Esophageal Mycobacterium avium-intracellulare infection in a bone marrow transplant patient: Case report and literature review.

Mycobacterium avium-intracellulare complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) disease in humans. We report a case of esophageal MAC disease in a patient who had allogeneic bone marrow transplant for acute lymphoblastic leukemia. Although pulmonary MAC in immunocompromised host is not uncommon, there are only a few cases of NTM-associated esophageal mass reported. Our report and literature review highlight the importance of considering MAC in the differential diagnosis of dysphagia or odynophagia.

Motivations and methods for analyzing pulsatile hormone secretion.

Endocrine glands communicate with remote target cells via a mixture of continuous and intermittent signal exchange. Continuous signaling allows slowly varying control, whereas intermittency permits large rapid adjustments. The control systems that mediate such homeostatic corrections operate in a species-, gender-, age-, and context-selective fashion. Significant progress has been made in understanding mechanisms of adaptive interglandular signaling in vivo. Principal goals are to understand the physiological origins, significance, and mechanisms of pulsatile hormone secretion. Key analytical issues are: 1) to quantify the number, size, shape, and uniformity of pulses, nonpulsatile (basal) secretion, and elimination kinetics; 2) to evaluate regulation of the axis as a whole; and 3) to reconstruct dose-response interactions without disrupting hormone connections. This review will focus on the motivations driving and the methodologies used for such analyses.

H5N1 virus-like particle vaccine elicits cross-reactive neutralizing antibodies that preferentially bind to the oligomeric form of influenza virus hemagglutinin in humans.

Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries around the world. In preparation for a potential AIV pandemic, multiple vaccine candidates are under development. In the case of H5N1 AIV, a clear shift in transmission from clade 1 to clade 2 viruses occurred in recent years. The virus-like particle (VLP) represents an economical approach to pandemic vaccine development. In the current study, we evaluated the humoral immune response in humans vaccinated with H5N1 A/Indonesia/05/2005 (clade 2.1) VLP vaccine manufactured in Sf9 insect cells. The VLPs were comprised of the influenza virus hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1) proteins. In an FDA-approved phase I/II human clinical study, two doses of H5N1 VLPs at 15, 45, or 90 µg HA/dose resulted in seroconversion and production of functional antibodies. Moreover, cross-reactivity against other clade 2 subtypes was demonstrated using virus neutralization assays. H5N1 whole-genome fragment phage display libraries (GFPDL) were used to elucidate the antibody epitope repertoire in postvaccination human sera. Diverse epitopes in HA1/HA2 and NA were recognized by postvaccination sera from the two high-dose groups, including large segments spanning the HA1 receptor binding domain. Importantly, the vaccine elicited sera that preferentially bound to an oligomeric form of recombinant HA1 compared with monomeric HA1. The oligomeric/monomeric HA1 binding ratios of the sera correlated with the virus neutralizing titers. Additionally, the two high-dose VLP vaccine groups generated NA-inhibiting antibodies that were associated with binding to a C-terminal epitope close to the sialic acid binding site. These findings represent the first report describing the quality of the antibody responses in humans following AIV VLP immunization and support further development of such vaccines against emerging influenza virus strains.

Modeling the Nonlinear Time Dynamics of Multidimensional Hormonal Systems.

In most hormonal systems (as well as many physiological systems more generally), the chemical signals from the brain, which drive much of the dynamics, can not be observed in humans. By the time the molecules reach peripheral blood, they have been so diluted so as to not be assayable. It is not possible to invasively (surgically) measure these agents in the brain. This creates a difficult situation in terms of assessing whether or not the dynamics may have changed due to disease or aging. Moreover, most biological feedforward and feedback interactions occur after time delays, and the time delays need to be properly estimated. We address the following two questions: (1) Is it possible to devise a combination of clinical experiments by which, via exogenous inputs, the hormonal system can be perturbed to new steady-states in such a way that information about the unobserved components can be ascertained; and, (2) Can one devise methods to estimate (possibly, time-varying) time delays between components of a multidimensional nonlinear time series, which are more robust than traditional methods? We present methods for both questions, using the Stress (ACTH-cortisol) hormonal system as a prototype, but the approach is more broadly applicable.

Oscillations in joint synchrony of reproductive hormones in healthy men.

Negative-feedback (inhibitory) and positive-feedforward (stimulatory) processes regulate physiological systems. Whether such processes are themselves rhythmic is not known. Here, we apply cross-approximate entropy (cross-ApEn), a noninvasive measurement of joint (pairwise) signal synchrony, to inferentially assess hypothesized circadian and ultradian variations in feedback coupling. The data comprised simultaneous measurements of three pituitary and one peripheral hormone (LH, FSH, prolactin, and testosterone) in 12 healthy men each sampled every 10 min for 4 days (5,760 min). Ergodicity, due to the time series stationarity of the measurements over the 4 days, allows for effective estimation of parameters based upon the 12 subjects. Cross-ApEn changes were quantified via moving-window estimates applied to 4-day time series pairs. The resultant ordered windowed cross-ApEn series (in time) were subjected to power spectrum analysis. Rhythmicity was assessed against the null hypothesis of randomness using 1,000 simulated periodograms derived by shuffling the interpulse-interval hormone-concentration segments and redoing cross-ApEn windows and spectral analysis. By forward cross-ApEn analysis, paired LH-testosterone, LH-prolactin, and LH-FSH synchrony maintained dominant rhythms with periodicities of 18-22.5, 18, and 22.5 h, respectively (each P < 0.001). By reverse (feedback) cross-ApEn analysis, testosterone-LH, testosterone-prolactin, and testosterone-FSH synchrony cycles were 30, 18, and 30-45 h, respectively (each P ≤ 0.001). Significant 8- or 24-h rhythms were also detected in most linkages, and maximal bihormonal synchrony occurred consistently at ∼0400-0500. Collectively, these analyses demonstrate significant ultradian (<24 h), circadian (∼24 h), and infradian (>24 h) oscillations in pituitary-testis synchrony, wherein maximal biglandular coordination is strongly constrained to the early morning hours.

Differentiation of women with premenstrual dysphoric disorder, recurrent brief depression, and healthy controls by daily mood rating dynamics.

Enhanced statistical characterization of mood-rating data holds the potential to more precisely classify and sub-classify recurrent mood disorders like premenstrual dysphoric disorder (PMDD) and recurrent brief depressive disorder (RBD). We applied several complementary statistical methods to differentiate mood rating dynamics among women with PMDD, RBD, and normal controls (NC). We compared three subgroups of women: NC (n=8); PMDD (n=15); and RBD (n=9) on the basis of daily self-ratings of sadness, study lengths between 50 and 120 days. We analyzed mean levels; overall variability, SD; sequential irregularity, approximate entropy (ApEn); and a quantification of the extent of brief and staccato dynamics, denoted 'Spikiness'. For each of SD, irregularity (ApEn), and Spikiness, we showed highly significant subgroup differences, ANOVA0.001 for each statistic; additionally, many paired subgroup comparisons showed highly significant differences. In contrast, mean levels were indistinct among the subgroups. For SD, normal controls had much smaller levels than the other subgroups, with RBD intermediate. ApEn showed PMDD to be significantly more regular than the other subgroups. Spikiness showed NC and RBD data sets to be much more staccato than their PMDD counterparts, and appears to suitably characterize the defining feature of RBD dynamics. Compound criteria based on these statistical measures discriminated diagnostic subgroups with high sensitivity and specificity. Taken together, the statistical suite provides well-defined specifications of each subgroup. This can facilitate accurate diagnosis, and augment the prediction and evaluation of response to treatment. The statistical methodologies have broad and direct applicability to behavioral studies for many psychiatric disorders, and indeed to similar analyses of associated biological signals across multiple axes.

Behavioural assessment unit improves outcomes for patients with complex psychosocial needs.

OBJECTIVE: We aimed to assess the impact of a new model of care for patients presenting to the ED with acute behavioural disturbance. METHODS: This pre-/post-intervention study involved creating a dedicated, highly resourced six bed unit, the behavioural assessment unit (BAU). Co-located with the ED at the Royal Melbourne Hospital, the unit was designed to fast-track the admission of patients affected by intoxication, mental illness or psychosocial crisis and provide front-loaded interventions. RESULTS: In 12 months from 1 April 2016, 2379 patients were admitted to the BAU. They were compared with a similar cohort of 3047 patients from the entire 2015 ED population. The BAU resulted in a decreased wait to be seen (40 min [interquartile range (IQR): 17-86] vs 68 min [IQR: 24-130], P < 0.001), a decreased wait for a mental health review (117 min [IQR: 49-224] vs 139 min [IQR: 57-262], P = 0.001) and a decreased ED length of stay (180 min [IQR: 101-237] vs 328 min [IQR: 227-534], P < 0.001). Patients admitted to the BAU were less likely to have a security code (349 (14.7%) vs 538 (17.7%), P = 0.003) and less likely to have mechanical restraint (156 episodes (6.6%) vs 275 (9.0%), P < 0.001) or therapeutic sedation (156 episodes (6.6%) vs 250 (8.2%), P < 0.001). CONCLUSION: A unit specifically designed to improve the care of patients requiring prolonged ED care due to mental illness and/or intoxication reduces the time spent in the ED and the use of some restrictive interventions. We recommend this model of care to EDs that care for this complex and challenging group of patients.

Early computerized tomography accurately determines the presence or absence of scaphoid and other fractures.

OBJECTIVE: To validate the use of early CT in predicting scaphoid fracture and other fractures in patients with suspected scaphoid fracture. METHOD: A prospective observational study of adult patients with a diagnosis of clinical scaphoid fracture presenting to a regional ED. Patients were immobilized in a scaphoid plaster and had a CT (wrist and carpals) same or next day. The gold standard used was the diagnosis on Day 10 with clinical examination and X-rays, with MRI performed in patients with persistent tenderness but normal X-rays. RESULTS: Forty-seven patients completed the study protocol from September 2004 until February 2006. For all fractures, early CT had a 96.8% negative predictive value and 100% positive predictive value (94.4% sensitive, 100% specific). No scaphoid fracture was missed by early CT. One patient had a trapezium fracture on CT, with a coexistent subtle capitate fracture only detected on MRI. CONCLUSION: Early CT scans show promise in the diagnosis of scaphoid and other fractures of the wrist and carpals. Further study is warranted to validate early CT in clinical scaphoid fracture as an alternative to other early advanced imaging, or plaster immobilization and 2 week review.

Heteropolymers: a novel technology against blood-borne infections.

Heteropolymer (HP) technology is a novel cassette technology which is being developed for the treatment of infectious and autoimmune diseases. HPs are dual antibody conjugates, composed of a monoclonal antibody (mAb) directed against the complement receptor type 1 (CR1) on primate red blood cells (RBCs) chemically cross-linked to mAbs that recognize blood-borne antigens. Upon administration of an HP, the target is bound to its counterpart mAb in the HP and immobilized on an RBC by binding of the anti-CR1 mAb to CR1 in a complement-independent manner, forming an immune complex. When the RBC traverses the liver during circulation, the immune complex is recognized by fixed tissue macrophages, the CR1 molecule is cleaved and the HP-pathogen complex is phagocytosed and destroyed. Due to rapid binding and immobilization of the target by HPs, the anti-target mAb used in the HP need not be directed to a neutralizing epitope on the target organism. Studies in animal models have shown that HPs are effective in treating infectious diseases and autoimmune diseases such as systemic lupus erythematosus. HPs are advantageous over natural immune adherence or conventional mAb therapies due to their complement-independent mechanism, low therapeutic dose and lack of the need for neutralizing mAbs against the target.

Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretion.

In humans, GH and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. Substitution therapy is given to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex. However, treatment with twice or three times daily oral hydrocortisone does not mimic physiological adrenal rhythms and may influence the activity of the GH/IGF-I axis. We investigated the pattern of GH and cortisol secretion and the synchrony of joint GH-cortisol secretory dynamics in 15 children with classic 21-hydroxylase deficiency (5 males and 10 females; median age 9.5 yr, range 6.1-11.0 yr) and 28 short normal children (23 males and 5 females; median age 7.7 yr, range 4.9-9.3 yr). All subjects were prepubertal. Serum GH and cortisol concentrations were determined at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol secretory patterns was computed at various time lags covering the 24-h period. Children with CAH had significantly lower mean 24-h serum cortisol concentrations (6.4 +/- 2.2 vs. 10.4 +/- 2.6 microg/dl, P < 0.001), ApEn (GH) (0.64 +/- 0.13 vs. 0.74 +/- 0.17, P = 0.04), ApEn (cortisol) (0.54 +/- 0.13 vs. 1.08 +/- 0.18, P < 0.001) and cross-ApEn values of paired GH-cortisol secretion (0.78 +/- 0.19 vs. 1.05 +/- 0.12, P < 0.001) than normal children. There was no difference in mean 24-h GH concentrations between the two groups (4.5 +/- 2.9 vs. 4.5 +/- 1.9 mU/liter). In children with CAH, a significant positive correlation between GH and cortisol was noted at lag time 0 min (r = 0.299, P < 0.01), peaking at 20 min (r = 0.406, P < 0.0001), whereas in normal children, a significant negative correlation between the two hormones was noted at lag time 0 min (r = -0.312, P < 0.01). The above findings suggest that children with classic CAH have a more regular pattern of GH secretion and a more synchronous joint GH-cortisol secretory dynamics than their normal counterparts. These differences reflect bidirectional interactions between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis in humans, and are likely to evolve as a result of the exogenous administration of hydrocortisone at fixed doses and at specific time intervals, which leads to a more regular pattern in circulating cortisol concentrations, independent of variations in CRH and ACTH concentrations.

Intracranial EEG evaluation of relationship within a resting state network.

OBJECTIVE: We tested if a relationship between distant parts of the default mode network (DMN), a resting state network defined by fMRI studies, can be observed with intracranial EEG recorded from patients with localization-related epilepsy. METHODS: Magnitude squared coherence, mutual information, cross-approximate entropy, and the coherence of the gamma power time-series were estimated, for one hour intracranial EEG recordings of background activity from 9 patients, to evaluate the relationship between two test areas which were within the DMN (anterior cingulate and orbital frontal, denoted as T1 and posterior cingulate and mesial parietal, denoted as T2), and one control area (denoted as C), which was outside the DMN. We tested if the relationship between T1 and T2 was stronger than the relationship between each of these areas and C. RESULTS: A low level of relationship was observed among the 3 areas tested. The relationships among T1, T2 and C did not demonstrate support for the DMN. CONCLUSIONS: This study suggests a lack of intracranial EEG support for the fMRI defined default mode network. SIGNIFICANCE: The results obtained underscore the considerable difference between electrophysiological and hemodynamic measurements of brain activity and possibly suggest a lack of neuronal involvement in the DMN.

Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults.

BACKGROUND: GH secretion is quantifiable as mean, peak, and nadir GH concentrations; degree of irregularity (approximate entropy); and spikiness (brief staccato-like fluctuations). HYPOTHESIS: Distinct GH dynamics reflect relatively distinct (combinations of) subject variables, such as gender, age, body mass index (BMI), and IGF-I concentrations. LOCATION: The study took place at a clinical translational research unit. SUBJECTS: Subjects included 100 healthy adults ages 20-77 yr (59 women and 41 men), BMI 18-42 kg/m(2), and IGF-I 9.2-38 nmol/liter. MEASURES: Immunofluorometric GH assay was done on 10-min samples collected for 24 h. RESULTS: Stepwise forward-selection multivariate regression analysis revealed that mean GH concentrations were simultaneously determined (overall r = 0.36; P < 0.001) by gender (higher in women, P < 0.001), BMI (negatively, P < 0.001), and IGF-I (positively, P < 0.001). Peak GH levels were influenced (r = 0.28) by both BMI (P < 0.001) and IGF-I (P = 0.001). Nadir GH values were jointly affected by gender (higher in women, P = 0.005) and BMI (negatively, P = 0.001). GH approximate entropy was triply defined (r = 0.29) by gender (greater irregularity in women, P < 0.001), age (P = 0.022), and BMI (P = 0.008) and dually (r = 0.25) by gender (P = 0.0001) and BMI (P = 0.017) if sex steroids were included. GH spikiness was determined (r = 0.29) by gender (higher in women, P = 0.0016) and BMI (positively, P = 0.0002). CONCLUSION: In healthy adults, combinations of gender, age, BMI, and IGF-I specify distinct GH dynamics, thus requiring balanced representation of these variables in comparative GH studies.

Influenza virus-like particles as a new tool for vaccine immunogenicity testing: validation of a neuraminidase neutralizing antibody assay.

Detection of neutralizing antibody to viral neuraminidase (NA) by testing for enzyme inhibition has been recognized as an important part of the immunogenicity of influenza vaccines. However, the absence of a well characterized standard source of active NA and validated assays has significantly limited clinical studies of NA immunity. Influenza virus-like particles (VLPs) containing hemagglutinin (HA), NA, and M1 proteins were produced from insect cells infected with a recombinant baculovirus and used as the NA source for the NA inhibition (NAI) assay. The NA activity of 6 different VLP strains varied from 0.43 to 1.61 (×10(-3)) enzyme units per µg of HA and was stable over 6 months of storage at 2-8°C. The NAI assay using 2'-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid as a substrate was modified for testing the antibody titer in clinical samples and validated. The advantages of the assay include: (1) stable, reproducible, and standardized source of NA; (2) testing the antibody titer specific to each subtype of NA in serum from subjects immunized with trivalent vaccines (H1N1, H3N2, B) with no interference from antibodies specific to the HA and to heterologous subtypes of the NA; (3) suitability for conducting long-term clinical trials as a result of low intra- and inter-assay variability, and (4) a wide analytical range due to 25% inhibition cut-off value for the NAI titer estimation.

Predicting response to leuprolide of women with premenstrual dysphoric disorder by daily mood rating dynamics.

Approximately 60-70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P ≤ 0.005); the composite measure was smaller for responders compared with nonresponders (P ≤ 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment.

Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine in a blinded, randomized, placebo-controlled trial of adults in Mexico.

Virus-like particles (VLPs) can be rapidly developed from influenza virus genetic sequences in order to supply vaccine after the onset of a pandemic. The safety and immunogenicity of one or two doses of a recombinant A (H1N1) 2009 influenza VLP vaccine was evaluated in a two-stage, Phase 2, randomized, double-blind, placebo-controlled study conducted in 4563 healthy adults, 18-64 years of age, during the H1N1 2009 pandemic in Mexico. In Part A, 1013 subjects were randomized into four treatment groups (5 µg, 15 µg, or 45 µg hemagglutinin [HA] VLP vaccine or placebo) and vaccinated 21 days apart, with sera collected on Days 1, 14 and 36 for hemagglutination inhibition (HAI) testing. After review of safety and immunogenicity data from Part A, additional subjects were immunized with a single dose of 15 µg VLP vaccine (N=2537) or placebo (N=1011) and assessed for safety in Part B. Results showed the H1N1 2009 VLP vaccine was safe and well-tolerated. Systemic solicited events were similar between placebo and VLP vaccinated groups with no vaccine-related serious adverse events. Dose response trends for solicited local adverse events were observed, with higher incidences of local pain, swelling, tenderness, and redness reported in the higher VLP dose groups (15 µg and 45 µg) compared to the placebo and 5 µg VLP groups following both vaccinations. Although the majority of local AEs were mild in severity, a dose trend in events of moderate or greater severity was also noted for these solicited events. The VLP vaccine groups demonstrated robust HAI immune responses after a single vaccination, with high rates of seroprotection (≥ 40 HAI titer) in 82-92% of all subjects and in 64-85% of subjects who were seronegative at the time of immunization. HAI geometric mean titers (GMTs), geometric mean ratios (GMRs) and seroconversion rates were also all statistically higher in the VLP groups compared to placebo for both post-baseline time points. Based on these data, additional clinical trials are in development to evaluate influenza vaccine candidate antigens manufactured using Spodoptera frugiperda (Sf9)/baculovirus-based VLP technology.

The effects of temperature, age and sex on presentations of renal colic in Melbourne, Australia.

OBJECTIVE: To determine whether renal colic incidence in the temperate environment of Melbourne, Australia, varies with ambient temperature and season. METHODS: This was a retrospective analysis of patients with renal colic who presented, between 1999 and 2005 inclusive, to a Victorian inner city emergency department. The emergency department database was interrogated to identify patients with an International Classification of Diseases 10th revision diagnostic code of renal colic. All weather data were obtained from the Bureau of Meteorology (Melbourne, Australia). The primary study endpoints were renal colic incidence and mean monthly temperature and humidity. Data were analysed using Spearman's correlation coefficient and the normal Z-test. RESULTS: About 3070 cases were identified. Mean age was 45.0 (SD 14.0) years. Males predominated with 2374 (77.3%) cases. For both sexes, renal colic incidence was lower amongst younger and older patients. The summer rate was significantly greater than the winter rate (1.53 vs. 1.24 presentations/day, rate difference 0.29, 95% confidence interval 0.15-0.43, P<0.001). There were significant positive correlations between the mean monthly maximum temperature and the absolute number (R = 0.34, P = 0.002) and rate (presentations/day, R = 0.26, P = 0.017) of presentations. The summer/winter ratio of renal colic incidence was not affected by age or sex. CONCLUSION: The incidence of renal colic in the temperate environment increases with sustained increases in ambient temperature and is unaffected by age or sex. Patients at risk of renal colic should increase their fluid intake over the whole of the summer period not just during periods of extreme heat.

Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype.

Hormone-secreting glands communicate via intermittent (pulsatile or rhythmic) signal exchange. Signals act upon target glands via implicit (not directly observable) stimulatory and inhibitory dose-response functions. Time delays operate, since secreted hormones do not arrive at or act on responsive cells instantaneously. Neuroendocrine systems are unique examples, therefore, of intermittent time-delayed dose-dependent homeostatic ensembles. Investigating such ensembles thus requires estimating secretion from plasma concentrations, recognizing biological time-delays and reconstructing unobserved feedforward (agonist) and feedback (antagonist) dose-response interfaces as illustrated primarily for the GnRH-LH-T-axis, and secondarily for the corticotropic and somatotropic axes. In this manner, each neuroendocrine system is viewed as a whole, rather than the sum of individual parts.

Background intracranial EEG spectral changes with anti-epileptic drug taper.

OBJECTIVE: Previous studies have revealed a surprising decrease in spike counts and Teager energy between on- and off-AEDs states during intracranial EEG (icEEG) monitoring. Here, we expand the measures evaluated to icEEG power and frequency band power. METHODS: Two icEEG epochs, on- and off-AEDs, each 1h in duration, were studied for each of 21 unselected adult patients. Spike counts, Teager energy and total power were evaluated for each electrode contact. Power was also evaluated for delta (0-4Hz), theta (4-8Hz), alpha (8-13Hz), beta (13-25Hz), gamma (25-55Hz) and high (65-128Hz) frequency bands. RESULTS: A decrease in power accompanies AED taper and the previously reported decrease in spike counts and Teager energy. The decrease in power was underpinned by a spatially widespread and broadband decrease in power in delta through gamma frequency bands with maximum decrease in the lowest frequency bands. An increase in high-frequency power was observed in some patients. CONCLUSIONS: There is a decrease in spike counts, Teager energy and power from on- to off-AEDs state during intracranial monitoring. The decrease in power is spatially widespread and broadband including power in the delta through gamma frequency bands. SIGNIFICANCE: The decrease in cortical activity with AED taper suggests that seizure generation during intracranial monitoring may not be mediated solely by poorly regulated cortical excitation.

Localization-related epilepsy exhibits significant connectivity away from the seizure-onset area.

In localization-related epilepsy, seizures are presumed to arise from a discrete cortical area. The control of seizures by epilepsy surgery can be poor, however, even when there has been complete resection of the area identified by standard clinical procedures to give rise to seizures. We used a coherence-based measure of functional connectivity to test for network effects within and outside the seizure-onset area. Connectivity was evaluated from the background intracranial electroencephalogram of six unselected patients. We show significant nonzero connectivity not only for the seizure-onset area but also several centimeters from it, for example, for the beta-frequency band (P<10(-5)), suggesting a nonlocal character to this disorder.

Basal, pulsatile, entropic (patterned), and spiky (staccato-like) properties of ACTH secretion: impact of age, gender, and body mass index.

BACKGROUND: Age, gender, and BMI determine ultradian modes of LH and GH secretion, viz., pulsatile, basal, pattern-defined regularity [approximate entropy (ApEn)] and spikiness (sharp, brief excursions). Whether the same determinants apply to ACTH secretion is not known. SETTING: The study was conducted at a tertiary medical center. SUBJECTS: We studied normal women (n = 22) and men (n = 26) [ages, 23-77 yr; body mass index (BMI), 21-32 kg/m(2)]. METHODS: Volunteers underwent 10-min blood sampling to create 24-h ACTH concentration profiles. OUTCOMES: Dynamic measures of ACTH secretion were studied. RESULTS: Mean ACTH concentrations (R(2) = 0.15; P = 0.006) and both pulsatile (R(2) = 0.12; P = 0.018) and basal (nonpulsatile) (R(2) = 0.16; P = 0.005) ACTH secretion correlated directly with BMI (n = 48). Men had greater basal (P = 0.047), pulsatile (P = 0.031), and total (P = 0.010) 24-h ACTH secretion than women, including when total secretion was normalized for BMI (P = 0.019). In men, both ACTH-cortisol feedforward and cortisol-ACTH feedback asynchrony (cross-ApEn) increased with age (R(2) = 0.20 and 0.22; P = 0.021 and 0.018). ACTH spikiness rose with age (P = 0.046), principally in women. Irregularity of cortisol secretion (ApEn) increased with age (n = 48; P = 0.010), especially in men. In both sexes, percentage pulsatile ACTH secretion predicted 24-h mean cortisol concentrations (R(2) = 0.14; P = 0.009). CONCLUSION: Valid comparisons of ultradian ACTH dynamics will require cohorts matched for age, gender, and BMI, conditions hitherto not satisfied in most physiological studies of this axis.