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Biomedical subjects

S M Pincus

Publications and source records attributed to S M Pincus.

At least 55 records · Page 3Linked to original sources
PubMed1997

Greater disorderliness of ACTH and cortisol release accompanies pituitary-dependent Cushing's disease.

We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and model-independent regularity statistic, approximate entropy (ApEn). The mean (+/-S.E.M.) ApEn value for plasma ACTH concentrations in Cushing's disease was 1.3817 +/- 0.033, and in controls 0.8394 +/- 0.049 (P < 10(-10)); for plasma cortisol concentrations the values were 1.4575 +/- 0.052 and 0.8637 +/- 0.020 respectively (P < 10(-10)), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release.

Adrenocorticotropic Hormone↗
PubMed1996

Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males.

New statistical perspectives on the secretory patterns of both luteinizing hormone (LH) and testosterone (T) may prove useful in further understanding the aging process, and possibly ultimately in improving the diagnosis and treatment of spermatogenetic failure and loss of sexual interest. We examined serum concentration time-series for LH and T in 14 young (21-34 years of age) and 11 aged (62-74 years of age) healthy men. For each subject, blood samples were obtained at 2.5-min intervals during a sleep period, with an average sampling duration of 7 hr. For each of LH and T, we used the model-independent statistic approximate entropy (ApEn) to quantify the irregularity of the serum concentration time-series; to quantify joint LH-T secretory asynchrony, we employed the recently introduced cross-ApEn. Although mean (and SD) LH and T concentrations were indistinguishable in the two age groups (P > 0.25), for LH, aged subjects had greater ApEn values (1.525 +/- 0.221) than younger individuals (1.207 +/- 0.252), P < 0.003, indicating more irregular secretion in the older cohort. For T, aged subjects also had greater ApEn values (1.622 +/- 0.120) than younger counterparts (1.384 +/- 0.228), P < 0.004. In young, but not older men, ApEn(T) significantly exceeded ApEn(LH), P < 0.02. Aged subjects had greater cross-ApEn values (1.961 +/- 0.121) than younger subjects (1.574 +/- 0.249), P < 10(-4), with nearly 100% sensitivity and specificity, indicating greater LH-T asynchrony in the older group. In conjunction with previous findings of greater irregularity of growth hormone release with increasing age, we propose that increased secretory irregularity with advancing age may be a widespread hormonal phenomenon. Finally, theoretically, we clarify the need for quantifications such as ApEn and cross-ApEn via a study of a "variable lag" pulsatile process, and empirically note the potential wide applicability of cross-ApEn to quantify asynchrony in interconnected (hormonal) networks.

Adult↗
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↗
PubMed1995

Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period.

Relapse after high-dose chemotherapy supported by peripheral blood stem cell transplantation (HDC-PBSCT) is the main cause of therapeutic failure in patients with lymphoma and breast cancer. Adoptive immunotherapy with activated natural killer (A-NK) cells and interleukin 2 might eliminate surviving residual tumor without adding to toxicity. Eleven patients with relapsed lymphoma and one with metastatic breast cancer were entered on a pilot clinical trial of HDC-PBSCT followed on day 2 after transplant by infusion of cultured autologous A-NK cells. Simultaneously, recombinant human interleukin 2 (rhIL-2) was initiated as a 4-day continuous i.v. infusion at 2 x 10(6) IU/m2/day, referred to as high-dose rhIL-2. Therapy with high-dose rhIL-2 was followed by a 90-day continuous i. v. infusion at 3 x 10(5) IU/m2/day, referred to as low-dose rhIL-2. All patients engrafted and nine completed treatment. Posttransplant days to a neutrophil count of 500/microliter and to a platelet count of 50,000/microliter were similar to comparable patients treated with HDC-PBSCT alone. Generation of A-NK cells for therapy was feasible in all patients except the three patients with Hodgkin's disease, whose cells did not proliferate in culture. Overall toxicity associated with early posttransplant transfer of A-NK cells and interleukin 2 did not differ from that observed with peripheral blood stem cell transplantation alone in comparable patients. There was early amplification of natural killer cell activity in the peripheral blood of four patients that appeared to result from the transfused A-NK cells. Adoptive transfer of A-NK cells and rhIL-2 during the pancytopenic phase after HDC-PBSCT was feasible and well tolerated, did not adversely affect engraftment, and resulted in amplified natural killer activity in the peripheral blood during the immediate posttransplantation period.

Adoptive Transfer↗
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

Approximating Markov chains.

A common framework of finite state approximating Markov chains is developed for discrete time deterministic and stochastic processes. Two types of approximating chains are introduced: (i) those based on stationary conditional probabilities (time averaging) and (ii) transient, based on the percentage of the Lebesgue measure of the image of cells intersecting any given cell. For general dynamical systems, stationary measures for both approximating chains converge weakly to stationary measures for the true process as partition width converges to 0. From governing equations, transient chains and resultant approximations of all n-time unit probabilities can be computed analytically, despite typically singular true-process stationary measures (no density function). Transition probabilities between cells account explicitly for correlation between successive time increments. For dynamical systems defined by uniformly convergent maps on a compact set (e.g., logistic, Henon maps), there also is weak continuity with a control parameter. Thus all moments are continuous with parameter change, across bifurcations and chaotic regimes. Approximate entropy is seen as the information-theoretic rate of entropy for approximating Markov chains and is suggested as a parameter for turbulence; a discontinuity in the Kolmogorov-Sinai entropy implies that in the physical world, some measure of coarse graining in a mixing parameter is required.

Journal Article↗
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

Approximate entropy as a measure of system complexity.

Techniques to determine changing system complexity from data are evaluated. Convergence of a frequently used correlation dimension algorithm to a finite value does not necessarily imply an underlying deterministic model or chaos. Analysis of a recently developed family of formulas and statistics, approximate entropy (ApEn), suggests that ApEn can classify complex systems, given at least 1000 data values in diverse settings that include both deterministic chaotic and stochastic processes. The capability to discern changing complexity from such a relatively small amount of data holds promise for applications of ApEn in a variety of contexts.

Journal Article↗