Time-dependent tegumental surface changes in juvenile Fasciola gigantica in response to triclabendazole treatment in goat

Triclabendazole (TCBZ), the anthelmintic drug active against both mature and immature liver flukes, was used to investigate the effect of in vivo treatment on the tegumental surface of juvenile Fasciola gigantica. Five goats were infected with 150 F. gigantica metacercariae each by oral gavage. Four of them were treated with single dose of TCBZ at 10mg/kg at four weeks post-infection. They were euthanized at 0 (untreated), 24, 48, 72 and 96h post treatment. Juvenile flukes were manually retrieved from the goat livers and processed for scanning electron microscopy. In control flukes, the anterior region was adorned with sharply pointed spines projecting away from the surface, while in the posterior region, spines become shorter and narrower, loosing serration and with the appearance of distinct furrows and papillae. The dorsal surface retained the same pattern of surface architecture similar to that of ventral surface. Flukes obtained from 24h post-treatment did not show any apparent change and were still very active. However, there were limited movements and some blebbing, swelling, deposition of tegumental secretions and some flattening displayed by the flukes of 48h post-treatment. All the worms were found dead 72h post-treatment and showed advanced level of tegumental disruptions, consisting of severe distortion of spines, sloughing off the tegument to expose the basal lamina, formation of pores and isolated patches of lesions. By 96h post-treatment, the disruption was extremely severe and the tegument was completely sheared off causing deeper lesions that exposed the underlying musculature. The disruption was more severe at posterior than anterior region and on ventral than dorsal surface. The present study further establishes the time-course of TCBZ action in vivo with 100% efficacy against the juvenile tropical liver fluke.

Time to Left Ventricular Reverse Remodeling after Cardiac Resynchronization Therapy: Better Late than Never

INTRODUCTION: Left ventricular reverse remodeling (LVRR), defined as reduction of end-diastolic and end-systolic dimensions and improvement of ejection fraction, is associated with the prognostic implications of cardiac resynchronization therapy (CRT). The time course of LVRR remains poorly characterized. Nevertheless, it has been suggested that it occurs ≤6 months after CRT. OBJECTIVE: To characterize the long-term echocardiographic and clinical evolution of patients with LVRR occurring >6 months after CRT and to identify predictors of a delayed LVRR response. METHODS: A total of 127 consecutive patients after successful CRT implantation were divided into three groups according to LVRR response: Group A, 19 patients (15%) with LVRR after >6 months (late LVRR); Group B, 58 patients (46%) with LVRR before 6 months (early LVRR); and Group C, 50 patients (39%) without LVRR during follow-up (no LVRR). RESULTS: The late LVRR group was older, more often had ischemic etiology and fewer patients were in NYHA class ≤II. Overall, group A presented LVRR between group B and C. This was also the case with the percentage of clinical response (68.4% vs. 94.8% vs. 38.3%, respectively, p<0.001), and hospital readmissions due to decompensated heart failure (31.6% vs. 12.1% vs. 57.1%, respectively, p<0.001). Ischemic etiology (OR 0.044; p=0.013) and NYHA functional class

Analysis of time-related metabolic fluctuations induced by ethionine in the rat

The time-course of metabolic events following response to a model hepatotoxin ethionine (800 mg/kg) was investigated over a 7 day period in rats using high-resolution (1)H NMR spectroscopic analysis of urine and multivariate statistics. Complementary information was obtained by multivariate analysis of (1)H MAS NMR spectra of intact liver and by conventional histopathology and clinical chemistry of blood plasma. (1)H MAS NMR spectra of liver showed toxin-induced lipidosis 24 h postdose consistent with the steatosis observed by histopathology, while hypertaurinuria was suggestive of liver injury. Early biochemical changes in urine included elevation of guanidinoacetate, suggesting impaired methylation reactions. Urinary increases in 5-oxoproline and glycine suggested disruption of the gamma-glutamyl cycle. Signs of ATP depletion together with impairment of the energy metabolism were given from the decreased levels in tricarboxylic acid cycle intermediates, the appearance of ketone bodies in urine, the depletion of hepatic glucose and glycogen, and also hypoglycemia. The observed increase in nicotinuric acid in urine could be an indication of an increase in NAD catabolism, a possible consequence of ATP depletion. Effects on the gut microbiota were suggested by the observed urinary reductions in the microbial metabolites 3-/4-hydroxyphenyl propionic acid, dimethylamine, and tryptamine. At later stages of toxicity, there was evidence of kidney damage, as indicated by the tubular damage observed by histopathology, supported by increased urinary excretion of lactic acid, amino acids, and glucose. These studies have given new insights into mechanisms of ethionine-induced toxicity and show the value of multisystem level data integration in the understanding of experimental models of toxicity or disease.

Time-dependent expression of annexin 1 in a model of chronic granulomatous inflammation

Objective and design: To determine the expression pattern and distribution of the glucocorticoid-inducible protein annexin 1 (ANXA1) in a murine model of chronic granulomatous inflammation.Materials or subjects: TO Mouse.Treatment: Chronic granulomatous inflammation was induced by injecting into dorsal sub-cutaneous air-pouches in mice, a mixture of croton oil and Freund's complete adjuvant (CO/FCA).Methods: Western and northern analysis, corticosterone assay, and immunohistochemistry. Statistical analysis was performed using ANOVA followed by Tukey's pair-wise comparisons or Dunnett's multiple comparisons.Results: ANXA1 protein levels changed significantly throughout the 4-week time course, with an initial peak at day 7 and a later elevation at 28 days. ANXA1 mRNA levels peaked at days 1 and 3, with a significant decline at day 7 followed by an upward trend to day 28. Plasma corticosterone measurements taken throughout the time course revealed an increase from 14 days onward, suggesting that corticosterone does not influence ANXA1 expression during the initial stages of the model. Immunogold staining revealed that ANXA1 expression in the inflamed tissue was mainly in extravasated neutrophils, with intact protein (37 kDa) being predominantly observed on the cell membrane.Conclusions: the pattern of ANXA1 expression indicates that infiltrated neutrophils are responsible for the majority of ANXA1 present both at early and later stages of this model of granulomatous inflammation.

Multiple time scales of temporal response in pyramidal and fast spiking cortical neurons

Neural dynamic processes correlated over several time scales are found in vivo, in stimulus-evoked as well as spontaneous activity, and are thought to affect the way sensory stimulation is processed. Despite their potential computational consequences, a systematic description of the presence of multiple time scales in single cortical neurons is lacking. In this study, we injected fast spiking and pyramidal (PYR) neurons in vitro with long-lasting episodes of step-like and noisy, in-vivo-like current. Several processes shaped the time course of the instantaneous spike frequency, which could be reduced to a small number (1-4) of phenomenological mechanisms, either reducing (adapting) or increasing (facilitating) the neuron's firing rate over time. The different adaptation/facilitation processes cover a wide range of time scales, ranging from initial adaptation (<10 ms, PYR neurons only), to fast adaptation (<300 ms), early facilitation (0.5-1 s, PYR only), and slow (or late) adaptation (order of seconds). These processes are characterized by broad distributions of their magnitudes and time constants across cells, showing that multiple time scales are at play in cortical neurons, even in response to stationary stimuli and in the presence of input fluctuations. These processes might be part of a cascade of processes responsible for the power-law behavior of adaptation observed in several preparations, and may have far-reaching computational consequences that have been recently described.

Proliferative kidney disease in rainbow trout: time- and temperature-related renal pathology and parasite distribution

Proliferative kidney disease is a parasitic infection of salmonid fishes caused by Tetracapsuloides bryosalmonae. The main target organ of the parasite in the fish is the kidney. To investigate the influence of water temperature on the disease in fish, rainbow trout Oncorhynchus mykiss infected with T bryosalmonae were kept at 12 degrees C and 18 degrees C. The number of parasites, the type and degree of lesions in the kidney and the mortality rate was evaluated from infection until full development of disease. While mortality stayed low at 12 degrees C, it reached 77% at 18 degrees C. At 12 degrees C, pathological lesions were dominated by a multifocal proliferative and granulomatous interstitial nephritis. This was accompanied by low numbers of T. bryosalmonae, mainly located in the interstitial lesions. With progression of the disease, small numbers of parasites appeared in the excretory tubuli, and parasite DNA was detected in the urine. Parasite degeneration in the interstitium was observed at late stages of the disease. At 18 degrees C, pathological lesions in kidneys were more severe and more widely distributed, and accompanied by significantly higher parasite numbers. Distribution of parasites in the renal compartments, onset of parasite degeneration and time course of appearance of parasite DNA in urine were not clearly different from the 12 degrees C group. These findings indicate that higher mortality at 18 degrees C compared to 12 degrees C is associated with an enhanced severity of renal pathology and increased parasite numbers.

Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

OBJECTIVES We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs). BACKGROUND The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an "all-or-nothing" response but may modify number and duration of AF episodes. METHODS In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up. RESULTS In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 +/- 37% before ablation, 26 +/- 41% directly after ablation, and 10 +/- 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions. CONCLUSIONS The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.

Studying changes in life circumstances and personality: It's about time

Most theories of personality development posit that changes in life circumstances (e.g. due to major life events) can lead to changes in personality, but few studies have examined the exact time course of these changes. In this article, we argue that time needs to be considered explicitly in theories and empirical studies on personality development. We discuss six notions on the role of time in personality development. First, people can differ before the event. Second, change can be non-linear and discontinuous. Third, change can be reversible. Fourth, change can occur before the event. Fifth, control groups are needed to disentangle age-related and event-related changes. Sixth, we need to move beyond examining single major life events and study the effects of non-normative events, non-events, multiple events, and minor events on personality. We conclude by summarizing the methodological and theoretical implications of these notions.

Transcriptional profiles of cytokine/chemokine factors of immune cell-homing to the parasitic lesions: a comprehensive one-year course study in the liver of E. multilocularis-infected mice.

Pathogenesis of chronically developing alveolar echinococcosis (AE) is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis) in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12α, IFN-γ and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-β. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to complement the only parasitostatic effect of benzimidazoles in AE.

Real-time detection of the surface delivery of newly synthesized membrane proteins.

Newly synthesized membrane proteins travel from the Golgi complex to the cell surface in transport vesicles. We have exploited the ion channel properties of the nicotinic acetylcholine receptor (AChR) to observe in real time the constitutive delivery of newly synthesized AChR proteins to the plasma membrane in cultured muscle cells. Whole-cell voltage clamp was employed to monitor the current fluctuations induced by carbamylcholine upon the insertion into the plasma membrane of newly synthesized AChRs, following release from a 20 degrees C temperature block. We find that the transit of vesicles to the cell surface occurs within a few minutes after release of the block. The time course of electrical signals is consistent with many of the fusion events being instantaneous, although some appear to reveal the flickering of a fusion pore. AChR-containing vesicles can fuse individually or as conglomerates. Intracellular application of guanosine 5'-[gamma-thio]triphosphate inhibits the constitutive traffic of AChRs in most cells. Individual exocytotic vesicles carry between 10 and 300 AChR molecules, suggesting that AChRs may be packed extremely densely.

Spatially localized distortions of event time

A fundamental question about the perception of time is whether the neural mechanisms underlying temporal judgements are universal and centralized in the brain or modality specific and distributed []. Time perception has traditionally been thought to be entirely dissociated from spatial vision. Here we show that the apparent duration of a dynamic stimulus can be manipulated in a local region of visual space by adapting to oscillatory motion or flicker. This implicates spatially localized temporal mechanisms in duration perception. We do not see concomitant changes in the time of onset or offset of the test patterns, demonstrating a direct local effect on duration perception rather than an indirect effect on the time course of neural processing. The effects of adaptation on duration perception can also be dissociated from motion or flicker perception per se. Although 20 Hz adaptation reduces both the apparent temporal frequency and duration of a 10 Hz test stimulus, 5 Hz adaptation increases apparent temporal frequency but has little effect on duration perception. We conclude that there is a peripheral, spatially localized, essentially visual component involved in sensing the duration of visual events.

Time-dependent evolution of tissue markers by MALDI-MS imaging

We have used MALDI-MS imaging (MALDI-MSI) to monitor the time dependent appearance and loss of signals when tissue slices are brought rapidly to room temperature for short to medium periods of time. Sections from mouse brain were cut in a cryostat microtome, placed on a MALDI target and allowed to warm to room temperature for 30 s to 3 h. Sections were then refrozen, fixed by ethanol treatment and analysed by MALDI-MSI. The intensity of a range of markers were seen to vary across the time course, both increasing and decreasing, with the intensity of some markers changing significantly within 30 s and markers also showed tissue location specific evolution. The markers resulting from this autolysis were compared directly to those that evolved in a comparable 16 h on-tissue trypsin digest, and the markers that evolved in the two studies were seen to be substantially different. These changes offer an important additional level of location-dependent information for mapping changes and seeking disease-dependent biomarkers in the tissue. They also indicate that considerable care is required to allow comparison of biomarkers between MALDI-MSI experiments and also has implications for the standard practice of thaw-mounting multiple tissue sections onto MALDI-MS targets.

Chlamydial infection and spatial ascension of the female genital tract : a novel hybrid cellular automata and continuum mathematical model

Sexually transmitted chlamydial infection initially establishes in the endocervix in females, but if the infection ascends the genital tract, significant disease, including infertility, can result. Many of the mechanisms associated with chlamydial infection kinetics and disease ascension are unknown. We attempt to elucidate some of these processes by developing a novel mathematical model, using a cellular automata–partial differential equation model. We matched our model outputs to experimental data of chlamydial infection of the guinea-pig cervix and carried out sensitivity analyses to determine the relative influence of model parameters. We found that the rate of recruitment and action of innate immune cells to clear extracellular chlamydial particles and the rate of passive movement of chlamydial particles are the dominant factors in determining the early course of infection, magnitude of the peak chlamydial time course and the time of the peak. The rate of passive movement was found to be the most important factor in determining whether infection would ascend to the upper genital tract. This study highlights the importance of early innate immunity in the control of chlamydial infection and the significance of motility-diffusive properties and the adaptive immune response in the magnitude of infection and in its ascension.

An exploration of varieties of visual attention : ERP findings

A set of five tasks was designed to examine dynamic aspects of visual attention: selective attention to color, selective attention to pattern, dividing and switching attention between color and pattern, and selective attention to pattern with changing target. These varieties of visual attention were examined using the same set of stimuli under different instruction sets; thus differences between tasks cannot be attributed to differences in the perceptual features of the stimuli. ERP data are presented for each of these tasks. A within-task analysis of different stimulus types varying in similarity to the attended target feature revealed that an early frontal selection positivity (FSP) was evident in selective attention tasks, regardless of whether color was the attended feature. The scalp distribution of a later posterior selection negativity (SN) was affected by whether the attended feature was color or pattern. The SN was largely unaffected by dividing attention across color and pattern. A large widespread positivity was evident in most conditions, consisting of at least three subcomponents which were differentially affected by the attention conditions. These findings are discussed in relation to prior research and the time course of visual attention processes in the brain.

Motor conflict in Stroop tasks : direct evidence from single-trial electro-myography and electro-encephalography

Several brain imaging studies have assumed that response conflict is present in Stroop tasks. However, this has not been demonstrated directly. We examined the time-course of stimulus and response conflict resolution in a numerical Stroop task by combining single-trial electro-myography (EMG) and event-related brain potentials (ERP). EMG enabled the direct tracking of response conflict and the peak latency of the P300 ERP wave was used to index stimulus conflict. In correctly responded trials of the incongruent condition EMG detected robust incorrect response hand activation which appeared consistently in single trials. In 50–80% of the trials correct and incorrect response hand activation coincided temporally, while in 20–50% of the trials incorrect hand activation preceded correct hand activation. EMG data provides robust direct evidence for response conflict. However, congruency effects also appeared in the peak latency of the P300 wave which suggests that stimulus conflict also played a role in the Stroop paradigm. Findings are explained by the continuous flow model of information processing: Partially processed task-irrelevant stimulus information can result in stimulus conflict and can prepare incorrect response activity. A robust congruency effect appeared in the amplitude of incongruent vs. congruent ERPs between 330–400 ms, this effect may be related to the activity of the anterior cingulate cortex.