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Results for “cell deconvolution”

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PubMed1993

Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fasting-induced hypoandrogenemia in normal men.

In the male rodent and primate, fasting or severe caloric restriction significantly decreases serum testosterone concentrations, putatively via inducing secondary hypogonadotrophism. To clarify this presumptive pathophysiology, we have used: 1) a high sensitivity immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay of LH; 2) blood sampling every 5 min for 24 h basally and every 10 min for 3 h after GnRH injection before and after a 5-day (water only) fast in eight healthy young men; and 3) deconvolution analysis to evaluate in vivo LH secretory burst frequency, amplitude, duration, and mass, and LH half-life simultaneously. We documented a 50% fall in serum total and free testosterone concentrations, and a 30% decrease in 24-h mean serum LH concentrations (viz., fed 3.0 +/- 0.47 vs. fasted 2.1 +/- 0.39 U/L, P = 0.043). Deconvolution analysis revealed preservation of LH secretory pulse frequency (fed 12.9 +/- 0.48 vs. fasted 12.6 +/- 0.78 secretory bursts/day, P = NS) during fasting-induced hypogonadotropism. The duration of computer-resolved LH secretory bursts, the interburst interval, and the calculated endogenous half-life of LH also did not change, whereas LH secretory burst mass declined significantly; viz. from 28 +/- 5 in the fed to 14 +/- 3.2 U/L of distribution volume/day in the fasted state (P = 0.034). In contrast, LH release after a 10 micrograms pulse of GnRH iv was enhanced during fasting in seven of the eight men. Fasting also decreased mean (24 h) serum TSH and PRL, increased cortisol, dehydroepiandrosterone sulfate and GH, and did not affect FSH concentrations or the radioiodinated albumen distribution space. In summary, in young men 5 days of nutrient deprivation selectively attenuates the mass of LH secreted per burst without altering LH secretory event frequency or LH half-life. We infer that decreased LH release per burst is due to decreased hypothalamic GnRH impulse strength, since LH release induced by a submaximally effective pulse of exogenous GnRH is amplified rather than attenuated.

Adult↗

PubMed1995

Alterations in the patterns of insulin secretion before and after diagnosis of IDDM.

OBJECTIVE: To study the natural history of beta-cell dysfunction in an individual who developed insulin-dependent diabetes mellitus (IDDM) over a 13-month period while under observation. RESEARCH DESIGN AND METHODS: Insulin secretion rates (ISR) in response to intravenous glucose and mixed meals were estimated by deconvolution of C-peptide levels. RESULTS: When fasting glucose and glycosylated hemoglobin concentrations were still within the normal range, insulin secretory responses to intravenous glucose infusion were reduced, but 80- to 100-min secretory oscillations could still be detected. Sequential glucose infusion studies over a 3-month period demonstrated a progressive reduction in insulin secretion. The tight temporal coupling between ultradian oscillations in ISR and glucose observed in nondiabetic subjects was lost. In response to mixed meals, the oscillatory pattern of secretion was preserved, but the magnitude of the secretory responses was reduced. CONCLUSIONS: Our results indicate that despite the lower absolute secretory rates, ultradian ISR oscillations persist in the period before and immediately after the onset of IDDM in this subject, but they are less tightly coupled to glucose than in nondiabetic subjects.

Adult↗

PubMed1997

Neuroendocrine mechanisms by which selective Leydig cell castration unleashes increased pulsatile LH release.

A novel pharmacological model of acute reversible Leydig cell "castration" induced by a steroidogenic enzyme inhibitor, ketoconazole, achieves marked hypoandrogenemia in healthy men with an attendant 2.5-fold increase in 24-h mean serum luteinizing hormone (LH) concentrations. Mechanistically, the unleashing of amplified pulsatile LH release can be accounted for by any of three distinct models of deconvolution-estimated gonadotropin secretion, all of which are marked by a nearly twofold acceleration in LH secretory burst frequency. In addition, the models variously also predict concomitant prolongation of the endogenous LH half-life, an augmented LH secretory burst mass and duration, and/or the emergence of significant basal LH secretion. The nyctohemeral (cosinor analysis) rhythmicity of serum LH concentrations is not disturbed when androgenic negative-feedback signaling is withdrawn abruptly, but the apparent process randomness of LH release increases, as quantified by higher approximate entropy values. Thus we conclude that an intact (closed loop) androgen-mediated negative-feedback network in the adult human male is required to sustain low-frequency pulsatile LH release in a quantifiably orderly manner.

Adolescent↗

PubMed1995

Insulin secretion and clearance during low-dose graded glucose infusion.

The present study was undertaken in normal volunteers to define the alterations in beta-cell responsiveness to glucose associated with different physiological states, including fasting and refeeding, and after prolonged intravenous glucose infusion. A low-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels using a two-compartment model utilizing individual kinetic parameters. From 5 to 9 mmol/l glucose, the relationship between glucose and ISR was linear. After a 42-h glucose infusion at a rate of 4 mg.kg-1.min-1, the ISR increased by 53% over the same glucose concentration range (P < 0.002), resulting in a shift of the dose-response curve to the left. Insulin clearance rates decreased 27% after the 42-h glucose infusion (P < 0.001). After a 72-h fast, ISR decreased by 32% from baseline over the 5-8 mmol/l glucose range (P = 0.056), resulting in a shift of the dose-response curve to the right. This shift was reversed by a 42-h period of refeeding, after which ISR was increased by 77% compared with the fasting study (P < 0.02). Refeeding enhanced the beta-cell responsiveness, and ISR increased by 31% after refeeding compared with the baseline study (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Conformationally restricted competitive antagonists of human/rat corticotropin-releasing factor.

Corticotropin releasing factor (CRF) is a 41-peptide amide which stimulates the release of ACTH (Vale et al. Science 1981, 213, 1394). CRF has been postulated to assume an alpha-helical conformation upon binding to its pituitary receptor (Hernandez et al. J. Med. Chem. 1993, 36, 2860). We have exploited this hypothesis in the design of a limited series of cyclic analogues and have taken into consideration the effects of side-chain deletion (Alanine scan, Kornreich et al. J. Med. Chem. 1992, 35, 1870) as well as of changes in chirality (Rivier et al. J. Med. Chem. 1993, 36, 2851), with the rationale that side chains necessary for binding could also be replaced by side-chain bridges. In particular, we have used computer modeling to predict likely side chain bridging opportunities and evaluated the effects of such replacements by correlating biological results with those derived from CD spectroscopy. We have synthesized 38 monocyclic peptide amides, competitive antagonists of human/rat CRF, using solid-phase methodology on MBHA resin. After purification by preparative RP-HPLC, the peptides were analyzed by RP-HPLC and capillary zone electrophoresis and characterized by mass spectroscopy and amino acid analysis. CRF antagonists were tested for their ability to interfere with CRF-induced release of ACTH by rat anterior pituitary cells. In most cases, one of the bridge heads was located at a position where substitution by a D-residue was tolerated (i.e., positions 12 and 20). It has become clear that careful optimization of bridge length and chirality is critical. This is best exemplified by the fact that out of the 38 analogues that were synthesized and tested, only two, [cyclo(20-23)[DPhe12,Glu20,Lys23, Nle21,38]h/rCRF12-41 and cyclo(20-23)[DPhe12,Glu20,Orn23,Nle21,38] h/rCRF12-41], were found to be more potent (3 and 2 times, respectively) than [DPhe12,Nle21,38]h/rCRF12-41, the parent compound. Six analogues belonging to two different families were found to be half as potent as the standard, 18 had 2-20% of the potency of the standard, and the others were significantly less potent. CD results of all analogues in 50% TFE (a concentration of TFE that induced nearly maximum helicity of [DPhe12,Nle21,38]h/rCRF12-41) suggest that while helicity may be an important factor for CRF analogue recognition, little correlation is found between percent helicity as determined by spectral deconvolution and biological activity in vitro.

Adrenocorticotropic Hormone↗

PubMed2001

Experimental and computational screening models for the prediction of intestinal drug absorption.

The aim of this study was to devise experimental protocols and computational models for the prediction of intestinal drug permeability. Both the required experimental and computational effort and the accuracy and quality of the resulting predictions were considered. In vitro intestinal Caco-2 cell monolayer permeabilities were determined both in a highly accurate experimental setting (Pc) and in a faster, but less accurate, mode (Papp). Computational models were built using four different principles for generation of molecular descriptors (atom counts, molecular mechanics calculations, fragmental, and quantum mechanics approaches) and were evaluated for their ability to predict intestinal membrane permeability. A theoretical deconvolution of the polar molecular surface area (PSA) was also performed to facilitate the interpretation of this composite descriptor and allow the calculation of PSA in a simplified and fast mode. The results indicate that it is possible to predict intestinal drug permeability from rather simple models with little or no loss of accuracy. A new, fast computational model, based on partitioned molecular surface areas, that predicts intestinal drug permeability with an accuracy comparable to that of time-consuming quantum mechanics calculations is presented.

Biological Transport↗

PubMed2006

Localization of Kv1.5 channels in rat and canine myocyte sarcolemma.

Voltage-gated potassium (Kv) channel subtypes localize to the plasma membrane of a number of cell types, and the sarcolemma in myocytes. Because many signaling molecules concentrate in subdomains of the plasma membrane, the localization of Kv channels to these sites may have important implications for channel function and regulation. In this study, the association of the voltage-gated potassium channel Kv1.5 with a specific subtype of lipid rafts, caveolae, in rat and canine cardiac myocytes has been investigated. Interactions between caveolin-3 and beta-dystroglycan or eNOS, as well as between Kv1.5 and alpha-actinin were readily detected in co-immunoprecipitation experiments, whereas no association between Kv1.5 and caveolin-3 was evident. Wide-field microscopy and deconvolution techniques revealed that the percent co-localization of Kv1.5 with caveolin-3 was extremely low in atrial myocytes from rat and canine hearts (8+/-1% and 12.2+/-2%, respectively), and limited in ventricular myocytes (11+/-4% and 20+/-3% in rat and canine, respectively). Immunoelectron microscopic imaging of rat atrial and ventricular tissues showed that Kv1.5 and caveolin-3 labeling generally did not overlap. In HEK293 cells stably expressing the channel, Kv1.5 did not target to the low buoyant density raft fraction along with flotillin but instead fractionated along with the non-raft associated transferrin receptor. Taken together, these results suggest that Kv1.5 is not present in caveolae of rat and canine heart.

Animals↗

PubMed1996

Intrasarcomere [Ca2+] gradients in ventricular myocytes revealed by high speed digital imaging microscopy.

Cardiac muscle contraction is triggered by a small and brief Ca2+ entry across the t-tubular membranes, which is believed to be locally amplified by release of Ca2+ from the adjacent junctional sarcoplasmic reticulum (SR). As Ca2+ diffusion is thought to be markedly attenuated in cells, it has been predicted that significant intrasarcomeric [Ca2+] gradients should exist during activation. To directly test for this, we measured [Ca2+] distribution in single cardiac myocytes using fluorescent [Ca2+] indicators and high speed, three-dimensional digital imaging microscopy and image deconvolution techniques. Steep cytosolic [Ca2+] gradients from the t-tubule region to the center of the sarcomere developed during the first 15 ms of systole. The steepness of these [Ca2+] gradients varied with treatments that altered Ca2+ release from internal stores. Electron probe microanalysis revealed a loss of Ca2+ from the junctional SR and an accumulation, principally in the A-band during activation. We propose that the prolonged existence of [Ca2+] gradients within the sarcomere reflects the relatively long period of Ca2+ release from the SR, the localization of Ca2+ binding sites and Ca2+ sinks remote from sites of release, and diffusion limitations within the sarcomere. The large [Ca2+] transient near the t-tubular/ junctional SR membranes is postulated to explain numerous features of excitation-contraction coupling in cardiac muscle.

Animals↗

PubMed2003

Activity-dependent trafficking and dynamic localization of zipcode binding protein 1 and beta-actin mRNA in dendrites and spines of hippocampal neurons.

RNA binding proteins may be important mediators of the activity-dependent transport of mRNAs to dendritic spines of activated synapses. We used fluorescence microscopy and digital imaging techniques applied to both fixed and live cultured hippocampal neurons to visualize the localization of the mRNA binding protein, zipcode binding protein 1 (ZBP1), and its dynamic movements in response to KCl-induced depolarization at high spatial and temporal resolution. With the use of immunofluorescence, image deconvolution, and three-dimensional reconstruction, ZBP1 was localized in the form of granules that were distributed in dendrites, spines, and subsynaptic sites. KCl depolarization increased the dendritic localization of ZBP1 that was not attributed to an increase in ZBP1 expression. Live cell imaging of single cells before and after perfusion of KCl revealed the rapid and directed efflux of ZBP1 granules from the cell body into dendrites in a proximo-distal gradient. High-speed imaging of enhanced green fluorescence protein-ZBP1 granules revealed rapid anterograde and retrograde movements in dendrites as well as dynamic movements in dendritic spines. A population of ZBP1 granules colocalized with beta-actin mRNA, and their spatial association in dendrites was increased by KCl depolarization. The NMDA receptor antagonist AP-5 impaired the dendritic localization of ZBP1 and beta-actin mRNA and inhibited the KCl-induced transport of ZBP1. The activity-dependent trafficking of ZBP1 and its dynamic movements within dendritic spines provide new evidence to implicate RNA binding proteins as regulators of mRNA transport to activated synapses in response to synaptic activity.

Actins↗

PubMed2003

Understanding peri-implant endosseous healing.

If dental implantology is an increasingly successful treatment modality, why should we still need to understand the mechanisms of peri-implant bone healing? Are there differences in cortical and trabecular healing? What does "poor quality" bone mean? What stages of healing are most important? How do calcium phosphate-coated implants accelerate healing? What is the mechanism of bone bonding? While there are still many aspects of peri-implant healing that need to be elucidated, it is now possible to deconvolute this biological reaction cascade, both phenomenologically and experimentally, into three distinct phases that mirror the evolution of bone into an exquisite tissue capable of regeneration. The first and most important healing phase, osteoconduction, relies on the recruitment and migration of osteogenic cells to the implant surface, through the residue of the peri-implant blood clot. Among the most important aspects of osteoconduction are the knock-on effects generated at the implant surface, by the initiation of platelet activation, which result in directed osteogenic cell migration. The second healing phase, de novo bone formation, results in a mineralized interfacial matrix equivalent to that seen in the cement line in natural bone tissue. These two healing phases, osteoconduction and de novo bone formation, result in contact osteogenesis and, given an appropriate implant surface, bone bonding. The third healing phase, bone remodeling, relies on slower processes and is not considered here. This discussion paper argues that it is the very success of dental implants that is driving their increased use in ever more challenging clinical situations and that many of the most important steps in the peri-implant healing cascade are profoundly influenced by implant surface microtopography. By understanding what is important in peri-implant bone healing, we are now able to answer all the questions listed above.

Bone Density↗

PubMed2001

GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve.

The present study was undertaken to establish in normal volunteers the alterations in beta-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol x kg(-1) x min(-1)) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 +/- 12.4 pmol x min(-1) x mM(-1) during the saline study to 241.7 +/- 36.6 pmol x min(-1) x mM(-1) during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta-cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

Adult↗

PubMed2001

Disruption of cytoskeletal integrity impairs Gi-mediated signaling due to displacement of Gi proteins.

beta1 integrins play a crucial role as cytoskeletal anchorage proteins. In this study, the coupling of the cytoskeleton and intracellular signaling pathways was investigated in beta1 integrin deficient (-/-) embryonic stem cells. Muscarinic inhibition of the L-type Ca2+ current (ICa) and activation of the acetylcholine-activated K+ current (IK,ACh) was found to be absent in beta1 integrin-/- cardiomyocytes. Conversely, beta adrenoceptor-mediated modulation of ICa was unaffected by the absence of beta1 integrins. This defect in muscarinic signaling was due to defective G protein coupling. This was supported by deconvolution microscopy, which demonstrated that Gi exhibited an atypical subcellular distribution in the beta1 integrin-/- cardiomyocytes. A critical role of the cytoskeleton was further demonstrated using cytochalasin D, which displaced Gi and impaired muscarinic signaling. We conclude that cytoskeletal integrity is required for correct localization and function of Gi-associated signaling microdomains.

Acetylcholine↗

PubMed2006

Spinning disk confocal microscopy of live, intraerythrocytic malarial parasites. 2. Altered vacuolar volume regulation in drug resistant malaria.

In the previous paper [Gligorijevic, B., et al. (2006) Biochemistry 45, pp 12400-12410], we reported on a customized Nipkow spinning disk confocal microscopy (SDCM) system and its initial application to DIC imaging of hemozoin within live, synchronized, intraerythrocytic Plasmodium falciparum malarial parasites. In this paper, we probe the biogenesis as well as the volume and pH regulation of the parasite digestive vacuole (DV), using the fluorescence imaging capabilities of the system. Several previous reports have suggested that mutant PfCRT protein, which causes chloroquine resistance (CQR) in P. falciparum, also causes increased acidification of the DV. Since pH and volume regulation are often linked, we wondered whether DV volume differences might be associated with CQR. Using fast acquisition of SDCM z stacks for synchronized parasites with OGd internalized into the DV, followed by iterative deconvolution using experimental point spread functions, we quantify the volume of the DV for live, intraerythrocytic HB3 (CQS), Dd2 (CQR via drug selection), GCO3 (CQS), and GCO3/C3(Dd2) (CQR via transfection with mutant pfcrt) malarial parasites as they develop within the human red blood cell. We find that relative to both CQS strains, both CQR strains show significantly increased DV volume as the organelle forms upon entry into the trophozoite stage of development and that this persists until the trophozoite-schizont boundary. A more acidic DV pH is found for CQR parasites as soon as the organelle forms and persists throughout the trophozoite stage. We probe DV volume and pH changes upon ATP depletion, hypo- and hypertonic shock, and rapid withdrawal of perfusate chloride. Taken together, these data suggest that the PfCRT mutations that cause CQR also lead to altered DV volume regulation.

Animals↗

PubMed2002

Visualization of replication initiation and elongation in Drosophila.

Chorion gene amplification in the ovaries of Drosophila melanogaster is a powerful system for the study of metazoan DNA replication in vivo. Using a combination of high-resolution confocal and deconvolution microscopy and quantitative realtime PCR, we found that initiation and elongation occur during separate developmental stages, thus permitting analysis of these two phases of replication in vivo. Bromodeoxyuridine, origin recognition complex, and the elongation factors minichromosome maintenance proteins (MCM)2-7 and proliferating cell nuclear antigen were precisely localized, and the DNA copy number along the third chromosome chorion amplicon was quantified during multiple developmental stages. These studies revealed that initiation takes place during stages 10B and 11 of egg chamber development, whereas only elongation of existing replication forks occurs during egg chamber stages 12 and 13. The ability to distinguish initiation from elongation makes this an outstanding model to decipher the roles of various replication factors during metazoan DNA replication. We utilized this system to demonstrate that the pre-replication complex component, double-parked protein/cell division cycle 10-dependent transcript 1, is not only necessary for proper MCM2-7 localization, but, unexpectedly, is present during elongation.

Animals↗

PubMed2005

Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men.

Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous luteinizing hormone (LH) pulses to stimulate Leydig cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective gonadotropin releasing hormone (GnRH)-receptor antagonist to yield four distinct strata of pulsatile LH release in each of 18 healthy men ages 23-72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-h interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the four stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship (r = -0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine systems.

Adult↗

PubMed2003

Lamellipodial motility in wounded endothelial cells exposed to physiologic flow is associated with different patterns of beta1-integrin and vinculin localization.

Integrins- and cytoskeletal-associated focal adhesion proteins may participate in the process of endothelial wound closure, but their relationship in these wounds and in the presence of shear forces has not been defined. The goal in this study was to test the hypotheses that (1) modulation of beta(1)-integrin in human coronary artery endothelial cells (HCAEC) would alter endothelial wound closure under shear stress, and (2) beta(1)-integrin association with vinculin would be necessary for mediating this closure. HCAEC monolayers were pre-conditioned to attain alignment by shearing at 12 dynes/cm(2) for 18 h in a parallel-plate flow chamber. Subsequently, they were divided into three groups: (a) control, (b) treated with anti-beta(1)-integrin adhesion blocking antibody, or (c) treated with anti-beta(1)-integrin adhesion promoting antibody. Next, the monolayers were wounded with a metal spatula, and re-sheared at 20 dynes/cm(2) or left static. Time-lapse imaging and deconvolution microscopy were then performed for 3 h. Immunocytochemistry for beta(1)-integrin expression and vinculin was performed on all wounded monolayers. Under shear stress, vinculin localized to the ends of stress fibers, while beta(1)-integrin took on an intracellular macroaggregate appearance. Treatment with anti-beta(1)-integrin adhesion blocking antibody enhanced wound closure, left the vinculin staining at the lamellipodial tips unchanged, but was associated with beta(1)-integrin staining at the lateral cell edges. Treatment with the anti-beta(1)-integrin adhesion promoting antibody retarded wound closure, increased vinculin staining at cell-cell junctions, and was associated with a fibrillar pattern of beta(1)-integrin staining. Modulation of beta(1)-integrin and changes in beta(1)-integrin and vinculin localization may further our understanding of laminar shear stress-induced endothelial repair in the coronary circulation.

Antibodies, Monoclonal↗

PubMed2000

Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction.

To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1,766 +/- 229 pmol/L x 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 +/- 0.2 v5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude (133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass.

Adult↗

PubMed2002

The representation of peripheral neural activity in the middle-latency evoked field of primary auditory cortex in humans(1).

Short sweeps with increasing instantaneous frequency (up-chirps) designed to compensate for the propagation delay along the human cochlea enhance the magnitude of wave V of the auditory brainstem responses, while time reversed sweeps (down-chirps) reduce the magnitude of wave V [Dau, T., Wegner, O., Mellert, V., Kollmeier, B., J. Acoust. Soc. Am. 107 (2000) 1530-1540]. This effect is due to synchronisation of frequency channels along the basilar membrane and it indicates that cochlear phase delays are preserved up to the input of the inferior colliculus. The present magnetoencephalography study was designed to investigate the influence of peripheral synchronisation on the activation in primary auditory cortex. Spatio-temporal source analysis of middle-latency auditory evoked fields (MAEFs) elicited by clicks and up- and down-chirps showed that up-chirps elicited significantly larger MAEF responses compared to clicks or down-chirps. Both N19m-P30m magnitude and its latency are influenced by peripheral cross-channel phase effects. Furthermore, deconvolution of the empirical source waveforms with spike probability functions simulated with a cochlear model indicated that the source waves for all stimulus conditions could be explained with the same unit-response function, i.e. a far field recorded cortical response of a very small cell assembly along the medio-lateral axis of Heschl's gyrus that receives input from a small number of excitatory fibres. The conclusion is that (i) phase delays between channels in the auditory pathway are preserved up to primary auditory cortex, and (ii) MAEFs can be described by a convolution of a unit-response function with the summary neural activity pattern of the auditory nerve.

Acoustic Stimulation↗