Right Ventricular Systolic Pressure Trajectory as a Predictor of Hospitalization and Mortality in Patients With Chronic Heart Failure.

Background: Pulmonary hypertension is common among patients with heart failure (HF). Right ventricular systolic pressure (RVSP) is frequently used to assess its presence and severity. Although RVSP has been associated with adverse outcomes, the importance of serial measurements has not been studied. We evaluated associations between serial RVSP measurements and cardiovascular events in patients with HF. Methods: Patients with HF and 2 echocardiograms performed ≥ 6 months apart were included. RVSP was categorized, using the second echocardiogram, as follows: normal (< 40 mm Hg); severely elevated (≥ 60 mm Hg); moderately elevated (50-59 mm Hg); or mildly elevated (40-49 mm Hg). Patients also were classified according to change in RVSP categories between echocardiograms. The primary outcome was time to HF hospitalization (HFH) or all-cause mortality (ACM) after the second echocardiogram. Results: In total, 4319 patients were included (median age: 78 years; 52.1% female). During a median follow-up period of 19.4 months, HFH/ACM occurred in 2714 patients (62.8%). In multivariable analysis, baseline RSVP that was mildly elevated (1069 patients, hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.12-1.54), moderately elevated (797 patients, HR 1.54, 95% CI 1.30-1.82), or severely elevated (837 patients, HR 1.92, 95% CI 1.60-2.31) was independently associated with HFH/ACM. Additionally, improving RVSP was associated with increased HFH/ACM in both categorical (HR 1.16, 95% CI 1.01-1.33) and continuous analyses. Conclusions: RVSP measurements identify patients at increased risk who may require more-aggressive monitoring and medical therapy. Our study raises the hypothesis that, in addition to the absolute value of RVSP, improving RVSP category may identify higher-risk patients, but further study is needed to elucidate the underlying reasons.

Contexte: L'hypertension pulmonaire est fréquente chez les patients atteints d'insuffisance cardiaque. La pression systolique ventriculaire droite (PSVD) est souvent utilisée pour évaluer la présence et la gravité de l'hypertension pulmonaire. Bien que la PSVD ait été associée à des complications, l'importance de mesures répétitives n'a pas été étudiée. Nous avons évalué les liens entre des mesures répétitives de la PSVD et des événements cardiovasculaires chez des patients atteints d'insuffisance cardiaque. Méthodologie: Ont été inclus des patients atteints d'insuffisance cardiaque pour lesquels on disposait de deux échocardiogrammes réalisés dans un intervalle ≥ 6 mois. La PSVD a été catégorisée comme suit, au moyen du deuxième échocardiogramme : normale (< 40 mmHg); gravement élevée (≥ 60 mmHg); modérément élevée (50 à 59 mmHg) ou légèrement élevée (40 à 49 mmHg). Les patients ont également été classés dans des catégories en fonction de la variation de la PSVD d'un échocardiogramme à l'autre. Le paramètre d'évaluation principal était le temps écoulé avant une hospitalisation pour insuffisance cardiaque ou un décès, toutes causes confondues, après le second échocardiogramme. Résultats: Au total, 4 319 patients ont été inclus (âge médian de 78 ans; 52,1 % de sexe féminin). Pendant une période de suivi médian de 19,4 mois, une hospitalisation pour insuffisance cardiaque ou un décès, toutes causes confondues, se sont produits chez 2 714 patients (62,8 %). Une analyse multivariée a déterminé qu'une PSVD initiale légèrement élevée (1 069 patients, rapport de risques instantanés [RRI] de 1,31, intervalle de confiance [IC] à 95 % de 1,12 à 1,54), modérément élevée (797 patients, RRI de 1,54, IC à 95 % de 1,30 à 1,82) ou gravement élevée (837 patients, RRI de 1,92, IC à 95 % de 1,60 à 2,31) était indépendamment associée à une hospitalisation pour insuffisance cardiaque ou à un décès, toutes causes confondues. En outre, l'amélioration de la PSVD était associée à une hausse des hospitalisations pour insuffisance cardiaque ou des décès, toutes causes confondues, dans les analyses des catégories (RRI de 1,16, IC à 95 % de 1,01 à 1,33) et continues. Conclusions: Les mesures de la PSVD ont permis de repérer les patients présentant un risque accru qui pourraient nécessiter une surveillance et un traitement médical plus intenses. Notre étude incite à poser l'hypothèse voulant qu'en plus de la valeur absolue de la PSVD, l'amélioration des catégories de PSVD puisse permettre de repérer les patients présentant un risque accru, mais des études plus approfondies sont nécessaires pour élucider les raisons sous-jacentes.

The posterior fossa syndrome questionnaire: using science to inform practice.

INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; Mage at diagnosis = 10.38 years, SD = 5.09, range 3-31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician's post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children's Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items ataxia (100.00%), dysmetria (95.45%), and speech/language changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speech/language changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components: (1) speech/language changes, (2) apraxias (including mutism), (3) motor/oromotor, and (4) emotional lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Female sex-specific and -predominant cardiovascular risk factors and heart failure practice guidelines.

Heart failure (HF) etiology, presentation and prognosis differ by sex, with female sex-specific and -predominant risk factors playing important roles. We systematically reviewed the studies cited by the 2017 American College of Cardiology/ American Heart Association/ Heart Failure Society of America Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. Female cardiovascular risk factors were broadly categorized as female sex-specific (reproductive, pregnancy, menopausal) and female sex-predominant (depression, anthracycline exposure, autoimmune disease) risk factors. Of the 205 cited articles, only 3 studies (1.6%) reported any female sex-specific cardiovascular risk factor in the data analysis or results sections. Oral contraceptive use (n = 1), menopausal status (n = 2) and hormone replacement therapy (n = 2) were the only female sex-specific cardiovascular risk factors reported. No other female sex-specific or -predominant cardiovascular risk factor was reported by any of the eligible studies. Our work highlights that in addition to the need for proportional representation of women in heart failure clinical studies, inclusion of female sex-specific and -predominant risk factors in data collection and analysis is of paramount importance to guide heart failure care in the female population.

Cancer Rehabilitation in the Pediatric and Adolescent/Young Adult Population.

OBJECTIVES: To identify body impairments, activity limitations, and participation restrictions in children, adolescents, and young adults with cancer amenable to rehabilitation, and provide the recommended screening, assessment and rehabilitation referral information for the health care community. DATA SOURCES: A review of the rehabilitation and pediatric oncology literature regarding functional impairments in combination with clinical expertise from practicing pediatric oncology rehabilitation therapists. CONCLUSION: Rehabilitation intervention has great potential to mitigate the impact of cancer and its treatment and may even have a role in reducing morbidity and mortality. All health care providers have a role in optimizing the function and quality of life in the pediatric cancer population. IMPLICATIONS FOR NURSING PRACTICE: It is imperative for nurses to utilize subjective and clinical screening to identify persons appropriate for rehabilitation referral, collaborate with the rehabilitation team, and support the patients and families in adhering to rehabilitation recommendations.

Impact of Current Versus Previous Cardiac Resynchronization Therapy Guidelines on the Proportion of Patients With Heart Failure Eligible for Therapy.

OBJECTIVES: This study sought to ascertain the impact of heart failure (HF) guideline change on the number of patients eligible to undergo cardiac resynchronization therapy (CRT). BACKGROUND: The 2013 HF guideline of the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) narrowed the recommendations for CRT. The impact of this guideline change on the number of eligible patients for CRT has not been described. METHODS: Using data from Get With The Guidelines-Heart Failure between 2012 and 2015, this study evaluated the proportion of hospitalized patients with HF who were eligible for CRT on the basis of historical and current guideline recommendations. The authors identified 25,102 hospitalizations for HF that included patients with a left ventricular ejection fraction (LVEF) ≤35% from 283 hospitals. Patients with a medical, system-related, or patient-related reason for not undergoing CRT were excluded. RESULTS: Overall, 49.1% (n = 12,336) of patients with HF, an LVEF ≤35%, and no documented contraindication were eligible for CRT on the basis of historical guidelines, and 33.1% (n = 8,299) of patients were eligible for CRT on the basis of current guidelines, a 16.1% absolute reduction in eligibility (p < 0.0001). Patients eligible for CRT on the basis of current guidelines were more likely to have CRT with an implantable cardioverter-defibrillator or CRT with pacing only placed or prescribed at discharge (57.8% vs. 54.9%; p < 0.0001) compared with patients eligible for CRT on the basis of historical guidelines. CONCLUSIONS: In this population of patients with HF, an LVEF ≤35%, and no documented contraindication for CRT, the current ACCF/AHA HF guidelines reduce the proportion of patients eligible for CRT by approximately 15%.

Noninvasive Bioelectrical Impedance for Predicting Clinical Outcomes in Outpatients With Heart Failure.

BACKGROUND: Noninvasive bioelectrical impedance analysis (BIA) has shown promise in acute heart failure (HF) management. To our knowledge, its use in predicting outcomes in outpatients with chronic HF patients has not been well described. METHODS AND RESULTS: BIA assessment of edema index was performed in 359 outpatients with HF using the InBody 520 scale. Edema index was calculated by dividing extracellular by total body water. Patients were stratified into those with low (≤0.39) and high (>0.39) edema indices. The outcome of interest was death, urgent transplant, or ventricular assist device over 2-year follow up. Patients with a high edema index were older, had higher B-type natriuretic peptide values and New York Heart Association Class. Patients with a high edema index had poorer outcomes (unadjusted hazard ratio 1.90, 95% confidence intervals 1.05-3.56). However, in multivariate analyses, a high edema index was not an independent predictor of outcomes (adjusted hazard ratio 1.21, 95% confidence interval 0.51-2.90). CONCLUSIONS: A high edema index using a bioimpedance scale in a HF clinic correlated with patient outcomes in unadjusted analyses, but was not a predictor of outcomes once other measures of HF severity are accounted for. As a noninvasive measure of volume status, use of BIA in a HF clinic may be beneficial in determining patient prognosis and treatment when other outcome predictors are not immediately available.

Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery.

The Canadian Cardiovascular Society Guidelines Committee and key Canadian opinion leaders believed there was a need for up to date guidelines that used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence assessment for patients who undergo noncardiac surgery. Strong recommendations included: 1) measuring brain natriuretic peptide (BNP) or N-terminal fragment of proBNP (NT-proBNP) before surgery to enhance perioperative cardiac risk estimation in patients who are 65 years of age or older, are 45-64 years of age with significant cardiovascular disease, or have a Revised Cardiac Risk Index score ≥ 1; 2) against performing preoperative resting echocardiography, coronary computed tomography angiography, exercise or cardiopulmonary exercise testing, or pharmacological stress echocardiography or radionuclide imaging to enhance perioperative cardiac risk estimation; 3) against the initiation or continuation of acetylsalicylic acid for the prevention of perioperative cardiac events, except in patients with a recent coronary artery stent or who will undergo carotid endarterectomy; 4) against α2 agonist or ß-blocker initiation within 24 hours before surgery; 5) withholding angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker starting 24 hours before surgery; 6) facilitating smoking cessation before surgery; 7) measuring daily troponin for 48 to 72 hours after surgery in patients with an elevated NT-proBNP/BNP measurement before surgery or if there is no NT-proBNP/BNP measurement before surgery, in those who have a Revised Cardiac Risk Index score ≥1, age 45-64 years with significant cardiovascular disease, or age 65 years or older; and 8) initiating of long-term acetylsalicylic acid and statin therapy in patients who suffer myocardial injury/infarction after surgery.

Rates and reasons for device-based guideline eligibility in patients with heart failure.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) are recommended by guidelines for patients with heart failure (HF) meeting specific criteria. Uncertainty exists regarding estimates of device eligibility, related in part to the method of assessing for guideline nonadherence. OBJECTIVE: The aim of this study was to identify the rates of guideline eligibility and device utilization after accounting for reasons for not receiving an ICD or CRT. METHODS: Patients were identified from 2006 to 2011 in a tertiary Heart Function Clinic in Canada. The chart-level data were collected that would indicate guideline eligibility and nonadherence. RESULTS: A total of 762 patients with HF were included (mean age 66 years; 527 (69%) were males; median left ventricular ejection fraction 33%). Over follow-up, 331 patients (43%) were never guideline eligible whereas 431 (57%) were guideline eligible for a device. Yearly rates for ICD and CRT adherence in "guideline-eligible" patients ranged from 59% to 68% and from 66% to 81%, respectively. "Patient preference" was the most commonly documented reason for guideline nonadherence in eligible patients. After removal of patients with reasons for nonadherence, rates of ICD and CRT adherence in the "truly eligible" patients were found to be higher (70%-81% and 71%-88%, respectively) than those in guideline-eligible patients. Independent predictors of device nonadherence in truly eligible patients were age >75 years, QRS duration <120 ms, left ventricular ejection fraction <30%, and female sex. CONCLUSION: Based on chart-level data, utilization rates of device-based therapies in patients with HF appear much higher than those of prior registry-based estimates. Given the importance of patient preferences for lack of device use, future quality-of-care metrics based on guideline adherence should capture detailed chart-level data and patient preferences.

Mortality outcomes among status Aboriginals and whites with heart failure.

BACKGROUND: Aboriginals have more cardiovascular risk factors than do non-Aboriginals that predispose them to the development of heart failure (HF). Whether long-term mortality outcomes and health care use differ between Aboriginals and whites with HF is unknown. METHODS: The population consisted of all Albertans aged ≥ 20 years with an incident HF hospitalization between 2000 and 2008. Aboriginal status is recorded in the Alberta Health Care Insurance Registry and white ethnicity was determined using previously validated surname analysis algorithms. Cox and logistic regression was used to examine mortality outcomes after adjustment for key variables. RESULTS: Compared with whites (n = 42,288), status aboriginal patients with HF (n = 1158) were significantly younger (mean age, 62.6 vs 75.4 years; P < 0.0001) and had higher rates of diabetes (45% vs 29%; P < 0.0001) and chronic obstructive pulmonary disease (40% vs 36%; P < 0.0001) but lower rates of most other comorbidities. Although crude mortality rates were lower in status Aboriginals than in whites at 1 year (22% vs 31%; P < 0.0001) and at 5 years (48% vs 59%; P < 0.0001), after adjustment, status Aboriginals exhibited increased mortality at 1 year (adjusted odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01-1.38) and 5 years (adjusted OR, 1.39; 95% CI, 1.16-1.67). Compared with whites, status Aboriginals used more health care resources in the years before and after an incident HF hospitalization but less specialist care. CONCLUSIONS: Although status Aboriginals hospitalized for the first time with HF are > 10 years younger, they use more health care resources and have increased short- and long-term mortality compared with their white counterparts.

The unrecognized burden of osteoporosis-related vertebral fractures in patients with heart failure.

BACKGROUND: Heart failure (HF) is associated with several factors that contribute to both reduced bone mineral density and increased risk of osteoporosis-related fractures. Our objectives were to describe the prevalence and predictors of the most common osteoporotic fracture, vertebral compression fractures (VCF), in patients with HF. METHODS AND RESULTS: We conducted a cross-sectional study in a random sample of patients attending a tertiary care HF Clinic in Edmonton, Alberta, Canada. We collected sociodemographic, clinical, medication, and chest radiograph information. Primary outcome was board-certified radiologist-documented VCF on chest radiographs. Multivariable logistic regression was used to determine independent correlates of VCF. Overall, 623 patients with HF were included; 32% were over 75 years of age, 31% were women, 65% had ischemic cardiomyopathy, and 38% had atrial fibrillation. Prevalence of VCF was 77 of 623 (12%; 95% confidence interval, 10% to 15%), and 42 of 77 (55%) patients had multiple fractures. Only 15% of those with VCF were treated for osteoporosis. In multivariable analyses adjusted for age, female sex, weight, and medications, the only remaining predictors independently associated with fracture were atrial fibrillation (present in 42 of 77 [55%] of those with VCF versus 197 of 540 [36%] of those without; adjusted odds ratio, 2.1; 95% confidence interval, 1.2 to 3.6; P=0.009) and lipid-lowering drugs (used by 36 of 77 [47%] of those with VCF versus 342 of 540 [63%] of those without; adjusted odds ratio, 0.2; 95% confidence interval, 0.1 to 0.9; P=0.03). CONCLUSIONS: About one-tenth of HF patients had a chest radiograph-documented VCF, and half of those with VCF had multiple fractures; most (85%) were not receiving an osteoporosis-specific therapy. A previously unrecognized risk factor-atrial fibrillation-was found to be independently associated with VCF. Chest radiograph reports may represent an important case-finding tool for osteoporosis-specific VCF, particularly in HF patients with atrial fibrillation.

Prevalence and predictors of vertebral fracture in patients with chronic obstructive pulmonary disease.

OBJECTIVES: Patients with COPD are at risk for osteoporosis-related vertebral compression fractures (VCF) which predispose to more fractures and worsening pulmonary function. Our objectives were to: 1 document VCF prevalence in COPD patients; and 2 determine the independent correlates of VCF. METHODS: From 2004-2006, we prospectively recruited consecutive consenting COPD patients presenting with acute exacerbation at three Canadian Emergency Departments (ED). We collected clinical and pulmonary function data. Primary outcome was radiologist documented VCF on chest radiograph. Multivariable logistic regression was used for all adjusted analyses. RESULTS: Overall, 245 patients were studied; 37% were >or=75 years and 44% were women. Prevalence of VCF documented by chest radiograph was 22 of 245 (9%; 95%CI 6-13%). Almost half (10 of 22 [43%]) of VCF patients were not treated for osteoporosis and all 10 received oral steroids. Compared to patients without fractures, those with VCF were older (p=0.014), had COPD of longer duration (p=0.09) and greater severity (mean FEV(1) 0.9 vs 1.1L; p=0.05), and had lower body mass index [BMI] (median 26 vs 28; p=0.01). Across BMI quartiles (from heaviest [median 37] to lightest [median 21]) the prevalence of VCF progressively increased (2%, 8%, 10%, 21%; p<0.001). In analyses adjusted for age, sex, and COPD duration, the only independent correlate of VCF was BMI: VCF increased as BMI decreased from heaviest (OR=1) to lightest (OR=11.0) quartiles (p=0.025). CONCLUSIONS: Almost one-tenth of COPD patients presenting with acute exacerbation have chest radiographs documenting VCF. About half of patients with VCF were not treated for osteoporosis, but all were started on oral steroids. Our findings suggest chest radiograph reports may represent an important case-finding tool for VCF, particularly in underweight patients with COPD.

Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial.

OBJECTIVES: To determine whether cardiovascular exercise training resulted in improved antibody responses to influenza vaccination in sedentary elderly people who exhibited poor vaccine responses. DESIGN: Single-site randomized parallel-arm 10-month controlled trial. SETTING: University of Illinois at Urbana-Champaign. PARTICIPANTS: One hundred forty-four sedentary, healthy older (69.9 +/- 0.4) adults. INTERVENTIONS: Moderate (60-70% maximal oxygen uptake) cardiovascular exercise was compared with flexibility and balance training. MEASUREMENTS: The primary outcome was influenza vaccine response, as measured according to hemagglutination inhibition (HI) anti-influenza antibody titer and seroprotective responses (HI titer > or =40). Secondary measures included cardiovascular fitness and body composition. RESULTS: Of the 160 participants enrolled, 144 (90%) completed the 10-month intervention with excellent compliance ( approximately 83%). Cardiovascular, but not flexibility, exercise intervention resulted in improvements in indices of cardiovascular fitness, including maximal oxygen uptake. Although not affecting peak (e.g., 3 and 6 weeks) postvaccine anti-influenza HI titers, cardiovascular exercise resulted in a significant increase in seroprotection 24 weeks after vaccination (30-100% dependent on vaccine variant), whereas flexibility training did not. CONCLUSION: Participants randomized to cardiovascular exercise experienced improvements in influenza seroprotection throughout the entire influenza season, whereas those in the balance and flexibility intervention did not. Although there were no differences in reported respiratory tract infections, the exercise group exhibited reduced overall illness severity and sleep disturbance. These data support the hypothesis that regular endurance exercise improves influenza vaccine responses.

Long-term propagation of distinct hematopoietic differentiation programs in vivo.

Heterogeneity in the differentiation behavior of hematopoietic stem cells is well documented but poorly understood. To investigate this question at a clonal level, we isolated a subpopulation of adult mouse bone marrow that is highly enriched for multilineage in vivo repopulating cells and transplanted these as single cells, or their short-term clonal progeny generated in vitro, into 352 recipients. Of the mice, 93 showed a donor-derived contribution to the circulating white blood cells for at least 4 months in one of four distinct patterns. Serial transplantation experiments indicated that two of the patterns were associated with extensive self-renewal of the original cell transplanted. However, within 4 days in vitro, the repopulation patterns subsequently obtained in vivo shifted in a clone-specific fashion to those with less myeloid contribution. Thus, primitive hematopoietic cells can maintain distinct repopulation properties upon serial transplantation in vivo, although these properties can also alter rapidly in vitro.

ABC transporter activities of murine hematopoietic stem cells vary according to their developmental and activation status.

Primitive hematopoietic cells from several species are known to efflux both Hoechst 33342 and Rhodamine-123. We now show that murine hematopoietic stem cells (HSCs) defined by long-term multilineage repopulation assays efflux both dyes variably according to their developmental or activation status. In day 14.5 murine fetal liver, very few HSCs efflux Hoechst 33342 efficiently, and they are thus not detected as "side population" (SP) cells. HSCs in mouse fetal liver also fail to efflux Rhodamine-123. Both of these features are retained by most of the HSCs present until 4 weeks after birth but are reversed by 8 weeks of age or after a new HSC population is regenerated in adult mice that receive transplants with murine fetal liver cells. Activation of adult HSCs in vivo following 5-fluorouracil treatment, or in vitro with cytokines, induces variable losses in Rhodamine-123 and Hoechst 33342 efflux activities, and HSCs from mdr-1a/1b(-/-) mice show a dramatic decrease in Rhodamine-123 efflux ability. Thus, the Rhodamine-123 and Hoechst 33342 efflux properties of murine HSCs fluctuate in the same fashion as a number of other HSC markers, suggesting these are regulated by a common control mechanism that operates independently of that regulating the regenerative function of HSCs.

Different in vivo repopulating activities of purified hematopoietic stem cells before and after being stimulated to divide in vitro with the same kinetics.

OBJECTIVE: The Hoechst 33342-effluxing side population (SP) of adult mouse bone marrow (BM) contains most of the hematopoietic stem cells (HSCs). Here we measured the HSC content of specific subsets of SP cells and then used a highly HSC-enriched fraction to investigate the effect of different growth factors on the initial rate of HSC proliferation in vitro and the accompanying maintenance (or loss) of HSCs in the first-division progeny. MATERIALS AND METHODS: Staining with Rhodamine-123 (Rho) was used to subfractionate lineage marker-negative (lin-) SP cells. Cells were assayed for HSCs by examining their ability to generate sustained (>4 months) multi-lineage lympho-myeloid clones in irradiated hosts. Cultures of single lin- Rho- SP cells were used to monitor growth factor effects on HSC proliferation and function. RESULTS: More than 40% of mice injected with single lin- Rho- SP cells showed long-term lympho-myeloid reconstitution. Some clones peaked within 8 weeks but others developed more slowly apparently unrelated to the pattern of lineage representation. 3/3 clones tested repopulated secondary mice. Either Steel factor+interleukin-11 (+/- flt3-ligand) or Steel factor+thrombopoietin stimulated at least 75% of single lin- Rho- SP cells to divide in vitro with the same synchronous kinetics. However, in the first cocktail, the frequency of HSCs among the first-division doublets was preserved but in the latter it was greatly diminished. CONCLUSION: Exogenous growth factors can differentially affect the ability of HSCs to execute a self-renewal division within a single cell cycle even when the kinetics of proliferation are the same.