk stratification by ATP Guidelines. For example, the ratio of TC:HDL above a high-risk standard of 4.546 was noted in 21 of 41 subjects. In most cases the risk of an elevated TC:HDL ratio was solely attributable to low HDL-C, as only 16 of 41 study participants had TC levels above 200mg/dL demarking moderate risk, and only 2 of 41 above 240mg/dL defining high risk. Interestingly, when assessing risk based on TC, TG, or LDL-C alone, 21 of 41 study participants had only 1 lipid or lipoprotein level outside standard reference range, making the study of more global CVD risks and adoption of guideline-driven assessments especially revealing. So far, only 1 other study has reported the CVD risk sustained by persons with SCI using NCEP Guidelines; the analysis used ATP II standards in place at the time of the report.47 Comparison of 52 age-matched and sex-matched persons without disability with 69 subjects having SCI showed higher percentages of diabetes mellitus, elevated TC and LDL-C, and low HDL. The ratios of TC:HDL and LDL:HDL in those with SCI revealed risks greater than observed in the matched comparison group. Although they showed elevated CVD risks, the need for intervention in these patients because they either satisfied or failed to satisfy LDL targets was not calculated. To our knowledge the current study is the first to do so for persons with SCI.

In several respects the findings of this study represent a conservative assessment of risk for those with SCI. First, in July 2004, the NCEP published a study examining “Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines,” which updated specific elements of the ATP III Guidelines released in 2001. This update has been endorsed by the National Heart, Lung, and Blood Institute, the American Heart Association, and the American College of Cardiology, and it offers physicians options of more intensive cholesterol-lowering treatment for people at “high risk” and “moderately high risk” for a heart attack.48 Although the ATP III update emphasized therapeutic lifestyle changes such as low saturated fat and low cholesterol diet, physical activity, and weight control as cornerstones of treatment for lowering CVD risk, several key modifications to risk assessment in ATP III were adopted. For “high-risk patients”—defined as people who have coronary heart disease or disease of the blood vessels to the brain or extremities, or diabetes, or multiple (≥2) risk factors that give them a greater than 20% chance of having a heart attack within 10 years—the overall LDL goal was still less than 100mg/dL. There was, however, a therapeutic option to set the goal at an LDL less than 70mg/dL for “very high-risk” patients, including those who have had a recent heart attack, or those who have CVD combined with either diabetes, or severe or poorly controlled risk factors (eg, continued smoking), or metabolic syndrome. The ATP III update further recommended consideration of drug treatment in addition to TLI for LDL levels at 100mg/dL or higher in high-risk patients, and characterized drug treatment as optional for LDL less than 100mg/dL. For “moderately high-risk patients”—including those who have multiple (≥2) coronary heart disease risk factors coupled with a 10% to 20% risk for a heart attack within 10 years—the overall LDL goal was still less than 130mg/dL, but defined an option to set the treatment goal at an LDL less than 100mg/dL, and to use drug treatment if LDL is 100 to 129mg/dL. Thus, it is possible that many of the participants in the current study would have qualified for drug intervention as well as for TLI, especially those having an LDL target of 70mg/dL. Second, a fasting blood glucose of 110mg/dL or higher is used as a criterion in ATP III (2001) for defining the metabolic syndrome (to conform to the accepted classification of impaired glucose tolerance), which was unaltered in the ATP III update. The Follow-up Report by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus lowered this value to greater than 100mg/dL, however, and the American Diabetes Association has lowered its cutpoint to this value in its criteria for diagnosis of the metabolic syndrome.49 If these standards were similarly adopted in the NCEP Guidelines, an additional 3 subjects in our study population would have qualified for this diagnosis, increasing the percentage of study participants with metabolic syndrome to 41.4%. Third, the study population is relatively young. An older cohort with SCI might be expected to have more body fat and a worsened metabolic profile,50 which together would increase the population prevalence of metabolic syndrome. Last, the elevated need for lifestyle intervention observed in this population occurs in the presence of unremarkable levels of TC, which illustrates the strength of other risk factors experienced by persons with paraplegia and makes the study findings even more persuasive.

The ATP III Guidelines establish need for TLI based on a constellation of lipid abnormalities, risk comorbidities, and family history. The measurement of HDL-C is essential among these predictors, because low HDL-C is now rated by ATP III as an independent risk, and is required for establishing risk from the metabolic syndrome. As a practical issue, many study participants requiring intervention might have been missed by clinical testing that failed to measure HDL-C. Such assessments may significantly underestimate CVD risk, and thus fail to define the need for TLI in a high percentage of people with SCI who truly qualify for, and require treatment. Concern for low HDL-C in persons with SCI has been widely expressed 36, 40, 43, 51, 52, 53 and has been reflected in consensus guidelines for those without disability. Authoritative guidelines and longitudinal population studies find HDL-C an independent, inverse coronary risk factor18, 20, 54, 55 with strong predictive power for future coronary risk. The strength of HDL-C in disease prevention has been reported in trial data from the Framingham Heart Study56 and the Prospective Cardiovascular Münster study.57 Interventional trials including the Lipid Research Clinics Primary Prevention Trial58 and the Helsinki Heart Study59 reported that treatment resulting in HDL-C elevation subsequently lowered coronary events, a finding independent of LDL-C lowering. Outcomes of the recent Veterans Affairs HDL Intervention Trial60, 61 further support the need to raise HDL-C levels independent of LDL-C lowering, because HDL-C elevation accompanied by lowering of TG but not of LDL-C significantly decreased the incidence of CVD-related events and stroke. This observation is consistent with the conclusion of the AFCAPS/TexCAPS Primary Prevention Trial62 that HDL-C should be included in the risk assessments of subjects having even average cholesterol or LDL-C concentrations.

The findings of this study were based on target-driven guidelines defining a need for intervention. At the time of testing none of the subjects had received specific recommendations for diet, activity, or drug intervention, which placed a high percentage of them with modifiable risk factors in jeopardy of coronary events. Unfortunately, previous surveys of clinical practice have revealed that health care practitioners often fail to adequately implement cholesterol-lowering guidelines. For example, in the Lipid Treatment Assessment Project—a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving LDL-C targets—only 38% of the study population reached intervention targets of the ATP II Guidelines, and patients at highest risk of future events from existing CVD had the lowest rate of LDL-C goal attainment (18%).63 The first EUROASPIRE survey conducted in 1995 and 1996 also reported frequent, modifiable heart disease risk factors as underdiagnosed and undertreated.64 Of particular concern was the finding that more than 85% of patients with coronary heart disease had a TC level above the criterion for acceptable risk. A follow-up survey (EUROASPIRE II) completed in 1999 and 2000 reported increased use of lipid-altering drugs, but that nearly 60% of coronary heart disease patients still had unacceptable levels of TC.65, 66 Thus, lack of needed intervention for those with SCI is typical, but still falls below standards for target-driven CVD risk reduction emphasized by authoritative guidelines.

Cardiovascular diseases pose several unique problems for those aging with spinal cord disability, suggesting a need for aggressive primary, not secondary intervention. For example, CVD in persons with SCI progresses at accelerated rates.53 Asymptomatic CVD also occurs at earlier ages in persons with SCI than those without7, 67 and its symptoms may be masked after SCI by interruption of ascending afferent pain fibers that typically convey warnings of impending heart damage or death.5, 6 The findings of this study are especially compelling because subjects undergoing study were relatively young, had injuries at spinal levels that fully spared adrenergic functions, and had motor loss fully sparing the upper extremities and part of the trunk. Nearly half of those surviving SCI will have higher levels of injury than participants in this study, and many of these will sustain adrenergic dysfunction as part of their SCI. Considerably more would be expected to use tobacco,68, 69, 70, 71 with a greater impact on pulmonary function72 and lipid levels. All of these factors suggest that our study population was an ideal representation, and that aging,47 higher levels of injury,73 and more extensive tobacco use would worsen the prognosis reported here.

To date, we have found no full appraisal of factors that influence the CVD risk after SCI, except for suggestions that physical inactivity imposed or adopted after SCI represents a risk. Other factors that would draw reasonable suspicion include visceral obesity,14 elevated body mass indices,13 reduced lean body mass,13, 51, 74, 75, 76 diabetes,15, 37, 73 the metabolic syndrome,36, 38, 77 advancing age,76, 77, 78 sympathetic dysfunction,11, 79 and atherogenic diet.80 Because many of these risks are comorbid for CVD in persons without SCI, it is likely that the same comorbidities exist in those with SCI. The study findings are thus limited in their ability to establish specific causes for the need for intervention, or to apportion CVD risk among these risks.

Conclusions

A high percentage of young, otherwise healthy people with paraplegia at T6 and lower spinal levels qualify for lipid-altering therapies based on guidelines of the NCEP ATP III. In most cases the application of more conservative guidelines for HDL-C worsened the risk prognosis, and qualified a higher percentage of people for TLI. The findings are supported by other benchmark characteristics of their lipid profiles. These observations were made in a relatively homogenous cohort that ruled out advanced age and adrenergic dysfunction as causes for the atherogenic lipid profiles. When coupled with the unique health risks and functional challenges sustained by those with SCI, these findings point to a need for guideline-driven primary intervention on these risks. They should also place additional emphasis on early risk assessment in this special-needs population.

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a Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL

b Department of Rehabilitation Medicine, Miller School of Medicine, University of Miami, Miami, FL

c Department of Physical Therapy, Miller School of Medicine, University of Miami, Miami, FL

d Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL

e Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL

f Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL.

Reprint requests to Mark S. Nash, PhD, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Lois Pope Life Center, R-48, 1095 NW 14th Ter, Miami, FL 33136

Supported by the Miami Project to Cure Paralysis and the State of Florida (allocation grant).

No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

a Roche Cobas-Mira F. Hoffmann-La Roche, Diagnostics Division, Grenzacherstr 124, CH-4070 Basel, Switzerland.

PII: S0003-9993(07)00167-0

doi:10.1016/j.apmr.2007.02.031

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