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PubMed1989

Fasting alters pulsatile and rhythmic cortisol release in normal man.

The effect of a 5-day fast on integrated, pulsatile, and periodic cortisol release was studied in 10 normal men by measuring serum cortisol concentrations every 20 min for 24 h before (day 0) and during the fifth day of fasting (day 5). Serum concentration profiles were analyzed for integrated cortisol release (area under the curve), pulsatile hormone release by an objective, statistically based pulse detection algorithm (cluster analysis), and periodic hormone release (circadian and ultradian rhythms) by Fourier expansion time series analysis. Urinary cortisol excretion per 24 h was measured in 5 men. The mean 24-h integrated serum cortisol concentration increased 1.7-fold during fasting (P = 0.0006). This increase resulted from a 2-fold increase in the serum cortisol concentrations between pulses (valley mean; P = 0.0004), an increase in the pulse height (P = 0.001), and an increase in pulse increment above baseline (P = 0.01). There were no changes in the number of pulses per 24 h, the interval between pulses, the width of the pulses, or the area of the pulses during fasting. Twenty-four-hour urinary cortisol excretion increased in all men, and the mean urinary cortisol (nanomoles per L)/creatinine clearance (milliliters per s) ratio increased from 119 on day 0 to 187 on day 5 (n = 5; P = 0.05). The pattern of periodic hormone release also changed during fasting; the mean (+/- SE) circadian rhythm (24-h) amplitude decreased from 160 +/- 14 nmol/L on day 0 to 102 +/- 105 nmol/L on day 5 (P = 0.06), and the amplitude of the 12-h rhythm increased from 68 +/- 11 to 99 +/- 11 nmol/L. There also were significant increases in the amplitudes of rhythms with periodicities of 8.1, 4.1, 2.4, 1.6, and 1.3 h (P = 0.02-0.008). Fasting in normal men results in distinct changes in the amount and pattern of pulsatile, circadian, and ultradian cortisol release.

Adult↗

PubMed1989

Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus.

The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1989

Specific, time-dependent actions of low-dose ethinyl estradiol administration on the episodic release of growth hormone, follicle-stimulating hormone, and luteinizing hormone in prepubertal girls with Turner's syndrome.

To investigate the actions of acute and chronic low doses of ethinyl estradiol (EE) on the pulsatile characteristics of GH and gonadotropin release we studied seven girls with Turner's syndrome [mean age, 7.5 +/- 0.75 (+/- SE) yr] on 3 separate study days. At baseline (study I), blood was drawn every 20 min from 2000-0800 h for GH, LH, and FSH determinations. One month after study I the patients were started on 100 ng/kg EE, orally, daily, and an identical study was repeated 1 week (study II) and 5 weeks (study III) from the initiation of low dose EE therapy. A pulse detection algorithm, Cluster, was used to objectively analyze pulsatility profiles. There were consistent and significant increases in all seven patients after 5 weeks of low dose EE therapy in mean GH concentrations (study I, 7.0 +/- 1.1 micrograms/L; study III, 13.4 +/- 1.7; P = 0.008), mean area under the GH pulse (study I, 602 +/- 52 micrograms/L.min; study III, 1350 +/- 261; P = 0.026), and mean GH pulse amplitude (study I, 14.0 +/- 2.2 micrograms/L; study III, 32.8 +/- 6.0; P = 0.018); with no detectable changes in GH pulse frequency (study I, 5.3 +/- 0.6 pulses/12 h; study III, 5.3 +/- 0.4). These findings were not accompanied by any significant changes in plasma somatomedin-C or serum estradiol concentrations or urinary cytological maturation indexes. Conversely, the amount of radioimmunoassayable FSH activity was suppressed after low dose EE therapy, with a decrease in mean FSH concentrations (study I, 23.5 +/- 6.6 IU/L; study III, 5.9 +/- 1.2; P = 0.035) and mean pulse amplitude (study I, 28.6 +/- 8.6 IU/L; study III, 8.2 +/- 1.8; P = 0.038), with no detectable changes in FSH pulse frequency (study I, 7.6 +/- 0.6 pulses/12 h; study III, 7.3 +/- 0.6). Similar qualitative changes in LH pulsatility were observed after low dose estradiol administration. In conclusion, our results demonstrate that low dose EE therapy results in a significant augmentation of pulsatile GH activity, with reciprocal decreases in gonadotropin concentrations in girls with Turner's syndrome. Such observations indicate an exquisite sensitivity of gonadotrope and somatotrope function to low dose estrogen action in this prepubertal hypogonadal model.

Adolescent↗

PubMed1990

Basal plasma growth hormone levels in man: new evidence for rhythmicity of growth hormone secretion.

Circulating GH levels in man fluctuate widely due to pulsatile GH secretion by the pituitary gland. During much of the time, plasma GH is undetectable by current assays. This is punctuated by occasional secretory episodes, resulting in plasma GH peaks of varying height. The principal diurnal secretory event for GH is that associated with early slow wave sleep, but little is known about the prevailing level and dynamics of GH during the day. We used a new ultrasensitive immunoradiometric assay for GH (Boots-Celltech IRMA; limit of detection, 20 ng/L) to measure plasma GH in the previously undetectable range and to assess its diurnal pattern. Plasma GH was measured every 20 min over a 24-h period in 12 normal subjects (6 men and 6 women, aged 20-47 yr) under physiological conditions. Time series analysis of plasma GH patterns was performed by the Cluster algorithm, autocorrelation, and spectral analysis. Plasma GH, as measured by IRMA, was detectable at all time points and ranged from 40-19,695 ng/L. Dynamic fluctuations occurred within and above the previously undetectable range, with amplitudes varying over 3 orders of magnitude. Women had significantly higher overall GH levels, higher peak amplitudes, and higher valley levels/nadirs than men. GH pulses occurred with an average frequency of about 13/day in both sexes, with a dominant, but not strictly periodic, 2-h rhythmicity. We conclude that in man pulsatile GH secretion occurs throughout the day, and that it is oscillatory rather than episodic. This neurosecretory pattern has eluded recognition heretofore because of the lack of assay sensitivity. Women of reproductive age have higher pulse amplitudes and a higher baseline but equal pulse frequency compared to men. Previous estimates of integrated GH concentrations and GH production rates were too high by a factor of 2 due to overestimation of GH levels in the undetectable range.

Adult↗

PubMed1990

Intensive venous sampling paradigms disclose high frequency adrenocorticotropin release episodes in normal men.

Recent studies in the rat and rhesus monkey have disclosed apparently high frequency in vivo ACTH release episodes. While the circadian pattern of plasma ACTH concentrations has been known for many years, the exact frequency of ultradian pulsatile ACTH release in man is not clear, due in part to variable intensities of blood-sampling schedules and the limited availability of sensitive ACTH assays. In this study we used a new sensitive and specific immunoradiometric assay to measure plasma ACTH concentrations in blood sampled at 1) 2-min intervals for 3 h, followed by 4-min intervals for 4 more h in six men; and 2) 10-min intervals for 24 h in eight other men. An objective peak detection algorithm (Cluster) and cosinor analyses were used to assess the episodic pulsatility and circadian rhythmicity of ACTH. Comparisons were made among the 2 min (3 h), 4, 8, and 12 min (7 h), and 10 min (24 h) time series. Mean ACTH interpulse intervals were significantly different among the five sampling groups (P less than 0.00001). Sampling every 2 min yielded a mean ACTH interpulse interval of 18 min, which was significantly shorter than the mean interpulse intervals of 35, 53, 52, and 73 min resulting, respectively, from sampling every 4, 8, 10, and 12 min (P less than 0.05). In contrast, maximal peak ACTH amplitudes (picomoles per L or percent increase) did not vary as a function of sampling frequency. The 24-h plasma ACTH concentration time series showed significant diurnal variation, with a mean circadian amplitude of 0.95 +/- 0.15 pmol/L occurring at 1008 h (+/- 25 min). Cosinor analysis of various ACTH pulse parameters deduced from the 24-h time series revealed significant circadian rhythmicity in the ACTH peak maxima (P less than 0.05), peak increments (P less than 0.05), and prepeak nadir (P less than 0.05) concentrations, but not in ACTH interpulse intervals. We conclude that in men, 1) intensive sampling at 2-min intervals unmasks high frequency ACTH release episodes that cannot be detected at conventional sampling rates; and 2) ACTH peak amplitude, but not frequency, varies significantly during the course of circadian changes in the plasma ACTH concentrations.

Adrenocorticotropic Hormone↗

PubMed1992

Spontaneous and stimulated growth hormone release in adolescents with type I diabetes mellitus: effects of metabolic control.

Abnormalities in GH release have been found in adults with poorly controlled type I diabetes mellitus. During puberty, circulating GH concentrations transiently increase. To investigate in pubertal diabetic adolescents, the physiological relationship between metabolic control and GH release, we compared spontaneous and GH-releasing hormone (GHRH)-stimulated GH release in six pubertal subjects during poor (study A) and improved (study B) metabolic control. The subjects included two females and four males (mean age +/- SE, 15.5 +/- 1 yr; duration of diabetes, 8.6 +/- 0.9 yr; Tanner stages II-V). Serum samples for glucose and GH determinations were obtained at 20-min intervals over a 24-h period. Significant pulses of GH release were identified using a pulse detection algorithm (Cluster). Fourier expansion time series was used to document the occurrence of significant periodicities in the GH concentration-time data series. All subjects received 1.0 microgram/kg GHRH-44, iv, at 0800 h on the day after the 24-h monitoring for GH. After GHRH administration, samples were taken for glucose and GH determinations over 90 min. The overall mean glucose level (+/- SE) during the 24-h monitoring was 11.5 +/- 0.2 mmol/L during study A and 7.2 +/- 0.2 during study B (P = 0.0001). During the 4 weeks of improved control, glycated hemoglobin fell from 13.9 +/- 1.4% to 11.7 +/- 0.8% (mean +/- SE; P < 0.025). All subjects had significant pulses of GH release during poor or improved metabolic control. Relative to that at night, the daytime pulse frequency was higher in study A (P < 0.025). The overnight pulse frequency increased during study B (P < 0.01). Other pulse parameters, including maximal and incremental pulse amplitudes, pulse width, and interpulse valley mean, did not change during improved control. The mean +/- SE 24-h GH concentration was 4.1 +/- 0.7 micrograms/L during study A and 4.3 +/- 0.8 during study B. The amplitude of the circadian GH rhythm was not different by Fourier analysis. The overall mean glucose +/- SE after GHRH administration was 15.3 +/- 0.2 mmol/L in study A and 6.8 +/- 0.1 in study B. In spite of the marked hyperglycemia during study A, the GH responses were similar during studies A and B. Maximal GH levels were obtained at 15-30 min (mean +/- SE) and were 36.0 +/- 16.9 micrograms/L in study A and 38.7 +/- 18.9 in study B.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1992

Immunoradiometric analysis of circulating human glycosylated and nonglycosylated prolactin forms: spontaneous and stimulated secretions.

The monoclonal antibodies (MAbs) obtained in mice immunized with human PRL coupled to an anti-PRL MAb were screened for their ability to distinguish the glycosylated (G-) and nonglycosylated (NG-) forms of PRL. The 431-29 MAb exhibited high affinity binding for NG-PRL but little or no cross-reactivity to G-PRL. Using this antibody in conjunction with other MAbs which equally recognized both forms, we developed 2 immunoradiometric assays which were used to determine the amount of G- and NG-PRL in plasma. In 85 normal subjects, NG-PRL baseline levels averaged 6.6 +/- 3 micrograms/L, and represented 76 +/- 8% of the total PRL immunoreactivity. In 74 pregnant women, this proportion was significantly higher during the last 2 trimesters (84 +/- 4% and 85 +/- 6%), as compared to the first trimester (76 +/- 7%). In 6 healthy volunteers studied over 24 h, 79% of the NG-PRL peaks detected using the cluster algorithm occurred concomitantly to a G-PRL peak. The mean NG-PRL/PRL ratio was significantly higher during NG-PRL pulses (81 +/- 9%) than during valleys (71 +/- 12%). Similarly, this ratio was significantly increased during TRH or metoclopramide stimulated PRL secretion (to 88 +/- 7% and 86 +/- 6%, respectively). We conclude that 1) NG-PRL is the predominant immunoassayable form of PRL in plasma; 2) both G- and NG-PRL are cosecreted but NG-PRL is the main PRL form released during spontaneous or pharmacologically induced PRL secretion.

Adult↗

PubMed1995

The concordance of pulsatile ultradian release of adrenocorticotropin and cortisol in male rhesus monkeys.

The ultradian release of ACTH and cortisol was investigated in six male rhesus monkeys (Macaca mulatta) with an intensive (2-min) blood-sampling procedure to investigate micropulsatile hormone secretory patterns. A sensitive and specific immunoradiometric assay was used to measure plasma ACTH concentrations. An objective pulse detection algorithm (Cluster) was used to assess the pulsatility of ACTH and cortisol release. The temporally coincident release of ACTH and cortisol was also examined. Venous blood samples were collected (over < 15 s) every 2 min for 120 min beginning at 1300 h. The number of ACTH peaks (3.2 peaks/h), interpulse intervals (19 +/- 2.4 min), and pulse amplitudes (9.7 +/- 1.6 pmol/L) in rhesus monkey were similar to corresponding measures of ACTH release in humans (3.3 peaks/h, 18 +/- 0.8 min, and 4.7 +/- 1.0 pmol/L, respectively). The number of cortisol peaks (2.3 peaks/h), interpulse interval (26 +/- 8.6 min), and other characteristics of pulsatile cortisol release were also determined. There was a 32.4% exact concordance of ACTH with cortisol peaks (11 of 34; P < 0.001). Fifty-six percent of ACTH peaks (19 of 34) were followed by a cortisol peak within 10 min (P < 0.02). There was a significant correlation between the ACTH and coincident cortisol pulse amplitudes (P < 0.0001). The amplitudes of ACTH peaks coincident with cortisol peaks at 0 min time lag were significantly higher than ACTH peaks not temporally coupled with cortisol peaks. Our data indicate that 1) high frequency, low amplitude micropulsatile ACTH secretion in rhesus monkeys is very similar to the high frequency ACTH rhythm in humans; 2) temporally concordant ACTH and cortisol release episodes may be amplitude coupled; and 3) an adequate incremental ACTH pulse amplitude may elicit a concurrent cortisol release episode from the adrenal cortex. These data suggest that the rhesus monkey is a potentially useful model for the study of neuroendocrine control of ACTH release.

Activity Cycles↗

PubMed1996

Entrainment of ultradian oscillations in the secretion of insulin and glucagon to the nonrapid eye movement/rapid eye movement sleep rhythm in humans.

The cause of ultradian oscillations in the secretion of glucagon and insulin with a period length between 70-140 min has been atttributed to feedback mechanisms of glucose and insulin. Influences of the central nervous system on these ultradian glucagon and insulin oscillations remained to be elucidated. In the present study on one occasion, concentrations of glucose, glucagon, insulin, and GH were determined at 15-min intervals from 2100-0700 h in 16 healthy subjects while they were infused with saline solution. On another occasion, concentrations of these hormones during nocturnal sleep were determined in 10 of these subjects while they were constantly infused with glucose (4.5 mg/kg x min). The order of the treatments (placebo vs. glucose) was balanced across subjects, and experiments were performed in a double blind manner. Significant glucagon and insulin peaks were determined by the peak detection algorithm Cluster. Sleep was recorded somnopolygraphically. During the infusion of saline solution, glucagon concentrations showed spontaneous oscillations, with a mean periodicity of 107.9 +/- 13.2 min. During the constant infusion of glucose, oscillations of similar periodicity (110.1 +/- 10.3 min) were observed for insulin. The phases of glucagon and insulin secretory activity on the respective nights were entrained to the nonrapid eye movement (non-REM)/REM sleep cycle. Significant increases in the concentrations of glucagon (chi 5.23; P < 0.02) and insulin (chi= 7.32; P < 0.01) generally fell into epochs of non-REM sleep, with a preference for the beginning of the epochs, whereas decreasing concentrations of these hormones coincided significantly with epochs of REM sleep (P < 0.05). The time spent in the different sleep stages was not altered during glucose infusion. In conclusion, ultradian oscillations of insulin and glucagon concentrations are modulated by central nervous system mechanisms entraining secretory pulses of the alpha- and beta-cells of the endocrine pancreas to the non-REM sleep epochs of the non-REM/REM sleep cycle.

Activity Cycles↗

PubMed1996

Both oral and transdermal estrogen increase growth hormone release in postmenopausal women--a clinical research center study.

To determine if the mode of 17 beta-estradiol (E2) administration affects growth hormone (GH) concentrations, eight postmenopausal women were studied under the following conditions: (1) control (no E2), (2) oral E2 (Estrace, 1 mg every 12 h for 2 weeks) and (3) transdermal E2 (Estraderm patch, 0.1 mg, two patches changed daily for 2 weeks). Blood was collected every 5 min for 24 h and assayed for serum GH concentrations using a sensitive chemiluminescence assay. Serum E2 levels were comparable during both E2 treatment regimens when measured with a specific chemiluminescence assay. The 24-h integrated GH concentrations (IGHC, min . micrograms/L) increased in all eight subjects from (mean +/- SE) 494 +/- 102 during control to 860 +/- 111 (P < 0.05) and 832 +/- 149 (P < 0.05) during oral and transdermal E2, respectively. Both E2 treatments significantly increased GH pulse height, individual pulse area, incremental pulse amplitude, interpeak valley concentration, and interpeak valley nadir (as measured by Cluster algorithm) when compared with control. No significant differences were observed in the number of GH pulses per 24 h. Insulin-like growth factor-I (IGF-I, micrograms/L) concentrations decreased from 165 +/- 19 (control) to 109 +/- 11 (oral E2, P < 0.05) and 122 +/- 15 (transdermal E2, P < 0.05). No statistically significant differences in attributes of pulsatile GH release or IGF-I concentrations were observed between the oral and transdermal E2 treatments. We conclude that both oral and transdermal E2 treatment increase serum GH concentrations in postmenopausal women. This increase is manifested by larger GH pulses and higher basal (interpulse) GH levels, not by changes in pulse frequency. Both routes of E2 administration decrease serum IGF-I concentrations, which may attenuate IGF-I negative feedback on pituitary somatotrophs and hypothalamic somatostatin secretion, resulting in enhanced pulsatile GH release.

Administration, Cutaneous↗

PubMed2001

The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy.

In patients with treated acromegaly, improved survival is associated with serum GH concentrations below 2 microgram/L (5 mU/L). A principal aim of therapy in acromegaly is to achieve a GH level less than 2 microgram/L, as such levels are thought to be "safe." However, such GH levels do not always equate with normalization of plasma insulin-like growth factor I (IGF-I), although epidemiological data linking survival or morbidity to IGF-I levels are at present lacking. The aims of this study were 1) to further define the nature of GH release in those acromegalic patients who achieve mean GH concentrations below 2 microgram/L post therapy, 2) to examine the effect of different therapeutic interventions on the 24-h GH profile (surgery alone or radiotherapy), and 3) to determine the relationship between the various characteristics of the 24-h GH profile and IGF-I production in acromegalic subjects who have achieved GH below 2 microgram/L. Spontaneous 24-h GH secretion was measured using both a conventional immunoradiometric assay (limit of detection, 0.4 microgram/L) and an ultrasensitive assay (limit of detection, 0.002 microgram/L). The GH data have been analyzed by several methods: 1) the pulse detection algorithm Cluster, 2) a distribution method for detection of peak [the observed concentration 95%, i.e. the threshold at or below which GH concentrations are assessed to be 95% of the time, as calculated by probability analysis (OC 95%)] and trough (OC, 5%) GH activity, 3) deconvolution analysis, and 4) approximate entropy analysis. GH was sampled every 20 min for 24 h, along with basal IGF-I and IGF-binding protein-3, in 21 treated acromegalic patients with a mean GH below 2 microgram/L [ACR; 9 women and 12 men; median age (range), 49 (31-76) yr] and 16 healthy controls [C; 6 women and 10 men; age, 50 (30-75) yr]. Mean 24-h serum GH concentrations were [median (range)]: ACR, 1.1 (0.04-1.5) microgram/L; C, 0.4 (0.02-3.3) microgram/L (P = 0.28). GH pulse frequency was: ACR, 11 (1-14)/24 h; C, 10 (8-18)/24 h (P = 0.41). In the GH profiles the mean heights of the GH peaks were: ACR, 1.2 (0.05-2.8) microgram/L; C, 0.8 (0.02-5.1) microgram/L (P = 0.91), and the mean GH valley nadirs were: ACR, 0.65 (0.03-1.1) microgram/L; C, 0.09 (0.01-1.8) microgram/L (P < 0.02). The OC 95% was: ACR, 1.0 (0.04-3.8) microgram/L; C, 1.0 (0.02-10) microgram/L (P = 0.65), and the OC 5% was: ACR, 0.09 (0.01-0.6) microgram/L; C, 0.01 (0.001-0.4) microgram/L (P < 0.001). The median IGF-I was: ACR, 227 (100-853) microgram/L; C, 156 (89-342) microgram/L (P < 0.005). Approximate entrophy values were: ACR, 1.06 (0.35-1.45); and C, 0.57 (0.27-1.19); P < 0.05. In the acromegaly group a significant positive correlation was found between IGF-I and the calculated GH secretory burst amplitude in the radiotherapy subset (r = 0.85; P < 0.0005) as well as between IGF-I and both the mean GH valley nadir (r = 0.60; P < 0.004) and the trough (OC 5%) GH activity for the acromegalic patients as a whole (r = 0.55; P < 0.02). We conclude that in treated acromegaly (GH, <2 microgram/L), 1) IGF-I (by approximately 50%) and basal GH secretion (by 5-fold) remain significantly elevated compared with control values despite similar mean 24-h GH concentrations; 2) the calculated GH secretory pulse amplitude, mean GH valley nadir, and OC 5% correlate positively with IGF-I; 3) the greater mean GH valley nadir and OC 5% in acromegalic patients compared with controls may account for the raised IGF-I; and 4) radiotherapy is unlikely to normalize the GH secretory pattern, which underlies the persisting elevated IGF-I levels.

Acromegaly↗

PubMed2005

Transcriptional response of human umbilical vein endothelial cells to low doses of ionizing radiation.

We used cDNA microarray hybridization technology to monitor the transcriptional response of Human Umbilical Vein Endothelial (HUVEC) cells to x-rays doses ranging from 2 to 200 cGy. An early time window from irradiation (4h) was selected in order to minimize the effects of the cell cycle blockage eventually induced at high doses of irradiation. Three different gene-clustering algorithms have been used to group the 4134 monitored ORF based on their transcriptional response in function of the irradiation dose. The results show that while few genes exhibit a typical dose-dependent modulation with a variable threshold, most of them have a different modulation pattern, peaking at the two intermediate doses. Strikingly even the lowest dose used (2 cGy) seems to be very effective in transcriptional modulation. These results confirm the physiological relevance of sublethal-dose exposures of endothelial cells and strengthens the hypothesis that alternative dose-specific pathways of radioadaptive response exist in the mammalian cells. 111 genes were found to be modulated at all doses of irradiation. These genes were functionally classified by cellular process or by molecular function. Genes involved in coagulation and peroxidase activity and structural constituent of ribosomes were over-represented among the up-regulated genes as compared with their expected statistical occurrence. Three genes coding for regulatory kinase activities (CDK6; PRCKB1 and TIE) are found down-regulated at all doses of irradiation.

Cells, Cultured↗

PubMed2006

Fuzzy clustering of Raman spectral imaging data with a wavelet-based noise-reduction approach.

Raman spectral imaging has been widely used for extracting chemical information from biological specimens. One of the challenges is to cluster the chemical groups from the vast amount of hyperdimensional spectral imaging data so that functionally similar groups can be identified. In this paper, we present an approach that combines a differential wavelet-based data smoothing with a fuzzy clustering algorithm for the classification of Raman spectral images. The preprocessing of the spectral data is facilitated by decomposing them in the differential wavelet domain, where the discrimination of true spectral features and noise can be easily performed using a multi-scale pointwise product (MPP) criterion. This approach is applied to the classification of spectral data collected from adhesive/dentin interface specimens where the spectral data exhibit different signal-to-noise ratios. The proposed wavelet approach has been compared to several conventional noise-removal algorithms.

Adhesives↗

PubMed2005

Proteome analysis of maternal serum samples for trisomy 21 pregnancies using ProteinChip arrays and bioinformatics.

A surface-enhanced laser desorption/ionization time of flight (SELDI-TOF)-based ProteinChip System was used as a tool for rapid discovery and identification of protein patterns in serum that discriminate between trisomy 21 and unaffected pregnancies. We analyzed 24 serum samples from women carrying a trisomy 21 pregnancy and 32 with an unaffected pregnancy, ranging from 10.0 to 14.0 weeks of gestation. The resulting protein profiles were submitted to a clustering algorithm, a rule extraction, a rating, and a rule base construction step. For the generated combined rule base, the specificity and sensitivity for the prediction of a trisomy 21 pregnancy reach 97% and 91%, respectively.

Computational Biology↗

PubMed2025

Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure.

Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.

Humans↗

PubMed1998

The effects of pubertal status and glycemic control on the growth hormone-IGF-I axis in boys with insulin-dependent diabetes mellitus.

Dysregulation of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis in children and adolescents with insulin-dependent diabetes mellitus (IDDM) is well documented. Elevated levels of circulating GH, increased GH secretory amplitude, and decreased concentrations of IGF-I, IGFBP-3, and GHBP have been related to poor glycemic control. We proposed that pubertal maturation may be a more significant factor, potentially overriding the effects of metabolic control, especially during mid-puberty when the GH-IGF-I axis is maximally stimulated. We studied 24 male children and adolescents with IDDM over a 5 year period. Subjects were grouped both by pubertal stage (prepubertal vs mid-pubertal) and by level of glycemic control (hemoglobin A1 (<9%, 9-11.5%, and >11.5%). Twenty-four hour every 20 minute blood sampling for GH determination was analyzed using the Cluster algorithm, and static measures of IGF-I, IGFBP-3, and GHBP were obtained. When analyzed by pubertal status, we found no difference in the number of GH secretory peaks or the interval between concentration peaks. The sum of the peak heights and area under the curve were significantly greater in the mid-pubertal boys, as was the average GH nadir. Serum levels of IGF-I and IGFBP-3 were greater in the mid-pubertal boys, but levels of GHBP were higher in the prepubertal boys. When analyzed by level of glycemic control, we found no differences in the number of GH secretory peaks or interval between peaks among the 3 groups. However, the sum of the peak heights, area under the curve, and average GH nadir were all lower in the group with the intermediate level of glycemic control (HgbA1 9-11.5%); no differences were observed between the other 2 groups. This relationship persisted when the mid-pubertal subjects were analyzed separately. No differences were found among the 3 groups for levels of IGF-I, IGFBP-3, or GHBP. We conclude that normal increases in GH secretion and levels of IGF-I and IGFBP-3 occur during mid-puberty in boys with IDDM. A concomitant increase in average GH nadir may reflect an underlying effect of metabolic control. Greater GH secretion was observed in the groups with the lowest and highest levels of glycemic control. We speculate that this may be related to an increased incidence of severe hypoglycemic episodes in the group with the lowest levels of glycosylated hemoglobin, resulting in metabolic derangements similar to those with elevated glycosylated hemoglobin levels.

Blood Glucose↗

PubMed2005

Spot detection and image segmentation in DNA microarray data.

Following the invention of microarrays in 1994, the development and applications of this technology have grown exponentially. The numerous applications of microarray technology include clinical diagnosis and treatment, drug design and discovery, tumour detection, and environmental health research. One of the key issues in the experimental approaches utilising microarrays is to extract quantitative information from the spots, which represent genes in a given experiment. For this process, the initial stages are important and they influence future steps in the analysis. Identifying the spots and separating the background from the foreground is a fundamental problem in DNA microarray data analysis. In this review, we present an overview of state-of-the-art methods for microarray image segmentation. We discuss the foundations of the circle-shaped approach, adaptive shape segmentation, histogram-based methods and the recently introduced clustering-based techniques. We analytically show that clustering-based techniques are equivalent to the one-dimensional, standard k-means clustering algorithm that utilises the Euclidean distance.

Algorithms↗

PubMed2026

Machine Learning-Based Preoperative Predicting TERT Promoter Mutation and EGFR Gene Amplification Phenotype in IDH Wild-Type Glioblastoma Using Advanced MR Habitat Imaging.

BACKGROUND AND PURPOSE: The telomerase reverse transcriptase (TERT) gene promoter mutation is a crucial factor for identifying an isocitrate dehydrogenase (IDH) wild-type glioblastoma with poor prognosis, and the epidermal growth factor receptor (EGFR) amplification may be a potential prognostic factor. The purpose of this study was to investigate the value of the tumor habitats imaging model on advanced MRI in predicting TERT promoter mutation and EGFR gene amplification phenotype of IDH wild-type glioblastoma. MATERIALS AND METHODS: One hundred seventy-nine patients with pretreatment conventional MRI, DWI, and DSC-PWI were included. The data were divided into the training set (n=112), test set (n=29), and time-independent validation set (n=38). Based on the ADC and CBV map, the solid tumor area was split into several habitat subregions using the k-means clustering algorithm (hypovascular hypercellular area, hypervascular area, and hypovascular hypocellular area). In the training set, TERT promoter mutation and EGFR gene amplification phenotype prediction models were constructed using the random forest method. The reliability of prediction models was validated in the test and the time-independent validation sets. Receiver operating characteristic (ROC) curve analysis, calibration curve, and decision curve analysis (DCA) were used. RESULTS: The area under the curve (AUC) of the training, test, and validation sets of the TERT promoter prediction model was 0.877, 0.783, and 0.796, respectively. The accuracy of the TERT promoter prediction model was 82.1%, 75.9%, and 76.3%, respectively. The AUCs of the 3 sets for the EGFR gene amplification status prediction model were 0.877, 0.784, and 0.878, respectively. The accuracy of the EGFR gene amplification status prediction model was 79.5%, 75.9%, and 89.5%, respectively. Moreover, the prediction probability of these models was in good agreement with the actual result. CONCLUSIONS: The tumor habitat imaging model based on advanced MRI was useful for accurately predicting TERT promoter mutation and EGFR amplification status in IDH wild-type glioblastoma.

Humans↗