Measuring the coupling of hormone concentration time series using polynomial transfer functions.
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Animals↗
Biomedical subjects
Michael L Johnson
Publications and source records attributed to Michael L Johnson.
Quantifying asynchronous breathing.
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Algorithms↗
Relation of leptin pulse dynamics to fat distribution in HIV-infected patients.
BACKGROUND: HIV-infected patients are affected by changes in fat distribution, ie, significant losses of subcutaneous fat in association with metabolic abnormalities. OBJECTIVE: The objective was to investigate the relation between leptin secretion and subcutaneous fat loss in HIV-infected patients. DESIGN: We investigated leptin pulse dynamics, measured every 20 min overnight from 2000 to 0800 in 41 HIV-infected patients with a mean (+/-SEM) age of 42.7 +/- 1.1 y and body mass index (in kg/m(2)) of 24.7 +/- 0.4 and in 20 healthy control subjects (age: 42.8 +/- 1.8 y; body mass index: 24.6 +/- 0.5). Leptin pulse variables were compared with total body fat, abdominal subcutaneous fat, and abdominal visceral fat in univariate and multivariate regression analyses. RESULTS: The number of leptin pulses was not significantly different between the HIV-infected and control subjects. Subcutaneous fat correlated significantly with mean leptin secretion (r = 0.72, P <0.0001), leptin pulse amplitude (r = 0.62, P <0.0001), and leptin nadir (r = 0.62, P <0.0001) in the HIV-infected patients. In stepwise regression modeling, subcutaneous fat (P <0.0001), but not visceral fat, was significantly associated with leptin secretion (overall R(2) for the model = 0.57, P <0.0001) in the HIV-infected patients. For each 1-cm(2) decrease in abdominal subcutaneous fat area, leptin decreased by 0.044 ng/mL when visceral fat was controlled for. Subcutaneous fat was also significantly related to leptin in the control subjects. CONCLUSIONS: This is the first study to investigate the relation between fat distribution and leptin pulse dynamics in HIV-infected patients. There was a significant reduction in leptin secretion with subcutaneous fat loss in this population.
Absorptiometry, Photon↗
Relationship between sex hormones and anterior knee laxity across the menstrual cycle.
PURPOSE: To comprehensively quantify through daily, serial measures changes in knee laxity as a function of changing sex-hormone levels across one complete menstrual cycle. METHODS: Twenty-five females, 18 - 30 yr, body mass index < or = 30, who reported normal menstrual cycles (28-32 d) over the past 6 months participated. Participants were tested daily across one complete menstrual cycle; 5-7 cc of venous blood were withdrawn to assay serum levels of estradiol, progesterone, and testosterone. Knee laxity was measured as the amount of anterior tibial displacement at 133 N, using a standard knee arthrometer. To evaluate the relationship of knee laxity to changes in sex hormone concentrations, a multiple linear regression model with the possibility of a time delay was performed on each individual subject and the group as a whole. RESULTS: Individual regression equations revealed an average of 63% of the variance in knee laxity was explained by the three hormones and their interactions. All three hormones significantly contributed to the prediction equation, and the amount of variance explained was substantially greater when a time delay was considered. On average, knee laxity changed approximately 3, 4, and 4.5 d after changes in estradiol, progesterone, and testosterone, respectively. When females were analyzed as a group, only 8% of the variance in knee laxity was explained by sex-hormones levels. CONCLUSION: Changes in sex hormones mediate changes in knee laxity across the menstrual cycle. However, the strength of this relationship, the relative contribution of each hormone, and the associated time delay are highly variable between women. This individual variability is consistent with the variability in menstrual cycle characteristics among women.
Adolescent↗
Fatigue models for applied research in warfighting.
The U.S. Department of Defense (DOD) has long pursued applied research concerning fatigue in sustained and continuous military operations. In 1996, Hursh developed a simple homeostatic fatigue model and programmed the model into an actigraph to give a continuous indication of performance. Based on this initial work, the Army conducted a study of 1 wk of restricted sleep in 66 subjects with multiple measures of performance, termed the Sleep Dose-Response Study (SDR). This study provided numerical estimation of parameters for the Walter Reed Army Institute of Research Sleep Performance Model (SPM) and elucidated the relationships among several sleep-related performance measures. Concurrently, Hursh extended the original actigraph modeling structure and software expressions for use in other practical applications. The model became known as the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) Model, and Hursh has applied it in the construction of a Fatigue Avoidance Scheduling Tool. This software is designed to help optimize the operational management of aviation ground and flight crews, but is not limited to that application. This paper describes the working fatigue model as it is being developed by the DOD laboratories, using the conceptual framework, vernacular, and notation of the SAFTE Model. At specific points where the SPM may differ from SAFTE, this is discussed. Extensions of the SAFTE Model to incorporate dynamic phase adjustment for both transmeridian relocation and shift work are described. The unexpected persistence of performance effects following chronic sleep restriction found in the SDR study necessitated some revisions of the SAFTE Model that are also described. The paper concludes with a discussion of several important modeling issues that remain to be addressed.
Aviation↗
Modulating the homeostatic process to predict performance during chronic sleep restriction.
BACKGROUND: In most current sleep/performance models, the homeostatic process is generally conceived as a simple reservoir in which performance capacity increases exponentially during sleep and decays either linearly or exponentially during wakefulness. Models that include this notional homeostatic process have been successful for describing sleep-performance data under conditions of irregular sleep schedules, jet lag, and short periods of total sleep loss. However, recently described data from sleep restriction studies indicate that recovery following chronically restricted sleep is considerably slower than would be predicted by these models. These findings suggest that chronic sleep restriction induces relatively long-term, slow-recovering changes in brain physiology that affect alertness and performance. METHODS: This paper describes, both conceptually and mathematically, a generic modification to sleep/performance models that facilitates the ability to predict the rate at which alertness and performance restoration occurs during recovery sleep following chronic sleep restriction. Weighted nonlinear least-squares methods were used to compare the proposed modulated homeostatic model with recent sleep/performance observations during chronic sleep restriction and recovery. RESULTS: When compared with the classical Walter Reed homeostatic model, this proposed model was found to provide a better description of sleep restriction and recovery observations. The proposed model was also found to be consistent with the data from a recent University of Pennsylvania study. CONCLUSIONS: These two models make significantly different predictions of performance during both the recovery phase and the chronic sleep restriction phase.
Data Interpretation, Statistical↗
Prevalence of comorbid hypertension and dyslipidemia and associated cardiovascular disease.
OBJECTIVES: To estimate the prevalence of concurrent hypertension and dyslipidemia among a general veteran population and separately among patients with diabetes mellitus, and to compare the prevalence of cardiovascular disease among groups with isolated versus concurrent hypertension and dyslipidemia. STUDY DESIGN: Retrospective cohort study. PATIENTS AND METHODS: This study was conducted in 6 medical centers of the Department of Veterans Affairs and included 371221 patients seen for any reason from October 1, 1998, to September 30, 2001. The proportion of patients with isolated or concurrent hypertension and dyslipidemia was estimated based on diagnostic, pharmacy, laboratory, and vital sign information, and the age-adjusted proportions of individuals with cardiovascular disease were compared between groups. RESULTS: We found that 57.8% of all patients had hypertension or dyslipidemia; 30.7% had both. Sixteen percent of all patients had diabetes mellitus, and 66.3% of these patients had concomitant hypertension and dyslipidemia. The prevalence of coronary artery disease was often more than doubled among patients with concomitant conditions compared with patients with either condition alone. The prevalence of stroke and peripheral arterial disease similarly increased among patients with both conditions. The prevalence of these cardiovascular diseases was highest among patients with diabetes mellitus. CONCLUSION: The prevalence of cardiovascular disease was high among this population of older, predominately male US veterans.
Adult↗
A mechanism for the direct regulation of T-type calcium channels by Ca2+/calmodulin-dependent kinase II.
Low-voltage-activated (LVA) Ca2+ channels are widely distributed throughout the CNS and are important determinants of neuronal excitability, initiating dendritic and somatic Ca2+ spikes that trigger and shape the pattern of action potential firing. Here, we define a molecular mechanism underlying the dynamic regulation of alpha1H channels (Cav3.2), by Ca2+/CaM-dependent protein kinase II (CaMKII). We show that channel regulation is selective for the LVA alpha1H Ca2+ channel subtype, depends on determinants in the alpha1H II-III intracellular loop, and requires the phosphorylation of a serine residue absent from unregulated alpha1G (Cav3.1) channels. These studies identify the alpha1H channel as a new substrate for CaMKII and provide the first molecular mechanism for the direct regulation of T-type Ca2+ channels by a protein kinase. Our data suggest a novel mechanism for modulating the integrative properties of neurons.
Binding Sites↗
Incidence and consequences of total body potassium depletion in chronic hemodialysis patients.
OBJECTIVE: This study determined relationship between total body potassium (TBK) and morbidity and mortality of patients with end stage renal disease (ESRD). DESIGN, PATIENTS, SETTING: Long term observational study of 15 ESRD patients receiving chronic hemodialysis in an academically affiliated Veterans Affairs Medical Center Hospital. METHODOLOGY AND OUTCOME MEASURE: TBK by whole-body counting of 40K, dialysis potassium losses, and patient demographic characteristics were determined. Survival was evaluated retrospectively after seven years of follow-up. RESULTS: Six of 15 patients (40%) had TBK depletion. All patients who were TBK depleted, expired by study end. In contrast, only 4 of 9 patients with normal K+ stores had died during the same time period (P<0.02). Median survival time of subjects with normal TBK was 100 vs 55 months for the depleted group (chi2=4.6, P<0.05). Patients with normal TBK were younger (41.9 vs 62.5 years, P<0.02) and predominantly black (78%). The ESRD group with normal TBK received more hours of hemodialysis (HD) per week (11.2 hours vs 9.7, P<0.02) and had greater K+ removal than the depleted patients (70.5 mmol/treatment vs 43.8). Urea reduction ratio was not statistically different between groups. Serum albumin, interdialytic increases in BUN and weight, and body mass index were not different between normal and TBK depleted groups. CONCLUSIONS: TBK depletion occurs in a significant proportion of HD patients and is associated with increased mortality. It is prudent to customize HD and dietary prescriptions to maintain normal levels of TBK in ESRD patients.
Adult↗
Characterization of leptin pulse dynamics and relationship to fat mass, growth hormone, cortisol, and insulin.
To investigate the regulation of leptin secretion and pulsatility by fat mass, we performed overnight leptin sampling every 20 min for 12 h and compared leptin dynamics with total body and regional fat measurements in 20 healthy male subjects. Simultaneous growth hormone (GH), cortisol, and insulin levels were assessed to determine relatedness and synchronicity during overnight fasting. Deconvolution analyses were performed to determine simultaneous hormonal dynamics, synchronicity, and interrelatedness using cross-correlation and cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 4.7 +/- 0.4 leptin pulses/12 h. Leptin secretion correlated highly with total body fat (r = 0.78, P < 0.001) and regional fat depots. In contrast, leptin pulsatility did not correlate with total fat (r = 0.07, P = 0.785) or other measures of fat. There was synchronicity between GH and leptin (lag -39 minutes), cortisol and leptin (lag -211 min), and leptin and insulin, with leptin following insulin by 275 min. The mean random X-ApEn was significant between leptin and GH (0.854 +/- 0.030), cortisol (0.891 +/- 0.023), and insulin (0.868 +/- 0.034), demonstrating a high degree of regularity and pattern frequency. These data demonstrate differential regulation of leptin secretion and pulsatility in adipocytes and suggest that the leptin pulse generator is extrinsic to fat, whereas fat mass acts as an amplifier to modulate secretion and amplitude for a given pulsatility. We demonstrate synchronicity between leptin and GH, cortisol, and insulin. The directionality of the cross correlation suggests a temporal construct in which changes in leptin follow those of insulin but precede those of GH and cortisol during overnight fasting.
Adipose Tissue↗
Risk assessment and adjustment: adjusting for sick patients or a sick system?
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Cost-Benefit Analysis↗
Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism.
Anorexia nervosa (AN) is a disorder that is increasing in frequency in adolescents, and the age of onset is often in the prepubertal years, potentially affecting the development of peak bone mass and linear growth. The GH-IGF-I axis plays an important role in bone formation, and alterations in GH secretory patterns have been described in adult women with AN. However, GH secretory dynamics in adolescents with AN have not been described, and the effects of alterations in GH secretory patterns and GH concentration on bone metabolism in AN are not known. We examined patterns of GH secretion by deconvolutional analysis, and GH concentration by Cluster analysis, in adolescent girls with AN (n = 22) and controls (n = 20) of comparable bone age and pubertal stage. We also examined the roles of cortisol, leptin, and estradiol in the regulation of GH secretion and concentration, and the relationship of GH secretory patterns and concentration to bone metabolism. Basal GH secretion and secretory pulse number in adolescent girls with AN were increased compared with control values (P = 0.03 and 0.007, respectively), and increased disorderliness of GH secretion (approximate entropy) was found in AN (P = 0.004). Mean and nadir GH concentrations and total area under the concentration curve were increased (P = 0.03, 0.002, and 0.03, respectively), and IGF-I levels were decreased (P = 0.0002) in girls with AN compared with healthy adolescent girls. IGF-I levels correlated negatively with nadir GH concentrations (r = -0.35; P = 0.02). Serum cortisol levels were higher in girls with AN than in controls (P < 0.0001) and correlated inversely with IGF-I (r = -0.58; P = 0.0001) and weakly with GH concentration (area under the concentration curve; r = -0.43; P = 0.05). A strong inverse relationship between markers of nutritional status (body mass index, fat mass, and leptin) and basal and pulsatile GH secretion, and mean and nadir GH concentrations was observed. GH concentration predicted levels of all markers of bone formation and a marker of bone resorption (N-telopeptide) in healthy controls, but not in AN. We demonstrate increases in basal GH secretion, number of secretory bursts, and GH concentration in adolescents with AN compared with controls, accompanied by low IGF-I levels. These data are consistent with the hypothesis that an acquired GH resistance occurs in this undernourished group. We also demonstrate that GH secretion and concentration are nutritionally regulated, and that the effects of nutrition exceed the effects of cortisol on GH concentration. Acquired GH resistance may play a role in the osteopenia and decreased peak bone mass frequently associated with AN.
Adolescent↗
Molecular characterization of expressed DQA and DQB genes in the California sea lion ( Zalophus californianus).
To date, there are no published MHC sequences from the California sea lion (Zalophus californianus), a thriving species that, by feeding high on the marine food web, could be a sentinel for disturbances in marine and coastal ecosystems. In this study, degenerate primers and RACE technology were used to amplify near-full-length (MhcZaca- DQB) and full-length (MhcZaca- DQA) expressed class II MHC gene products from the peripheral blood mononuclear cells of two California sea lions in rehabilitation. Five unique Zaca- DQA sequences and eight unique Zaca- DQB sequences, all encoding functional proteins, were identified in the two animals, indicating the presence of multiple DQ- loci in this species. An additional three Zaca- DQB sequences containing features compatible with pseudogenes or null alleles were also identified. Despite the identification of multiple DQA and DQB sequences, the degree of heterogeneity between them was extremely low. To confirm the limited degree of Zaca-DQ nucleotide variation between individuals, we used denaturing gradient gel electrophoresis to examine putative peptide binding region sequences from the peripheral blood leukocyte-derived RNAs of 19 wild-caught California sea lions from physically distinct populations. The pattern of Zaca-DQ sequence migration was identical between individuals and independent of geographical region. This apparent Zaca-DQ sequence identity between sea lions was confirmed by direct sequencing of individual bands. In combination, these findings raise important questions regarding immunogenetic diversity within this thriving species, and should prompt further research into the existence of a highly polymorphic sea lion class II MHC molecule with sequence features that support traditional peptide binding functions.
Alleles↗
Effect of definition of mortality on hospital profiles.
BACKGROUND: Hospitals are ranked based on risk-adjusted measures of postoperative mortality, but definitions differ about which deaths following surgery should be included. OBJECTIVE: To determine whether varying the case definition of deaths following surgery that are included in coronary artery bypass surgery quality assessment affects the identification of outlier hospitals. RESEARCH DESIGN: The study used a prospective cohort design. SUBJECTS: A total of 15,288 patients undergoing coronary artery bypass surgery without other cardiac procedures from October 1993 to March 1996 at all (N = 43) Veterans Affairs hospitals that conduct cardiac surgery. MEASURES: The first measure included any death occurring within 30 days after surgery, regardless of cause, in or out of the hospital (30-day mortality). The second measure included 30-day mortality plus any death occurring 30 days to 6 months after surgery that was judged to be a direct result of a perioperative complication of the surgery (all procedure-related mortality). RESULTS: Hospital performance as assessed by the two different definitions of death varied substantially. The rankings of hospitals differed for 86% (37/43) of hospitals. Twenty-one percent (9/43) changed their quartile of rank, and five hospitals changed their outlier status. The correlation of observed-to-expected ratios was high (r = 0.96), but there was disagreement of outlier status (kappa = 0.71). CONCLUSIONS: Judgments regarding the quality of a hospital's performance of coronary artery bypass surgery vary depending on the definition of postoperative mortality that is used. Further research is needed to assess what definition is most appropriate to identify quality of care problems.
Benchmarking↗
Process of care in Hispanic, black, and white VA beneficiaries.
OBJECTIVE: To examine whether process of hospital care differs among Hispanic, black, and white VA beneficiaries. SUBJECTS: Two thousand eight-hundred fifty-two Hispanic, black, and white male VA beneficiaries from a case-control study discharged alive from one of twelve southern veterans hospitals with one of three diagnoses, diabetes mellitus (DM), congestive heart failure (CHF), or chronic obstructive pulmonary disease (COPD). METHODS: We applied diagnosis-specific explicit criteria for the process of hospital care to each patient's hospital record and computed the adherence score; the percentage of applicable criteria performed during the hospital stay. We compared mean scores in Hispanic, black, and white patients and then compared adjusted scores using multiple linear regression. MAIN OUTCOME MEASURE: Process of inpatient care (adherence score) in Hispanic, black, and white patients at admission, treatment, and discharge. RESULTS: Mean admission adherence scores differed (P = 0.003) among Hispanic patients, black patients, and white patients for CHF and COPD, but not DM. Mean treatment and discharge scores were not different among Hispanic patients, black patients, and white patients. In bivariate comparisons, mean admission scores were higher in black patients compared with white patients for CHF (P= 0.003) and COPD (P= 0.01). In stratified analyses, admission and treatment scores were higher (P= 0.0001) in patients admitted to teaching compared with nonteaching hospitals. Process of inpatient care did not differ among Hispanic, black, and white patients after adjusting for admission to a teaching hospital and other covariates. CONCLUSION: In contrast to findings in other studies, process of inpatient care was generally similar in Hispanic patients, black patients, and white patients. Our findings may reflect several characteristics of veterans' hospitals that may lead to care that is more equitable.
Black or African American↗
Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics.
Growth hormone (GH) secretion, controlled principally by a GH-releasing hormone (GHRH) and GH release-inhibiting hormone [somatostatin (SRIF)] displays vivid sexual dimorphism in many species. We hypothesized that relatively small differences within a dynamic core GH network driven by regulatory interactions among GH, GHRH, and SRIF explain the gender contrast. To investigate this notion, we implemented a minimal biomathematical model based on two coupled oscillators: time-delayed reciprocal interactions between GH and GHRH, which endow high-frequency (40-60 min) GH oscillations, and time-lagged bidirectional GH-SRIF interactions, which mediate low-frequency (occurring every 3.3 h) GH volleys. We show that this basic formulation, sufficient to explain GH dynamics in the male rat [Farhy LS, Straume M, Johnson ML, Kovatchev BP, and Veldhuis JD. Am J Physiol Regulatory Integrative Comp Physiol 281: R38-R51, 2001], emulates the female pattern of GH release, if autofeedback of GH on SRIF is relaxed. Relief of GH-stimulated SRIF release damps the slower volleylike oscillator, allowing emergence of the underlying high-frequency oscillations that are sustained by the GH-GHRH interactions. Concurrently, increasing variability of basal somatostatin outflow introduces quantifiable, sex-specific disorderliness of the release process typical of female GH dynamics. Accordingly, modulation of GH autofeedback on SRIF within the interactive GH-GHRH-SRIF ensemble and heightened basal SRIF variability are sufficient to transform the well-ordered, 3.3-h-interval, multiphasic, volleylike male GH pattern into a femalelike profile with irregular pulses of higher frequency.
Animals↗
Pulsatile insulin secretion by human pancreatic islets.
Insulin is secreted in discrete bursts. These pulses are also present when individual or groups of islets are perifused. Interpretation of the measured frequency and magnitude of pulsatile hormone secretion requires an examination of the sensitivity and specificity of the methods for pulse detection and validation of these for the experimental apparatus and hormone assay in which they are applied. In the present study we achieve these aims for a perfusion method for measurement of pulsatile insulin release by human islets. A deconvolution technique previously developed for measurement of pulsatile hormone secretion in vivo was specifically validated for in vitro pulse detection in the present study. Deconvolution analysis reliably (>90%) detected insulin pulses with an amplitude 20% or more above baseline and recovered quantitatively the insulin secretion profile, insulin secretion rate, and insulin pulse mass from single as well as multiple perifused islets. Cluster analysis was less sensitive, but was able to detect most (>80%) pulses with an amplitude of 40% or more above baseline. With this limitation, cluster analysis is potentially useful for groups, but not single perifused human islets. Analysis of single human islets showed that enhanced insulin secretion by increased glucose concentrations in the perfusate is achieved by enhancing insulin pulse mass with no change in pulse frequency. Perfused single or groups of human islets exhibited an interpulse interval ( approximately 6-8 min) comparable to that observed in humans in vivo. Dynamic in vitro perifusion should facilitate studies of the mechanisms driving pulsatile insulin secretion.
Cluster Analysis↗
Just-in-time IRB review: capitalizing on scientific merit review to improve human subjects research compliance.
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Ethical Review↗