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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

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

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

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

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

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

Variability analysis of visual evoked potentials in humans by pattern recognition in phase domain.

A novel approach to single trial visually evoked potentials (VEP) variability analysis based on a new model of post-stimulus brain electrical activity is presented. The convolution model introduced by the author is experimentally verified by the analysis of flash stimulus effects on EEG amplitude and phase spectra. Pattern recognition in the signal phase domain is proposed for detection of any time locked transient signals. This is illustrated by an application of a clustering algorithm in two-dimensional unwrapped phase of EEG Fourier transform space for occipitally recorded VEPs in human subjects.

Adult

A flow-system multiangle light-scattering instrument for cell characterization.

A flow-system cell-analysis instrument is described in which cells from a heterogeneous population are characterized by their light-scatter patterns alone. As the cells pass at high speed through a focused helium/neon laser beam, the scatter pattern from each cell is sampled simultaneously at up to 32 angles between 0 degrees and 30 degrees with respect to the laser beam axis, and the scatter pattern for each cell is transferred to a computer. A mathematical clustering algorithm is used to determine the number of classes into which the cells can be divided, and a linear separation algorithm is used to find the boundaries between the classes. Preliminary results on exfoliated cells from gynecological specimens are presented. This technique may be useful for automated prescreening of gynecological specimens.

Autoanalysis

Emotion differentiation. A correlate of symptom severity in major depression.

The relationship of emotion differentiation to symptom severity in depression was investigated. The subjects were 25 patients diagnosed with unipolar major depression. Subjects were clinically assessed using the Schedule for Affective Disorders and Schizophrenia and the Hamilton rating scales for anxiety and depression. In addition, subjects completed a number of self-report measures of symptoms and attitudes. Twelve basic emotion terms were incorporated into free-response attribute lists which subjects used to rate aspects of themselves and of other significant people in their lives. A clustering algorithm (HICLAS) was used to derive a social perception structure from this data for each subject. The differentiation of negative emotion within an individual's structure (NES) was measured by dividing the number of attribute categories containing negative emotions by the total number of categories in that person's structure. The results indicated that NES is a significant correlate of depressive symptomatology independent of self-esteem and other variables. Relatively undifferentiated emotion structure (low NES) was associated with significantly higher levels of depressive symptomatology.

Adult

Multivariate procedures to describe clinical staging of melanoma.

Analyzing multivariate clinical data to identify subclasses of patients being treated for a specific disease may improve patient management and increase understanding of the behavior of disease under clinical conditions. In some cases, patients have been classified on prognostic characteristics using standard risk assessment procedures (e.g., Cox' regression). This requires long term follow-up, differentiates patients only on attributes relevant to survival, and assumes that patients are sampled from a common population. Other approaches involve the use of clustering algorithms to classify patients into categories based on multiple clinical attributes. We illustrate the use of a multivariate statistical procedure to directly characterize patients on multiple clinical characteristics. The procedure is designed to analyze discrete response data with parameters representing individual differences within groups. Its use is illustrated for patients with Stage I melanoma in determining how age is related to treatment response in different patient groups.

Adult

From biopsy to automatic diagnosis.

High resolution two-dimensional gel electrophoresis is a very powerful biochemical tool for analysis of complex protein mixtures. In well defined situations, protein maps, obtained from tissue biopsies or biological fluids by this technique, can be automatically analyzed by computer. Some polypeptide patterns are the fingerprints of diseases. Applying clustering algorithm and learning techniques, the prototype expert system MELANIE recognized patterns and associated the correct diagnosis to the specific pattern.

Diagnosis, Computer-Assisted

[Phylogenetic analysis of partial nucleotide sequences of 18S rRNA for 14 plant species].

The variable 260 base long region from the interior of 18S rRNA of 14 plant species was determined by chain termination method with the use of reverse transcriptase. The hairpin revealed in this region appeared to be conservative in all species compared. Thermodynamic stability of such hairpin is lower than of an alternative structure with different base pairing mode. From sequence data dendrograms were produced by clustering algorithms and by the compatibility method. In addition to the plant sequences these dendrograms included also the homologous regions from yeast and Xenopus 18S rRNAs. The compatibility method seems to be more reliable. Inferences were drawn on relations between gymnosperms and angiosperms, monocots and dicots on the bases of the analysis of this tree.

Base Sequence

Quantification of progressive diabetic macular nonperfusion.

We used the IS-2000 Image Analyzer to estimate the extent of progressive diabetic macular nonperfusion in a patient by means of an automatic clustering algorithm applied to digitized fluorescein angiograms of the patient's macula taken over time. This method may provide an objective and reproducible quantification of progressive macular nonperfusion.

Adult

Quantification of gray/white matter in neonates and adults.

Quantitation of gray/white matter is important in evaluation of cerebral blood flow, atrophy, and development of the brain. First-order statistical analysis of neonatal computed tomographic (CT) images revealed that there was only a 6 Hounsfield unit (H) difference between gray and white matter compared with the observed 3 H for the standard deviation over the field of a skull water phantom. Scene segmentation methods based on first-order statistics proved unsuccessful in separating gray and white matter. A new regional clustering algorithm based on local textural properties was developed for separation of these structures.

Adult

Automatic classification of EEG segments and extraction of representative ones by dynamic clusters method.

Use of the dynamic clusters method for automatic extraction of compressed information about recorded EEG signal is presented. The computer first divides the record into quasi-stationary segments by means of adaptive segmentation. Second, the extracted segments are classified by a method of dynamic clusters into homogeneous classes. One part of the used clustering algorithm permits to specify and draw the most typical class members, which may represent the whole studied EEG signal and may be used as input for the further phase of the automatic EEG analysis, i.e. for the classification of the whole EEG records. The above procedure was applied to a 75 sec long EEG record of anaesthetized cat intoxicated by CO.

Computers

Numerical taxonomy of staphylococci.

Over two hundred staphylococci from human and animal sources and representatives of established species of Staphylococcus, Micrococcus and Planococcus were compared in a numerical phenetic survey using 115 unit characters. Data were analyzed using the Jaccard coefficient and the unweighted pair group method with averages algorithm. Cluster composition was not markedly affected by test error, estimated as 3.49%. The staphylococci were assigned to eighteen clusters containing four or more strains and to three single member clusters. Most of the clusters were distinct and homogeneous though two were divided into subclusters. Some of the clusters and subclusters were equated with the established taxa S. aureus, S. capitis, S. cohnii, S. epidermidis, S. haemolyticus, S. hominis, S. hyicus, S. saprophyticus, S. sciuri subspecies lentus, S. sciuri subspecies sciuri, S. simulans, S. warneri and S. xylosus, the remaining ones may represent the nuclei of additional centres of variation. The numerical data also cast doubts upon the reliability of some of the tests recommended for the identification of coagulase-negative staphylococci.

Computers

[Sectorization of the central 10 degrees visual field in open-angle glaucoma].

In an attempt to determine an optimal sector pattern of the central 10 degrees visual field in glaucoma, we applied the VARCLUS procedure, a new clustering algorithm provided by SAS Institute, to 379 glaucoma visual fields of the central 10-2 program of the Humphrey visual field analyzer. The subjects were 211 normal-tension glaucoma (NTG) and 168 primary open angle glaucoma (POAG) eyes with early to moderately advanced stages of visual field defects. The 68 2-degree grid test points in the central 10 degrees visual field were divided into 10 sectors. The sector pattern was compatible with the projection of nerve fiber layers and no sectors extended over the horizontal meridian. Comparison of the mean of total deviation in the sector of 76 eyes of 76 POAG patients with the maximum intraocular pressure: (IOP) > or = 25 mmHg (high-tension group) and 85 eyes of 85 NTG patients with the maximum IOP < or = 18 mmHg (low-tension group) revealed that four sectors nasal superior to the fixation were significantly more damaged in the low-tension group. We suggest that the sector pattern obtained here is useful in studying the visual field of glaucoma and that the damaging processes in the optic nervehead are not the same in the high-tension and low-tension groups.

Aged

A detection algorithm for multiform premature ventricular contractions.

This paper reports an algorithm developed to identify and quantify multiform PVCs. The algorithm clusters PVCs of similar morphology using a combination of time-domain and frequency-domain analysis. Initially, PVCs are grouped together on the basis of four time-domain-based morphological feature measurements. However, these time-domain-based clusters many times are nonunique because commonly encountered signal changes can cause substantial variations in the feature measurements of clinically similar beats. These redundant clusters are consolidated using two frequency-domain parameters: The First Spectral Moment (FSM) (center of gravity) of the amplitude spectrum, and the 5-Hz phase angle.

Cardiac Complexes, Premature