Disrupted Functional and Structural Connectivity in Angelman Syndrome.

BACKGROUND AND PURPOSE: This work investigated alterations in functional connectivity (FC) and associated structures in patients with Angelman syndrome (AS) by using integrated quantitative imaging analysis and connectivity measures. MATERIALS AND METHODS: We obtained 3T brain MR imaging, including resting-state functional MR imaging, diffusion tensor imaging, and 3D T1-weighted imaging from children with AS (n = 14) and age- and sex-matched controls (n = 28). The brains of patients with AS were analyzed by measuring FC, white matter microstructural analysis, cortical thickness, and brain volumes; these were compared with brains of controls. RESULTS: Interregional FC analysis revealed significantly reduced intra- and interhemispheric FC, especially in the basal ganglia and thalamus, in patients with AS. Significant reductions in fractional anisotropy were found in the corpus callosum, cingulum, posterior limb of the internal capsules, and arcuate fasciculus in patients with AS. Quantitative structural analysis also showed gray matter volume loss of the basal ganglia and diffuse WM volume reduction in AS compared with the control group. CONCLUSIONS: This integrated quantitative MR imaging analysis demonstrated poor functional and structural connectivity, as well as brain volume reduction, in children with AS, which may explain the motor and language dysfunction observed in this well-characterized neurobehavioral phenotype.

Effects of sevoflurane on QT parameters in children with congenital sensorineural hearing loss.

Sevoflurane prolongs the QT interval (QTI). Patients with congenital sensorineural hearing loss (SNHL) often have a prolonged QTI. This study was to investigate the effects of sevoflurane on the QTI in SNHL and control children. Thirty patients with SNHL and 30 controls were studied. The corrected QT interval (QTc), interval from peak to end of T wave (Tp-e) and QT variability index (QTVI) were analysed. QTc and Tp-e were estimated by the average QTc and Tp-e measured beat-by-beat for 15 min. Heart rate power spectral analysis was performed. In both groups, QTc and QTVI increased during anaesthesia, but Tp-e did not change. There were no differences in QTc, QTVI, Tp-e, low- and high-frequency power between the two groups. In both groups, sevoflurane lengthened the QTc and QTVI intervals but not Tp-e.

Increased non-stationarity of heart rate during general anaesthesia with sevoflurane or desflurane in children.

BACKGROUND: During general anaesthesia, the most prominent change in heart rate variability (HRV) is a decrease in the magnitude of heart rate (HR) oscillation in the high- and low-frequency ranges. In children receiving sevoflurane or desflurane, we observed a significant increase in HR non-stationarity, that is, a significant change of mean HR over time. The aim of our study was to describe this increased non-stationarity and compare it with the decrease in the magnitude of HR oscillation. METHODS: Sixty children received sevoflurane (n=30) or desflurane anaesthesia (n=30). The magnitude of HR oscillation and non-stationarity during pre-anaesthesia and anaesthesia were measured by spectral and Hurst analyses using structure function, respectively. RESULTS: Low- and high-frequency powers decreased significantly and the very-short-term (2

Prediction of severity of mean arterial pressure elevation after tracheal intubation in hypertensive patients by preanesthetic recurrence quantification analysis of heart rates.

BACKGROUND: We tried to determine whether the severity of additional mean arterial pressure (MAP) elevation after endotracheal intubation during general anesthesia could be predicted with preanesthetic recurrence quantification analysis of heart rates in hypertensive and normotensive patients. METHODS: Twenty-four newly diagnosed hypertensive patients and 34 normotensive patients were included. We defined DeltaMAP = maximal mean MAP after endotracheal intubation - average MAP before general anesthesia. We classified each of the hypertensive and normotensive patients into mild (DeltaMAP 35 mmHg). Using preanesthetic RR interval data, we calculated classical linear and non-linear indices of RR interval dynamics, and performed recurrence quantification analysis to calculate three preanesthetic recurrence indices, percentage of recurrence (%REC), percentage of determinism (%DET), and maximal length of recurrence (Lmax). RESULTS: In the hypertensive patients, all preanesthetic classical indices showed no significant difference between the mild and severe group and showed no significant linear correlation with the DeltaMAP. However, the Lmax was significantly higher in the severe than in the mild group (16.10 +/- 3.79 vs. 7.90 +/- 0.73, P < 0.005) and, moreover, linearly correlated with the DeltaMAP (r = 0.671, P = 0.001). In the normotensive patients, all preanesthetic classical and recurrence indices showed no significant difference between the two groups. CONCLUSION: In hypertensive patients, the severity of additional MAP elevation after tracheal intubation during general anesthesia can be predicted by the preanesthetic recurrence quantification analysis of heart rates.

Alterations in irregular and fractal heart rate behavior in growth restricted fetuses.

OBJECTIVES: To determine whether irregularity, and short- and long-term fractal correlation reflecting smoothness of heart rate behavior are changed in intrauterine growth restricted fetuses. STUDY DESIGN: Fetal heart rate data of 192 normal fetuses and 86 intrauterine growth restricted fetuses between 31 and 42 weeks of gestation were studied. Approximate entropy to quantify irregularity, and short-term (< or =80 beats, alpha1) and long-term (>80 beats, alpha2) fractal scaling exponents to quantify the short- and long-term fractal correlation were calculated. RESULTS: In the intrauterine growth restricted fetuses, the approximate entropy was significantly lower (P<0.001). The alpha2 value was significantly higher (P=0.0001) than in the normal fetuses, which performed better (F=34.2, P<0.0001) than other heart rate variability indexes in differentiating the intrauterine growth restricted fetuses from the normal fetuses in stepwise discriminant analysis. CONCLUSIONS: Compared to normal fetuses, intrauterine growth restricted fetuses show a difference in that the irregularity of the fetal heart is decreased. A more apparent difference is that the long-term fractal correlation of the fetal heart is increased and the fetal heart is smoother in the long-term scale.

Decreased entropy of symbolic heart rate dynamics during daily activity as a predictor of positive head-up tilt test in patients with alleged neurocardiogenic syncope.

Entropy measures of RR interval variability during daily activity over a 24h period were compared in 30 patients with a positive head-up tilt (HUT) test and 30 patients with a negative HUT test who had a history of alleged neurocardiogenic syncope. Two different entropies, approximate entropy (ApEn) and entropy of symbolic dynamics (SymEn), were employed. In patients showing a positive HUT test, the entropies were significantly decreased when compared with the patients with a negative HUT test. In addition, SymEn in the patients with a negative HUT test was significantly lower than in the normal controls. Discriminant analysis using SymEn could correctly identify 89.3% (520/582) of the 1 h RR interval data of the patients with a positive HUT test regardless of the time of day. Baseline entropies of heart rate dynamics during daily activity were found to be significantly lower in patients with alleged neurocardiogenic syncope and a positive HUT test than in those with the same history but with a negative HUT test. The decreased entropy of symbolic heart rate dynamics may be of predictive value of a positive HUT test in patients with alleged neurocardiogenic syncope.

Prediction of the oculocardiac reflex from pre-operative linear and nonlinear heart rate dynamics in children.

This study was aimed to determine whether pre-operatively measured linear and nonlinear analysis of heart rate variability might predict the occurrence of the oculocardiac reflex (OCR) or other arrhythmia during strabismus surgery in children (n = 185, mean (SD) age = 8.09 (3.31) years). We compared time- and frequency-domain, and nonlinear dynamic indices of pre-operatively measured RR interval data between the OCR-positive group (maximum heart rate decrement = 20 beat.min-1 during the traction of extraocular muscle, n = 54), OCR-negative group (< 20 beat x min(-1), n = 78) and arrhythmia-positive group (all other arrhythmias; n = 53). pNN50, rMSSD, high-frequency power and nonlinear prediction error were significantly lower in the OCR-positive and arrhythmia-positive groups than in the OCR-negative group. Discriminant analysis using these indices could correctly identify 39/54 (72.2%) OCR-positive patients. Some pre-operatively measured indices of linear and nonlinear heart rate variability, especially when used in combination, are valuable for predicting significant bradycardia during strabismus surgery in children.

ECP level in nasopharyngeal secretions and serum from children with respiratory virus infections and asthmatic children.

Infection with respiratory virus has been shown to exacerbate asthma in humans. However, the role of a respiratory virus in the pathogenesis of chronic asthma and/or wheezing in young children has not been clearly defined. It has also been debated whether virus-induced wheezing in young children is one entity and allergic asthma another, or whether they are different expressions of the same disease. The present study was done to compare ECP concentrations in nasopharyngeal secretions and serum from 32 nonasthmatic wheezing children with viral infections (RSV in 15 children; influenza B virus in 17 children detected by immunofluorescence antibody technique), 8 asthmatic children without viral infections, and 13 normal children as the controls to understand the role of eosinophil inflammation. The geometric mean of ECP in nasopharyngeal secretions was significantly higher in asthmatic children than in children with virus-induced wheezing (p < 0.05). ECP levels of nasopharyngeal secretions from children with the virus-induced wheezing were significantly greater than those of the controls. However, there were no significant differences in ECP levels in serum among subjects.

Acute tubulointerstitial nephritis attributable to indinavir therapy.

Indinavir sulfate has been reported to cause asymptomatic crystalluria and nephrolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients taking indinavir may present with asymptomatic crystalluria, nephrolithiasis with frank renal colic and obstruction, flank pain in the absence of nephrolithiasis, and dysuria or urgency. Asymptomatic crystalluria has been described as benign. Discontinuation of the drug has not been recommended in the absence of nephrolithiasis. We report two HIV-positive patients receiving indinavir who developed acute interstitial nephritis with foreign body giant cell reaction on renal biopsies. Both patients had asymptomatic crystalluria, although crystals were associated with clumps of white blood cells (WBCs) on urinalysis in one patient. Both cases show that the inflammatory response was significant enough to lead to tubular injury and acute renal impairment. Our findings suggest that asymptomatic crystalluria attributable to indinavir may illicit an inflammatory response with acute renal insufficiency, warranting monitoring of renal function, especially in patients with crystalluria.

Decreased RR interval complexity and loss of circadian rhythm in patients with congestive heart failure.

The present study investigated how the RR interval complexity and variability and their circadian rhythms alter for patients with congestive heart failure (CHF). Sixteen patients aged between 41 and 72 years with CHF and 20 control subjects were included. 24-h ambulatory electrocardiographic recordings were analyzed, and digitized data was partitioned into sections of 30-min duration. For each section, time- and frequency-domain indices, and complexity indices of heart rate variability were calculated. For CHF patients, 24-h average values of all indices were significantly decreased. The circadian rhythms of mean RR intervals were preserved and resembled the abnormal circadian rhythms of the low-frequency power. The circadian rhythms of high-frequency power and all complexity indices shown in the normal control were lost. Conclusively, the patients with CHF showed decreased RR interval complexity and loss of its circadian rhythm, in addition to decreased frequency-domain RR interval variability and its abnormal circadian rhythm.

True histiocytic lymphoma of the esophagus in an HIV-positive patient: an ultrastructural study.

A 56-year-old white woman, seropositive for human immunodeficiency virus for 18 months without signs of acquired immunodeficiency syndrome, presented with retrosternal pain and progressive dysphagia secondary to an exophytic esophageal mass. Biopsies of the tumor showed a malignant neoplasm composed of pleomorphic, noncohesive cells growing in a diffuse, sheet-like fashion. Immunohistochemically, tumor cells were nonreactive with epithelial, lymphoid, neural, and monocyte/macrophage markers. Despite the noncontributory immunohistochemical findings, ultrastructural study of the tumor cells revealed convincing histiocytic features. Individual cells possessed long, slender filopodial projections, prominent Golgi apparatus, residual bodies, rare lysosomes, and prelysosomes. Immunoglobulin heavy chain and T-cell receptor gamma gene rearrangement studies detected no evidence of a clonal gene rearrangement. The patient responded poorly to chemotherapy and died 5 months after her initial symptom of dysphagia.

Abnormal cardiac autonomic activity and complexity in newly diagnosed and untreated hypertensive patients after general anesthesia.

To investigate change of cardiac autonomic activity and cardiac complexity during general anesthesia in hypertensive patients, we analyzed electrocardiographic (ECG) data using power spectral analysis and approximate entropy (ApEn). Anesthesia was performed by a mixture of enflurane and nitrous oxide. From 10 minutes before induction of anesthesia(resting state) until 20 minutes after induction, ECG data were obtained from newly diagnosed and untreated hypertensive (n = 18) and normotensive patients (n = 18). Period 1 was defined as the initial 10 minutes after induction and period 2 as the following 10 minutes. The low-, mid-, and high-frequency power and the values of ApEn of the two groups were calculated from ECG recording. At resting state, the powers in all frequency bands and the values of ApEn in hypertensive patients did not differ from those of normotensive patients. During periods 1 and 2, the powers of all frequency range significantly decreased in normotensive group (p<0.05), while they did not change in hypertensive group. The values of ApEn in normotensive patients decreased significantly only during period 2, while those in hypertensive patients decreased during periods 1 and 2 (p<0.05 and p<0.05, respectively). These results suggest that, in the hypertensive patients, persistent autonomic activity under the condition of suppressed cardiac complexity may contribute to the unstable hemodynamic insults from the outset of general anesthesia.

Analysis of induced sputum to examine the effects of inhaled corticosteroid on airway inflammation in children with asthma.

BACKGROUND: Analysis of induced sputum can be performed safely in children with asthma and is useful for both cellular and biochemical markers of inflammation. Glucocorticosteroid inhalation has become the first line therapy for chronic asthma by suppressing airway inflammation, which produces the decrease of bronchial hyperreactivity and reduces the number of eosinophil in bronchial submucosa. OBJECTIVE: To determine the characteristics of the inflammatory cells and their markers in sputum and to examine the pharmacokinetic effects of glucocorticoid within 3 hours after inhalation therapy on FEV1 and sputum inflammatory indices in children with clinically defined chronic asthma. METHODS: Thirty subjects with asthma included 14 current symptomatic asthmatics and 14 normal controls inhaled 4.5% hypertonic saline for 10 minutes by nebulizer. The expectorated sputum were collected from all asthmatics before and 3 hours after corticosteroid inhalation for children with asthma and were reduced by dithiotreitol. Total cell counts and differentials were determined. ECP was measured by CAP system. Interleukin-5, GM-CSF and albumin were measured by double sandwich ELISA. RESULTS: The mean eosinophil percentage and ECP in induced sputum of asthmatics were significantly higher than that of controls. The induced sputum samples obtained after glucocorticoid inhalation showed a significant reduction in mean eosinophil percentage, but FEV1, IL-5, GM-CSF, albumin, and ECP values were not significantly decreased. CONCLUSION: The present results in induced sputum may be interpreted to reflect direct steroid action on airways and lack of effect on bone marrow effectors at 3 hours after glucocorticoid inhalation.

Adenosquamous carcinoma of the pancreas.

HYPOTHESIS: Adenosquamous carcinoma of the pancreas is a rare but particularly virulent variant of invasive ductal carcinoma. This review will demonstrate the aggressive biologic activity, histopathologic features, and DNA flow cytometric characteristics of this aggressive lesion. In addition, the outcome is less favorable than in other pancreatic neoplasms, in spite of aggressive surgical and postoperative adjuvant therapy. DESIGN: A retrospective review of 6 patients treated during an 8-year period. SETTING: A major urban university tertiary referral hospital. PATIENTS: There were 6 patients with this unusual tumor seen between 1990 and 1998. There were 4 men and 2 women, all white, with a mean+/-SD age of 63.5+/-14.7 years. Symptoms were similar to those in patients with more common pancreatic malignant neoplasms. RESULTS: Four patients with tumors in the head of the pancreas had pancreatoduodenectomy, and 2 with body and or tail lesions had distal pancreatectomy and splenectomy. Pathologically, all the tumors were poorly differentiated and aneuploid, and 5 of the 6 were locally metastatic. All but 1 patient had postoperative complications, but there were no operative deaths. One half of the patients received postoperative adjuvant chemotherapy and radiation therapy. Only 1 patient is still alive at 9 months after surgery, but has known residual cancer around his portal vein noted during palliative distal pancreatectomy. CONCLUSIONS: Adenosquamous carcinoma of the pancreas is an uncommon variant of exocrine pancreatic neoplasm. It is characterized by an admixture of adenomatous and squamous cell elements and demonstrates aggressive biologic behavior. This series of 6 patients is similar to the 134 cases reported since 1907, in that survival is short despite aggressive surgical therapy. Few patients with this disease live more than 1 year. Aggressive therapy should be tempered by the realization of the uniform poor prognosis associated with this malignant neoplasm.

Non-linear cardiac dynamics and morning dip: an unsound circadian rhythm.

The frequency of sudden cardiac death increases in the morning. The relationship between decreased complexity of heart rate dynamics and sudden cardiac death has been documented. An understanding of circadian variation in the complexity of cardiac dynamics may be important to predict and prevent sudden cardiac death. Dynamic 24-h electrocardiographic recordings were obtained from 30 healthy ambulant subjects aged 41-50 years, and the digitized data were partitioned into sections of 30 min duration. For each section, four indexes obtained from separate algorithms of non-linear dynamics of the RR interval--modified correlation dimension, Lyapunov exponent, approximate entropy, and fractal dimension--were calculated. Normalized low-(0.04-0.15 hertz) and high-frequency (> 0.15 hertz) components were also calculated. All four indexes of non-linear dynamics showed a remarkably similar circadian rhythm: a prominent morning dip preceded by a steep decline during the late night, a recovery during the evening and a peak around midnight. In the morning, the low-frequency component rose rapidly with concomitant reduction in the high-frequency component. The complexity of cardiac dynamics decreases significantly in the morning, and this may contribute to the ominously increased rate of cardiac death in the morning hours.

Chaotic and periodic heart rate dynamics in uncomplicated intrauterine growth restricted fetuses.

We studied how chaotic and periodic heart rate dynamics differ between normal fetuses (n = 192) and uncomplicated intrauterine growth restricted fetuses (n = 86), aged 31-42 weeks of gestation. We analyzed each fetal heart rate time series for 25 min. We quantified the chaotic dynamics of each fetal heart rate time series by correlation dimension. The periodic dynamics were analyzed by power spectral analysis. The correlation dimension and, therefore, the complexity, of the heart rate dynamics of the uncomplicated intrauterine growth restricted fetuses was significantly lower than that of the normal fetuses, which was marked at 38-42 weeks of gestation. The low-frequency (0.04-0.15 Hz) component and, therefore, the periodicity of the low-frequency range was significantly higher than that of the normal fetuses during all the gestational weeks. These results mean that, although the intrauterine growth restricted fetuses are not severely compromised, the overall integrity of their cardiovascular control is impaired, especially at term; and sympathetic modulation is increased, both of which may contribute to increased perinatal mortality.

Change of complex and periodic heart rate dynamics with change of pulmonary artery pressure in infants with left-to-right shunt lesion.

We studied how complex and periodic heart rate dynamic changed as pulmonary artery pressure elevated in 32 infants with ventricular septal defect. In addition, we tested the possibility that the dynamical change could be used to predict the pulmonary artery pressure noninvasively. During cardiac catheterization, mean pulmonary artery pressure was measured and, at the same time, 5-min segments of continuous electrocardiographic recording was stored into computer files. High- (>0.15 hertz) and low- (0.03-0.15 hertz) frequency components of heart rate variability were computed using spectral analysis. The overall complexity of heart rate time series was quantified by its approximate entropy. Pulmonary hypertensive infants (mean pulmonary artery pressure >20 mm Hg, n=17) have significantly lower low- (p<0.05) and high- (p<0.05) frequency power and lower approximate entropy (p<0.0001) than pulmonary normotensive infants (mean pulmonary artery pressure < or =20 mm Hg, n=15). The mean pulmonary artery pressure is significantly correlated not with the spectral powers but with the approximate entropy (r=-0.71, p=0.0001). It can be concluded that, in infants, pulmonary hypertension induced by left- to-right shunt lesions suppresses both periodic and complex heart rate oscillation and that mean pulmonary artery pressure can be predicted by calculating the approximate entropy of heart rate variability.

Adenine phosphoribosyltransferase-deficient mice develop 2,8-dihydroxyadenine nephrolithiasis.

Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.