Autonomic imbalance induced breakdown of long-range dependence in healthy heart rate.

OBJECTIVES: The investigation of the relation between the long-range correlation property of heart rate and autonomic balance. METHODS: An investigation of the fractal scaling properties of heart rate variability was carried out by using detrended fluctuation analysis (DFA). Eleven healthy subjects were examined for two consecutive days, which included usual daily activity, strenuous prolonged experimental exercise, and sleep. We also considered two patient groups with autonomic dysfunction characterized by selective sympathetic and parasympathetic dominance. RESULTS: Robust long-range dependence in heart rate is observed only in the state of usual daily activity, characterized by normal heart rate typical of balanced autonomic sympathetic and parasympathetic regulation. This confirms the previously postulated behavioral independence of heart rate regulation, but reveals that the occurrence of 1/f, long-range dependence is restricted to only the state of autonomic balance. Both the sympathetic dominant high heart rate state, realized during strenuous experimental exercise, and the parasympathetic dominant low heart rate state, prevalent in (deep) sleep, are characterized by uncorrelated, near white-noise-like scaling, lacking long-range dependence. CONCLUSION: Remarkably, the breakdown of the long-range correlations observed in healthy heart rate in the states of sympathetic and parasympathetic dominance is in stark contrast to the increased correlations which have previously been observed in neurogenic parasympathetic and sympathetic dominance in patients suffering from primary autonomic failure and congestive heart failure, respectively. Our findings further reveal the diagnostic capabilities of heart rate dynamics, by differentiating physiological healthy states from pathology.

Long-range correlated glucose fluctuations in diabetes.

OBJECTIVES: Our objective is to investigate diabetes-related alteration of glucose control in diurnal fluctuations in normal daily life by detrended fluctuation analysis (DFA). METHODS: The fluctuations of glucose of 12 non-diabetic subjects and 15 diabetic patients were measured using a continuous glucose monitoring system (CGMS) over a period of one day. The glucose data was calculated by the DFA method, which is capable of revealing the presence of long-range correlations in time series with inherent non-stationarity. RESULTS: Compared with the non-diabetic subjects, the mean glucose level and the standard deviation are significantly higher in the diabetic group. The DFA exponent alpha is calculated, and glucose time series are searched for the presence of negatively (0.5 < alpha < 1.5) or positively (1.5 < alpha) correlated fluctuations. A crossover phenomenon, i.e. a change in the level of correlations, is observed in the non-diabetic subjects at about two hours; the net effects of glucose flux/reflux causing temporal changes in glucose concentration are negatively correlated in a "long-range" (> two hours) regime. However, for diabetic patients, the DFA exponent alpha = 1.65 +/- 0.30, and in the same regime positively correlated fluctuations are observed, suggesting that the net effects of the flux and reflux persist for many hours. CONCLUSIONS: Such long-range positive correlation in glucose homeostasis may reflect pathogenic mechanisms of diabetes, i.e., the lack of the tight control in blood glucose regulation. Using modern time series analysis methods such as DFA, continuous evaluation of glucose dynamics could promote better diagnoses and prognoses of diabetes and a better understanding of the fundamental mechanism of glucose dysregulation in diabetes.

Multiscale properties of instantaneous parasympathetic activity in severe congestive heart failure: A survivor vs non-survivor study.

Multifractal analysis of cardiovascular variability series is an effective tool for the characterization of pathological states associated with congestive heart failure (CHF). Consequently, variations of heartbeat scaling properties have been associated with the dynamical balancing of nonlinear sympathetic/vagal activity. Nevertheless, whether vagal dynamics has multifractal properties yet alone is currently unknown. In this study, we answer this question by conducting multifractal analysis through wavelet leader-based multiscale representations of instantaneous series of vagal activity as estimated from inhomogeneous point process models. Experimental tests were performed on data gathered from 57 CHF patients, aiming to investigate the automatic recognition accuracy in predicting survivor and non-survivor patients after a 4 years follow up. Results clearly indicate that, on both CHF groups, the instantaneous vagal activity displays power-law scaling for a large range of scales, from ≃ 0.5s to ≃ 100s. Using standard SVM algorithms, this information also allows for a prediction of mortality at a single-subject level with an accuracy of 72.72%.

A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis.

The genetic alteration of p53 is associated with neovascularization during progression of glioma to its more malignant form, glioblastoma. Hence, one or more of the genes transactivated by p53 is likely to function as an angiogenesis inhibitors. We isolated a novel p53-inducible gene that encodes a 1584-amino-acid product containing five thrombospondin type 1 (TSP-type 1) repeats and is specifically expressed in the brain. A recombinant protein corresponding to the TSP-type 1 repeats of this gene product inhibited in vivo neovascularization induced by bFGF in the rat cornea. The expression of this gene, designated BAI1 (brain-specific angiogenesis inhibitor 1) was absent or significantly reduced in eight of nine glioblastoma cell lines, suggesting BAI1 plays a significant role in angiogenesis inhibition, as a mediator of p53.

Saccharomyces cerevisiae cultured under aerobic and anaerobic conditions: air-level oxygen stress and protection against stress.

Cells of Saccharomyces cerevisiae were grown aerobically and anaerobically, and levels of the protective compounds, cysteine and glutathione, and activities of defensive enzymes, catalase and superoxide dismutase, against an oxygen stress were determined and compared in both cells. Aerobiosis increased both the compounds and enzyme activities. The elevated synthesis of glutathione could be associated with the increased levels of cysteine which in its turn was found to be controlled by the oxygen-dependent activation of cystathionine beta-synthase.

Point-process high-resolution representations of heartbeat dynamics for multiscale analysis: A CHF survivor prediction study.

Multiscale analysis of human heartbeat dynamics has been proved effective in characterizeing cardiovascular control physiology in health and disease. However, estimation of multiscale properties can be affected by the interpolation procedure used to preprocess the unevenly sampled R-R intervals derived from the ECG. To this extent, in this study we propose the estimation of wavelet coefficients and wavelet leaders on the output of inhomogeneous point process models of heartbeat dynamics. The RR interval series is modeled using probability density functions (pdfs) characterizing and predicting the time until the next heartbeat event occurs, as a linear function of the past history. Multiscale analysis is then applied to the pdfs' instantaneous first order moment. The proposed approach is tested on experimental data gathered from 57 congestive heart failure (CHF) patients by evaluating the recognition accuracy in predicting survivor and non-survivor patients, and by comparing performances from the informative point-process based interpolation and non-informative spline-based interpolation. Results demonstrate that multiscale analysis of point-process high-resolution representations achieves the highest prediction accuracy of 65.45%, proving our method as a promising tool to assess risk prediction in CHF patients.

Experiences of 23 patients > or = 90 years of age treated with radiation therapy.

PURPOSE: To present 23 patients > or = 90 years old treated with radiotherapy, and to retrospectively evaluate the results of radiotherapy and tolerance in these patients. METHODS AND MATERIALS: The clinical records of 27 patients over 90 years of age who were treated with radiotherapy at the Department of Radiology, Shinshu University Hospital, and eight affiliated general hospitals from 1990 until 1995 were reviewed. The strategy of radiotherapy was individually planned depending on the stage of the disease and performance status (PS) of the patient; however, it was not modified, based solely on chronologic age. The overall survival rate and disease-free survival rate were determined using the Kaplan-Meier method. The Radiation Therapy Oncology Group scoring criteria of acute and late reactions of radiation therapy were used. RESULTS: This group of patients accounted for 0.37% of all patients treated with radiotherapy in these hospitals. Of these, 23 patients in whom cancer was pathologically confirmed and whose follow-up data were available for retrospective analysis were included in the final evaluation of data. The age of the 23 patients ranged from 90 to 96 years (median 93). Tumor was untreated and in the early stage in five patients, locoregionally advanced in 13, recurrent in four, and systemic in one. Definitive radiation therapy was administered in 12 patients (13 sites), preoperative intent in one, and palliative intent in 10. The period of observation ranged from 2.5 to 6 years (median 18 months). Seven patients were alive for 15-67 months. Fourteen patients died because of intercurrent diseases or senility associated with active cancer, and two because of senility without evidence of cancer. The overall and relapse-free survival rates were 65% and 30% at 1 year and 30% and 21% at 2 years, respectively. Definitive radiation therapy was completed in 13 of 13 patients (100%), and local control was attained in 9 of 13 patients at 6 months (62%). Palliative radiation therapy was completed as intended in 7 of 11 (64%), and effects of palliation were observed in 9 of 11 patients (81%). Acute dermatitis, mucositis, pharyngitis, esophagitis, and cystitis of grade 2-3 related to the definitive radiation therapy were tolerable for the patients with good PS. It took 3-7 weeks (median 5) for acute moist desquamation of six lesions of skin cancer to heal. Depending on the radiation doses, grade 1-2 atrophy of skin and telangiectasia were documented for eight patients followed up for more than 1 year. A brief description of representative case is presented. CONCLUSION: Patients older than 90 years with good PS may tolerate the acute effects of radiotherapy administered according to conventional fractionation schedules. Definitive radiation therapy should be considered, when applicable, even for patients older than 90 years.

Disruption of the CHO1 gene encoding phosphatidylserine synthase in Saccharomyces cerevisiae.

A Saccharomyces cerevisiae mutant that lacked phosphatidylserine synthase [EC 2.7.8.8] (CDP-1,2-diacyl-sn-glycerol: L-serine O-phosphatidyltransferase) completely was constructed by disrupting its structural gene, CHO1. Over two-thirds of its coding region, from the starting to the 200th codon, was replaced with a LEU2 DNA fragment. This new cho1 mutant showed no detectable synthesis of phosphatidylserine but grew slowly in a medium that contained either ethanolamine or choline. These results indicate that phosphatidylserine synthase and most probably phosphatidylserine are dispensable in S. cerevisiae but necessary for its optimal growth. Additional supplementation with myo-inositol raised the cellular content of phosphatidylinositol and improved the growth of the mutant, suggesting the importance of the negative charges of the membrane surface. The CHO1-disrupted mutant, when grown on choline, accumulated phosphatidylethanolamine to a significant level even after extensive dilution of the initial culture. It segregated prototrophic revertants that could synthesize phosphatidylethanolamine without recovery of phosphatidylserine synthesis. These results imply the presence of a route(s) for the formation of ethanolamine or its phosphorylated derivative in S. cerevisiae.

3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.

Primary structure and product characterization of the Saccharomyces cerevisiae CHO1 gene that encodes phosphatidylserine synthase.

An open reading frame of 828 base pairs was found in the CHO1 gene region of Saccharomyces cerevisiae by nucleotide sequencing analysis. Its enhanced expression with the aid of the PHO5 regulatory sequence resulted in an overproduction of a protein with a molecular weight of approximately 30,000, which in turn was converted by proteolysis to active phosphatidylserine synthase, whose molecular weight was approximately 23,000. The larger protein was concluded to be the primary product of the CHO1 gene, since its amino-terminal sequence was identical to that deduced from the nucleotide sequence of the above open reading frame, except for the terminal methionine residue. A partial homology in primary structures was noticed between this yeast enzyme and phosphatidylglycerophosphate synthase of Escherichia coli which also uses CDP-diacylglycerol as a substrate. The overproduced phosphatidylserine synthase in both microsomal and extensively purified fractions displayed two different Km values for L-serine, i.e., 0.14 mM at low L-serine concentrations and 9.5 mM at high L-serine concentrations. This may indicate a negatively cooperative regulation of this enzyme activity or the presence of two active components with different affinities for L-serine.

MR evaluation of laryngohypopharyngeal cancer: value of gadopentetate dimeglumine enhancement.

PURPOSE: To investigate the value of gadopentetate dimeglumine-enhanced MR imaging in determining the extent of laryngohypopharyngeal cancer. METHODS: Unenhanced and contrast-enhanced T1-weighted, proton-density-weighted, and T2-weighted images from 24 patients with laryngohypopharyngeal cancer were reviewed and compared with the pathologic findings of resected specimens. In 18 patients, ex vivo MR images of the resected specimens were also compared with pathologic findings. RESULTS: Laryngohypopharyngeal cancer showed intermediate intensity on T1-weighted and proton-density-weighted images, high intensity on T2-weighted images, and moderate enhancement on T1-weighted enhanced images. Cartilage-invaded tumor enhanced moderately, whereas unossified cartilage in contact with tumors but without tumor invasion showed no enhancement. Laryngohypopharyngeal mucosa enhanced intensely; endolaryngeal muscles enhanced less. CONCLUSIONS: Enhanced MR images were more useful in assessing the extent of tumors and the presence of laryngeal cartilage invasion than were proton-density-weighted and T2-weighted images.

High resolution ultrasound of the chest wall.

To study the detailed normal ultrasonic anatomy of the pleura and chest wall, high resolution (7.5 MHz) ultrasonograms were obtained from cadaver chest wall specimens and compared with thin section computed tomograms and anatomical specimens. Ultrasonograms show three layers of the intercostal muscles (internal, external and innermost), covered by the "echogenic pleural line." The "echogenic pleural line" is caused by composite echoes from the inner parietal pleura, and the outer endothoracic fascia, with the fatty tissue covering both sides of the fascia, which are located deep to the chest wall muscles. On ultrasonograms, the subpleural fat tissue, when abundant, appeared as an apron-like structure hanging down from the inner surface of the rib (subpleural fat pad), or diffuse fat accumulation mimicking the pleural thickening.

MR of pulmonary hamartoma: pathologic correlation.

We describe the magnetic resonance (MR) appearance with pathologic correlation of six pulmonary hamartomas. All six tumors showed intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Four of the six tumors showed a lobulated appearance separated by septa on precontrast T1-weighted or T2-weighted images. Gadolinium-enhanced T1-weighted images showed marked enhancement of the septa that separated the tumors into less well enhanced lobules; this was seen in all six tumors. Comparison between MR images and pathologic specimens showed that the regions with less enhancement corresponded to core cartilaginous tissue and septa; areas of marked contrast enhancement corresponded to cleft-like branching mesenchymal connective tissue that dipped into the cartilaginous core. MR images correlated well with the surgically resected tumors.

Magnetic resonance imaging of neurogenic tumors of the thoracic inlet: determination of the parent nerve.

To investigate the value of magnetic resonance imaging (MRI) in determining the parent nerves of neurogenic tumors in the thoracic inlet, analysis of MR images was performed in nine patients with surgically resected neurogenic tumors in the thoracic inlet (two neurofibromas and one schwannoma of the vagus nerve, three schwannomas of the brachial plexus, and two schwannomas and one ganglioneuroma of the sympathetic nerves). These MR images were compared with surgical and pathologic findings. The multidirectional capability and excellent tissue contrast of MRI facilitated recognition of the location, shape, and extent of the tumors. MRI, which permitted an easy understanding of the spatial relation between the tumors and the subclavian vessels, scalenus muscles, and brachial plexus, was useful in determining the nerves of origin. Two neurofibromas, four of six schwannomas, and one ganglioneuroma were recognized to extend along the axes of the parent nerves on MR images. MRI is useful in determining the parent nerve of neurogenic tumors in the thoracic inlet and is helpful in planning surgical treatment of these tumors.

Computed tomography of neck lymph nodes involved with malignant lymphoma: comparison with ultrasound.

CT images of 24 patients with head and neck lymphoma were retrospectively reviewed, compared with ultrasonograms, and compared with CT images of 13 patients with lymph node metastases. In nine (38%) of 24 patients, some lymph nodes with lymphomatous involvement showed a spotty or linear pattern of contrast enhancement. In two of these nine patients, a dendritic pattern of contrast enhancement between multiple enlarged lymph nodes was observed. The same pattern appeared as spotty, linear, or dendritic hyperechoic areas on the ultrasonogram. None of 13 patients with lymph node metastases showed a spotty, linear, or dendritic pattern of contrast enhancement. Ten of 13 (77%) showed ring-like contrast enhancement on CE-CT images. The spotty or linear contrast enhancement in enlarged lymph nodes and the dendritic contrast enhancement in confluent lymph nodes could be useful CT findings in diagnosing nodal involvement with malignant lymphoma.

[Effects of Er:YAG laser irradiation on human extracted teeth].

The ablation effects of the Erbium:YAG laser (wave length: 2.94 microns) on the human extracted teeth were examined histopathologically. The enamel surface of the human extracted tooth was irradiated by the laser at 500 mJ, 1 pps or 3 pps: 3, 15, 30, 50 and 100 shots. After observation under a dissecting microscope, the teeth were placed in a demineralizing solution of 0.1 M lactate buffer with 6% hydroxyethyl cellulose (pH 4.5) in order to evaluate the acid resistance of the enamel adjacent to the ablated area. After 4 days, the degree of demineralization of the surrounding enamel was assessed by contact microradiography. The result showed that every irradiated tooth had a clear-cut defect, and almost all the teeth had acquired acid resistance at the enamel surrounding the ablated portion. The other experiment was carried out to estimate the effects of the Er:YAG laser through a contact probe. The enamel, dentin and cementum of the extracted teeth were irradiated at 39 mJ or 74 mJ, 10 pps; 10 shots. The teeth were observed under a dissecting microscope. The result clearly indicated that the Er:YAG laser guided by the contact probe could also produce a defect in the dental hard tissue. The above-mentioned findings suggested that the Er:YAG laser could pave the way for the cavity preparation with acid-resistant cavity margin.

Multiscale wavelet p-leader based heart rate variability analysis for survival probability assessment in CHF patients.

A priori discrimination of high mortality risk amongst congestive heart failure patients constitutes an important clinical stake in cardiology and involves challenging analyses of the temporal dynamics of heart rate variability (HRV). The present contribution investigates the potential of a new multifractal formalism, constructed on wavelet p-leader coefficients, to help discrimination between survivor and non survivor patients. The formalism, applied to a high quality database of 108 patients collected in a Japanese hospital, enables to assess the existence of multifractal properties amongst congestive heart failure patients and to reveal significant differences in the multiscale properties of HRV between survivor and non survivor patients, for scales ranging from approximately 60 to 250 beats.