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S M Pincus

Publications and source records attributed to S M Pincus.

At least 19 recordsLinked to original sources
PubMed1996

Generation of activated natural killer (A-NK) cells in patients with chronic myelogenous leukaemia and their role in the in vitro disappearance of BCR/abl-positive targets.

Activated natural killer (A-NK) cells, a subset of CD56(dim)CD3- lymphocytes, are obtained from PBMC of normal donors by adherence to plastic and culture in the presence of IL2. In this study we tested the feasibility of generating A-NK cells in patients with Ph+ chronic myeloid leukaemia (CML). Cultures obtained from patients with early chronic phase (ECP; n=7) contained a mean (+/-SD) of83 +/- 7% of CD3- cells, and those from patients with advanced chronic phase (ACP; n=7) contained 27+/-33% CD56+CD3- cells. In three patients with leukaemia in a blastic phase (BP) it was only possible to obtain one culture enriched in CD56+CD3- cells (81%). Cellular aggregates of myeloid cells and large granular lymphocytes were observed in early A-NK cell cultures. Paired freshly-adherent and cultured A-NK cells were tested for the presence of BCR/abl mRNA by RT-PCR. The BCR/abl+ cells were detected in all 12 preparations of the freshly adherent A-NK cells tested. In 6/12 the BCR/abl+ cells were no longer detectable by RT-PCR on day 14 of culture. Both proliferation and antileukaemic cytotoxicity were significantly higher (P=0.002 and P=0.029, respectively) in the BCR/abl- cultures than those in the six BCR/abl+ cultures. 5/6 BCR/abl- cultures were highly enriched in A-NK cells on day 14, and 1/6 contained predominantly CD56+CD3+ cells. Only 2/6 BCR/abl + cultures were enriched in A-NK cells on day 14, but they had poor cytotoxicity and a low proliferative index. Myeloid cells (CD33+) were more frequently detected in the BCR/abl+ than BCR/abl- A-NK cell cultures (P=0.028). These observations suggest that: (1) populations of benign A-NK cells can be generated from the peripheral blood of CML patients; (2) the ability to generate A-NK cells is impaired in patients with advanced CML; and (3) the ability to generate A-NK cells with antileukaemic activity correlates with the disappearance of BCR/abl+ cells from these cultures.

Antigens, CD↗
PubMed1996

High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer.

This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy.

Adult↗
PubMed1996

Females secrete growth hormone with more process irregularity than males in both humans and rats.

In humans, serum growth hormone (GH) concentrations are significantly higher in women than in men, but the neuroendocrine mechanisms that underlie such gender differences are not known. We compared normal episodic GH secretion in males and females in three distinct settings: two human studies employing quite different assay techniques (immunoradiometric assay and a high-sensitivity immunofluorimetric method) and a rat study. To quantify the amount of regularity in data, we utilized approximate entropy (ApEn), a scale- and model-independent statistic. In each study, females exhibited significantly greater statistical irregularity in GH concentration series than their male counterparts (P < 10(-3) for each human study, P < 10(-6) for the rat study), implying that mass and mode of GH secretion are regulated differently in males and females. The regularity comparisons indicated complete gender separation (100% specificity and sensitivity) for the rat study and nearly complete separation for the immunofluorimetric assay study. The consistency and statistical significance of these findings suggest that this gender difference may be broadly based within higher animals and that this may be readily evaluated objectively by analysis of ApEn.

Adult↗
PubMed1994

Greater signal regularity may indicate increased system isolation.

Numerous calculations in diverse biological settings associate greater regularity and decreased complexity of experimental time series with disease and pathology, often accompanied by claims that such calculations indicate chaotic behavior. While the claims of chaos are unresolved, it nonetheless seems important to determine a unifying theme suggesting greater signal regularity in myriad complicated physiologic systems. Our major hypothesis is that in many systems, greater regularity corresponds to greater component autonomy and isolation. The idea is that healthy systems have good lines of communication, whereas crucial biologic messages in diseased states are either slow to transmit and receive or unable to arrive. We employ ApEn, approximate entropy, to quantify regularity and confirm the hypothesis via analysis of several very different, representational mathematical model forms, conferring a robustness to model form of the hypothesis. This hypothesis is experimentally verifiable in settings where some of the crucial network nodes and connections are known.

Animals↗
PubMed1994

Gender- and age-related differences in heart rate dynamics: are women more complex than men?

OBJECTIVES: This study aimed to quantify the complex dynamics of beat-to-beat sinus rhythm heart rate fluctuations and to determine their differences as a function of gender and age. BACKGROUND: Recently, measures of heart rate variability and the nonlinear "complexity" of heart rate dynamics have been used as indicators of cardiovascular health. Because women have lower cardiovascular risk and greater longevity than men, we postulated that there are important gender-related differences in beat-to-beat heart rate dynamics. METHODS: We analyzed heart rate dynamics during 8-min segments of continuous electrocardiographic recording in healthy young (20 to 39 years old), middle-aged (40 to 64 years old) and elderly (65 to 90 years old) men (n = 40) and women (n = 27) while they performed spontaneous and metronomic (15 breaths/min) breathing. Relatively high (0.15 to 0.40 Hz) and low (0.01 to 0.15 Hz) frequency components of heart rate variability were computed using spectral analysis. The overall "complexity" of each heart rate time series was quantified by its approximate entropy, a measure of regularity derived from nonlinear dynamics ("chaos" theory). RESULTS: Mean heart rate did not differ between the age groups or genders. High frequency heart rate power and the high/low frequency power ratio decreased with age in both men and women (p < 0.05). The high/low frequency power ratio during spontaneous and metronomic breathing was greater in women than men (p < 0.05). Heart rate approximate entropy decreased with age and was higher in women than men (p < 0.05). CONCLUSIONS: High frequency heart rate spectral power (associated with parasympathetic activity) and the overall complexity of heart rate dynamics are higher in women than men. These complementary findings indicate the need to account for gender-as well as age-related differences in heart rate dynamics. Whether these gender differences are related to lower cardiovascular disease risk and greater longevity in women requires further study.

Adult↗
PubMed1994

Quantification of evolution from order to randomness in practical time series analysis.

The principal focus of this chapter is the description of a recently developed, readily usable regularity statistic, ApEn, that quantifies the continuum from perfectly orderly to completely random in time series data. Several properties of ApEn facilitate its utility for practical time series analysis: (1) ApEn is nearly unaffected by noise of magnitude below a de facto specified filter level; (2) ApEn is robust to outliers; (3) ApEn can be applied to time series of 100 or more points, with good confidence (established by standard deviation calculations); (4) ApEn is finite for stochastic, noisy deterministic, and composite (mixed) processes, the last of which are likely models for complicated biological systems; (5) increasing ApEn corresponds to intuitively increasing process complexity in the settings of (4). This applicability to medium-sized data sets and general stochastic processes is in marked contrast to capabilities of "chaos" algorithms such as the correlation dimension, which are properly applied to low-dimensional iterated deterministic dynamical systems. The potential uses of ApEn to provide new insights in biological settings are thus myriad, from a perspective complementary to that given by classic statistical methods. The ApEn statistic is typically calculated by a computer program, with a FORTRAN listing for a "basic" code referenced above. It is imperative to view ApEn as a family of statistics, each of which is a relative measure of process regularity. For proper implementation, the two input parameters m (window length) and r (tolerance width, de facto filter) must remain fixed in all calculations, as must N, the data length, to ensure meaningful comparisons. Guidelines for m and r selection are indicated above. We have found normalized regularity to be especially useful; "r" is chosen as a fixed percentage (often 15 or 20%) of the SD of the subject rather than of a group SD. This version of ApEn has the property that it is decorrelated from process SD, in that it remains unchanged under uniform process magnification or reduction; thus we can entirely separate the questions of SD change and regularity change in data analysis. Because regularity questions are thematically orthogonal to the type of information that, for example, moment statistics ascertain, we highly recommend that ApEn be used in conjunction with other such statistics, rather than as a sole indicator of process typicality. Last and yet foremost, we recommend the following order of detail in Practical analysis. First, either visually or algorithmically, eliminate outliers.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗
PubMed1994

Physiological time-series analysis: what does regularity quantify?

Approximate entropy (ApEn) is a recently developed statistic quantifying regularity and complexity that appears to have potential application to a wide variety of physiological and clinical time-series data. The focus here is to provide a better understanding of ApEn to facilitate its proper utilization, application, and interpretation. After giving the formal mathematical description of ApEn, we provide a multistep description of the algorithm as applied to two contrasting clinical heart rate data sets. We discuss algorithm implementation and interpretation and introduce a general mathematical hypothesis of the dynamics of a wide class of diseases, indicating the utility of ApEn to test this hypothesis. We indicate the relationship of ApEn to variability measures, the Fourier spectrum, and algorithms motivated by study of chaotic dynamics. We discuss further mathematical properties of ApEn, including the choice of input parameters, statistical issues, and modeling considerations, and we conclude with a section on caveats to ensure correct ApEn utilization.

Algorithms↗
PubMed1994

Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release.

Pulses of growth hormone (GH) release in acromegaly may arise from hypothalamic regulation or from random events intrinsic to adenomatous tissue. To distinguish between these possibilities, serum GH concentrations were measured at 5-min intervals for 24 h in acromegalic men and women with active (n = 19) and inactive (n = 9) disease and in normal young adults in the fed (n = 20) and fasted (n = 16) states. Daily GH secretion rates, calculated by deconvolution analysis, were greater in patients with active acromegaly than in fed (P < 0.05) but not fasted normal subjects. Significant basal (nonpulsatile) GH secretion was present in virtually all active acromegalics but not those in remission or in fed and fasted normal subjects. A recently introduced scale- and model-independent statistic, approximate entropy (ApEn), was used to test for regularity (orderliness) in the GH data. All but one acromegalic had ApEn values greater than the absolute range in normal subjects, indicating reduced orderliness of GH release; ApEn distinguished acromegalic from normal GH secretion (fed, P < 10(-12); fasted, P < 10(-7)) with high sensitivity (95%) and specificity (100%). Acromegalics in remission had ApEn scores larger than those of normal subjects (P < 0.0001) but smaller than those of active acromegalics (P < 0.001). The coefficient of variation of successive incremental changes in GH concentrations was significantly lower in acromegalics than in normal subjects (P < 0.001). Fourier analysis in acromegalics revealed reduced fractional amplitudes compared to normal subjects (P < 0.05). We conclude that GH secretion in acromegaly is highly irregular with disorderly release accompanying significant basal secretion.

Acromegaly↗
PubMed1993

Approximate entropy of heart rate as a correlate of postoperative ventricular dysfunction.

BACKGROUND: Instantaneous changes in the heart rate, i.e., heart rate variation, traditionally have been quantified by the standard deviation of a series of intervals between successive heart beats. Approximate entropy provides another measure of variability by calculating the logarithmic likelihood that patterns that are similar remain similar on the next incremental comparisons. Approximate entropy is a nonnegative number that will distinguish data sets by their amount of regularity, with larger numbers indicating more randomness. We hypothesized that a decrease in the approximate entropy of heart rate would be associated with postoperative ventricular dysfunction (e.g., myocardial infarction, unstable angina, congestive heart failure, prolonged inotropic support). METHODS: Twenty-three high-risk noncardiac patients were continuously monitored by ambulatory electrocardiographic recorders from the evening before surgery up to 80 h during the postoperative period: 9 demonstrated postoperative ventricular dysfunction, and 14 had an uncomplicated postoperative course. Hourly approximate entropy average values were calculated. RESULTS: Approximate entropy was high (> 0.7) in all but two patients preoperatively. Postoperative approximate entropy <0.55 had a sensitivity of 88% and a specificity of 71% for being associated with postoperative ventricular dysfunction; preoperative approximate entropy values were not significantly different between the two groups. CONCLUSIONS: These results suggest that changes in approximate entropy can distinguish between patients who sustained poor outcome and those who had an uncomplicated course.

Aged↗
PubMed1993

Heart rate control in normal and aborted-SIDS infants.

Approximate entropy (ApEn), a mathematical formula quantifying regularity in data, was applied to heart rate data from normal and aborted-sudden infant death syndrome (SIDS) infants. We distinguished quiet from rapid-eye-movement (REM) sleep via the following three criteria, refining the notion of REM as more "variable": 1) REM sleep has greater overall variability (0.0374 +/- 0.0138 vs. 0.0205 +/- 0.0090 s, P < 0.005); 2) REM sleep is less stationary (StatAv = 0.742 +/- 0.110) than quiet sleep (StatAv = 0.599 +/- 0.159, P < 0.03); 3) after normalization to overall variability, REM sleep is more regular (ApEnsub = 1.224 +/- 0.092) than quiet sleep (ApEnsub = 1.448 +/- 0.071, P < 0.0001). Fifty percent of aborted-SIDS infants showed greater ApEn instability across quiet sleep than any normal infant exhibited, suggesting that autonomic regulation of heart rate occasionally becomes abnormal in a high-risk subject. There was an association between low ApEn values and aborted-SIDS events; 5 of 14 aborted-SIDS infants had at least one quiet sleep epoch with an ApEn value below the minimum of 45 normal-infant ApEn values.

Electroencephalography↗
PubMed1992

Quantification of hormone pulsatility via an approximate entropy algorithm.

Approximate entropy (ApEn) is a recently developed formula to quantify the amount of regularity in data. We examine the potential applicability of ApEn to clinical endocrinology to quantify pulsatility in hormone secretion data. We evaluate the role of ApEn as a complementary statistic to widely employed pulse-detection algorithms, represented herein by ULTRA, via the analysis of two different classes of models that generate episodic data. We conclude that ApEn is able to discern subtle system changes and to provide insights separate from those given by ULTRA. ApEn evaluates subordinate as well as peak behavior and often provides a direct measure of feedback between subsystems. ApEn generally can distinguish systems given 180 data points and an intra-assay coefficient of variation of 8%. This suggests ApEn as applicable to clinical hormone secretion data within the foreseeable future. Additionally, the models analyzed and extant clinical data are both consistent with episodic, not periodic, normative physiology.

Algorithms↗
PubMed1992

Approximate entropy: a regularity measure for fetal heart rate analysis.

Approximate entropy (ApEn), a recently developed mathematical formula quantifying regularity, was applied to fetal heart rate (FHR) data. Three groups were analyzed: 1) 19 women had normal labors (uncomplicated course of labor, vaginal delivery, no unusual FHR tracings, and 1- and 5-minute Apgar scores of at least 7 and 9, respectively; 2) 15 women had presumed fetal distress (severe cord or late decelerations, bradycardia, or tachycardia; delivery by cesarean with both arterial and venous cord pH above 7.20); and 3) 20 women had acidotic fetuses (both venous and arterial cord pH less than 7.20). Hourly mean (+/- SD) ApEn values for the three groups were: acidotic fetuses, 0.924 +/- 0.235, 102 hours; normal fetuses, 1.051 +/- 0.145, 97 hours; and nonacidotic "distressed" fetuses, 1.043 +/- 0.147, 74 hours. The ApEn values for nonacidotic, presumed distressed fetuses were not significantly different from those of normal fetuses (P greater than .75). Acidotic fetuses had many more instances of ApEn hourly values less than 0.8 (28%, 29 of 102) than did the normal and the nonacidotic, presumed distressed fetuses combined (5%, nine of 171). The probability that ApEn was less than 0.8 was larger for acidotic fetuses than for the other groups (P less than .00003), supporting the hypothesis that extremely regular FHR patterns imply a greater likelihood of acidosis. Significant hourly deviations in ApEn generally corresponded to drug administration or to physiologic changes such as cord compression and its relief. Thus ApEn, a major departure from variability statistics, appears to be able to detect subtle and possibly important differences in heart rate that are not visually apparent.

Biometry↗
PubMed1991

A regularity statistic for medical data analysis.

A new statistic has been developed to quantify the amount of regularity in data. This statistic, ApEn (approximate entropy), appears to have potential application throughout medicine, notably in electrocardiogram and related heart rate data analyses and in the analysis of endocrine hormone release pulsatility. The focus of this article is ApEn. We commence with a simple example of what we are trying to discern. We then discuss exact regularity statistics and practical difficulties of using them in data analysis. The mathematic formula development for ApEn concludes the Solution section. We next discuss the two key input requirements, followed by an account of a pilot study successfully applying ApEn to neonatal heart rate analysis. We conclude with the important topic of ApEn as a relative (not absolute) measure, potential applications, and some caveats about appropriate usage of ApEn. Appendix A provides example ApEn and entropy computations to develop intuition about these measures. Appendix B contains a Fortran program for computing ApEn. This article can be read from at least three viewpoints. The practitioner who wishes to use a "black box" to measure regularity should concentrate on the exact formula, choices for the two input variables, potential applications, and caveats about appropriate usage. The physician who wishes to apply ApEn to heart rate analysis should particularly note the pilot study discussion. The more mathematically inclined reader will benefit from discussions of the relative (comparative) property of ApEn and from Appendix A.

Algorithms↗
PubMed1991

Aging and the complexity of cardiovascular dynamics.

Biomedical signals often vary in a complex and irregular manner. Analysis of variability in such signals generally does not address directly their complexity, and so may miss potentially useful information. We analyze the complexity of heart rate and beat-to-beat blood pressure using two methods motivated by nonlinear dynamics (chaos theory). A comparison of a group of healthy elderly subjects with healthy young adults indicates that the complexity of cardiovascular dynamics is reduced with aging. This suggests that complexity of variability may be a useful physiological marker.

Adult↗
PubMed1990

Early changes in phosphoprotein patterns of Friend erythroleukaemia cells induced by dimethylsulphoxide or phorbol esters.

Immediate changes in protein phosphorylation in Friend erythroleukaemia cells (FELC) were examined in response to stimulation with dimethylsulphoxide (DMSO), which triggers cell differentiation, 12-O-tetra-decanoyl-phorbol 13-acetate (TPA), a tumour promoter, and the Ca++ ionophore A23187. The effects of the cyclic nucleotides, cAMP and cGMP, on the patterns of phosphoproteins were also analysed. Autoradiographs of two-dimensional gels reveal that within 30 min of treatment by the various agents differences in the patterns of protein phosphorylation can be seen. Treatment with DMSO and TPA altered the phosphoprotein patterns in different ways. These patterns were distinct from those observed in untreated and cyclic nucleotide treated cells. Treatment with the calcium ionophore caused a unique phosphorylation pattern unlike any of the others. These data suggest that the very early changes seen in the patterns of protein phosphorylation in FELC may be related to the induction of differentiation.

Animals↗
PubMed1989

Interleukin-3 and bryostatin 1 mediate rapid nuclear envelope protein phosphorylation in growth factor-dependent FDC-P1 hematopoietic cells. A possible role for nuclear protein kinase C.

Interleukin-3 (IL-3) is a lymphokine which stimulates the proliferation of normal and transformed multilineage hematopoietic cells. Recently we reported that bryostatin 1, a macrocyclic lactone and potent activator of protein kinase C, could stimulate normal multipotential hematopoietic progenitor cells in vitro in the absence of added polypeptide growth factors. We have now used the murine IL-3-dependent cell line FDC-P1, derived from normal murine marrow cells, to examine the early biochemical events associated with stimulation of hematopoietic cells. We find that both IL-3 and bryostatin 1 are mitogenic and stimulate the growth of FDC-P1 cells. Cells grown for extended periods in the presence of bryostatin 1 (1 nM) alone retain IL-3 responsiveness, indicating that bryostatin 1 does not induce an IL-3-independent state. Protein phosphorylation studies in cells treated with either IL-3 or bryostatin 1 indicate that both stimulators can mediate the rapid (within 5 min) serine-specific phosphorylation of several nuclear envelope polypeptides, including lamin B. Both IL-3- and bryostatin 1-mediated nuclear envelope phosphorylation is dose-dependent, occurring at concentrations which are mitogenic to FDC-P1 cells. The extent of nuclear envelope phosphorylation mediated by IL-3 and bryostatin 1 correlates with the mitogenic response. Furthermore, both mitogens mediate the rapid immunologic translocation of protein kinase C to the nuclear envelope where phosphorylation occurs. These data indicate that the early mitogenic signal(s) generated by IL-3 and bryostatin 1 may converge at the level of the nuclear envelope, perhaps through a protein kinase C-like activity which mediates phosphorylation of specific nuclear envelope polypeptides such as lamin B.

Animals↗
PubMed1985

Effects of dibutyryl adenosine 3',5'-cyclic monophosphate on erythropoietin production in human renal carcinoma cell cultures.

A human renal carcinoma from a patient with erythrocytosis, serially transplanted into athymic nude mice, was grown in primary monolayer cell cultures. After reaching confluency, the cultured cells formed multicellular hemicysts (domes), which became more abundant as the cultures approached saturation density. Erythropoietin (Ep) production by this renal carcinoma in culture was only slightly increased at the time of semiconfluency but showed a marked increase after the cultures reached confluency, in parallel with dome formation. Dibutyryl adenosine 3',5'-cyclic monophosphate significantly (P less than .01) stimulated Ep production and dome formation in the semiconfluent and confluent cultures of the renal carcinoma.

Animals↗