Roles of calcium and IP3 in impaired colon contractility of rats following multiple organ dysfunction syndrome

The purpose of the present study was to explore changes in rat colon motility, and determine the roles of calcium and inositol (1,4,5)-triphosphate (IP3) in colon dysmotility induced by multiple organ dysfunction syndrome (MODS) caused by bacteria peritonitis. The number of stools, the contractility of the muscle strips and the length of smooth muscle cells (SMC) in the colon, the concentration of calcium and IP3 in SMC, and serum nitric oxide were measured. Number of stools, fecal weight, IP3 concentration in SMC and serum nitric oxide concentration were 0.77 ± 0.52 pellets, 2.51 ± 0.39 g, 4.14 ± 2.07 pmol/tube, and 113.95 ± 37.89 µmol/L, respectively, for the MODS group (N = 11) vs 1.54 ± 0.64 pellets, 4.32 ± 0.57 g, 8.19 ± 3.11 pmol/tube, and 37.42 ± 19.56 µmol/L for the control group (N = 20; P < 0.05). After treatment with 0.1 mM acetylcholine and 0.1 M potassium chloride, the maximum contraction stress of smooth muscle strips, the length of SMC and the changes of calcium concentration were 593 ± 81 and 458 ± 69 g/cm³, 48.1 ± 11.8 and 69.2 ± 15.7 µM, 250 ± 70 and 167 ± 48%, respectively, for the control group vs 321 ± 53 and 284 ± 56 g/cm³, 65.1 ± 18.5 and 87.2 ± 23.7 µM, 127 ± 35 and 112 ± 35% for the MODS group (P < 0.05). Thus, colon contractility was decreased in MODS, a result possibly related to reduced calcium concentration and IP3 in SMC.

Endothelium-dependent and -independent hepatic artery vasodilatation is not impaired in a canine model of liver ischemia-reperfusion injury

We investigated whether hepatic artery endothelium may be the earliest site of injury consequent to liver ischemia and reperfusion. Twenty-four heartworm-free mongrel dogs of either sex exposed to liver ischemia/reperfusion in vivo were randomized into four experimental groups (N = 6): a) control, sham-operated dogs, b) dogs subjected to 60 min of ischemia, c) dogs subjected to 30 min of ischemia and 60 min of reperfusion, and d) animals subjected to 45 min of ischemia and 120 min of reperfusion. The nitric oxide endothelium-dependent relaxation of hepatic artery rings contracted with prostaglandin F2a and exposed to increasing concentrations of acetylcholine, calcium ionophore A23187, sodium fluoride, phospholipase-C, poly-L-arginine, isoproterenol, and sodium nitroprusside was evaluated in organ-chamber experiments. Lipid peroxidation was estimated by malondialdehyde activity in liver tissue samples and by blood lactic dehydrogenase (LDH), serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) activities. No changes were observed in hepatic artery relaxation for any agonist tested. The group subjected to 45 min of ischemia and 120 min of reperfusion presented marked increases of serum aminotransferases (ALT = 2989 ± 1056 U/L and AST = 1268 ± 371 U/L; P < 0.01), LDH = 2887 ± 1213 IU/L; P < 0.01) and malondialdehyde in liver samples (0.360 ± 0.020 nmol/mgPT; P < 0.05). Under the experimental conditions utilized, no abnormal changes in hepatic arterial vasoreactivity were observed: endothelium-dependent and independent hepatic artery vasodilation were not impaired in this canine model of ischemia/reperfusion injury. In contrast to other vital organs and in the ischemia/reperfusion injury environment, dysfunction of the main artery endothelium is not the first site of reperfusion injury.

Transplantation and survival of mouse inner ear progenitor/stem cells in the organ of Corti after cochleostomy of hearing-impaired guinea pigs: preliminary results

In mammals, damage to sensory receptor cells (hair cells) of the inner ear results in permanent sensorineural hearing loss. Here, we investigated whether postnatal mouse inner ear progenitor/stem cells (mIESCs) are viable after transplantation into the basal turns of neomycin-injured guinea pig cochleas. We also examined the effects of mIESC transplantation on auditory functions. Eight adult female Cavia porcellus guinea pigs (250-350g) were deafened by intratympanic neomycin delivery. After 7 days, the animals were randomly divided in two groups. The study group (n=4) received transplantation of LacZ-positive mIESCs in culture medium into the scala tympani. The control group (n=4) received culture medium only. At 2 weeks after transplantation, functional analyses were performed by auditory brainstem response measurement, and the animals were sacrificed. The presence of mIESCs was evaluated by immunohistochemistry of sections of the cochlea from the study group. Non-parametric tests were used for statistical analysis of the data. Intratympanic neomycin delivery damaged hair cells and increased auditory thresholds prior to cell transplantation. There were no significant differences between auditory brainstem thresholds before and after transplantation in individual guinea pigs. Some mIESCs were observed in all scalae of the basal turns of the injured cochleas, and a proportion of these cells expressed the hair cell marker myosin VIIa. Some transplanted mIESCs engrafted in the cochlear basilar membrane. Our study demonstrates that transplanted cells survived and engrafted in the organ of Corti after cochleostomy.

An Electrophysiological Investigation into the Role of Cognitive Control in the Attentional Blink

Accuracy at reporting a second-target (T2) is reduced if it is presented within approximately 500 ms of the first target (T1) – an attentional blink (AB). Early models explained the AB in terms of attentional limitations creating a processing bottleneck such that T2 processing would be impaired while T1 processing was ongoing. Theoretical models of the AB have more recently been expanded to include the role of cognitive control. In this dissertation I propose that cognitive control, defined as the optimization of information processing in order to achieve goals, is maladapted to the dual-task conditions of the AB task in that cognitive control optimizes the T1 goal, due to its temporal proximity, at the cost of T2. I start with the concept that the role of cognitive control is to serve goals, and that how goals are conceived of and the degree of motivation associated with those goals will determine whether cognitive control will create the condition that cause the AB. This leads to the hypothesis that electrophysiological measures of cognitive control and the degree of attentional investment resulting from cognitive control modulate the AB and explain individual differences in the AB. In a series of four studies feedback-related N2 amplitude, (reflecting individual differences in the strength of cognitive control), and event-related and resting alpha frequency oscillatory activity (reflecting degree of attentional investment), are used to explain both intra- and inter-individual variability in performance on the AB task. Results supported the hypothesis that stronger cognitive control and greater attentional investment are associated with larger AB magnitudes. Attentional investment, as measured by alpha frequency oscillations, and cognitive control, as measured by the feedback-related N2, did not relate to each other as hypothesized. It is proposed that instead of a measure of attentional investment alone, alpha frequency oscillatory activity actually reflects control over information processing over time, in other words the timing of attention. With this conceptualization, various aspects of cognitive control, either related to the management of goals (feedback-related N2) or the management of attention over time to meet goals, explain variability in the AB.

The reproductive response of rams to thyroidectomy: mediation by impaired inhibin feedback rather than a change in LH pulsatility

A series of experiments was conducted to examine the mechanism by which removal of the thyroid glands in seasonally suppressed rams brings about rapid testicular growth. In the first experiment, thyroidectomy at the nadir of the testicular cycle (late winter) initiated testis growth without any detectable change in the extent of spermatogenesis compared with sham-operated controls. The serum concentration of FSH, but not LH, was also markedly increased by thyroidectomy. In the second experiment, serum FSH concentration was again increased by thyroidectomy in late winter but there was no effect of thyroidectomy on LH concentration, LH pulses (measured in frequent blood samples) or testosterone concentration. Furthermore, there was no evidence of a change in central dopaminergic inhibition of GnRH, as measured by the pulsatile LH response to an i.m. injection of the dopaminergic D-2 agonist bromocriptine or antagonist sulpiride. The rapid increase in FSH concentration occurred despite a markedly increased serum inhibin A concentration in thyroidectomized rams. Therefore, the efficacy of inhibin feedback was examined by testing the FSH-suppressive effect of an inhibin preparation (5 ml charcoal-stripped bovine follicular fluid i.v.) in long-term thyroidectomized and thyroid intact castrated rams. Bovine follicular fluid suppressed FSH concentrations in control rams as expected but in marked contrast, was completely without effect in thyroidectomized animals. In castrated rams, the FSH concentration was only marginally increased by thyroidectomy, indicating that there is a major component of the mediation of the effects of thyroidectomy that is testicular in origin. It was concluded that a reduction in the ability of endogenous inhibin to inhibit FSH release at the pituitary, rather than a hypothalamic mechanism, is the primary cause of the stimulation of testis growth by thyroidectomy.

The use of cursor measures for motion-impaired computer users

“Point and click” interactions remain one of the key features of graphical user interfaces (GUIs). People with motion-impairments, however, can often have difficulty with accurate control of standard pointing devices. This paper discusses work that aims to reveal the nature of these difficulties through analyses that consider the cursor’s path of movement. A range of cursor measures was applied, and a number of them were found to be significant in capturing the differences between able-bodied users and motion-impaired users, as well as the differences between a haptic force feedback condition and a control condition. The cursor measures found in the literature, however, do not make up a comprehensive list, but provide a starting point for analysing cursor movements more completely. Six new cursor characteristics for motion-impaired users are introduced to capture aspects of cursor movement different from those already proposed.

Using cursor measures to determine appropriate computer input assistance for motion-impaired users

People with motion-impairments can often have difficulty with accurate control of standard pointing devices for computer input. The nature of the difficulties may vary, so to be most effective, methods of assisting cursor control must be suited to each user's needs. The work presented here involves a study of cursor trajectories as a means of assessing the requirements of motion-impaired computer users. A new cursor characteristic is proposed that attempts to capture difficulties with moving the cursor in a smooth trajectory. A study was conducted to see if haptic tunnels could improve performance in "point and click" tasks. Results indicate that the tunnels reduced times to target for those users identified by the new characteristic as having the most difficulty moving in a smooth trajectory. This suggests that cursor characteristics have potential applications in performing assessments of a user's cursor control capabilities which can then be used to determine appropriate methods of assistance.

Wernicke’s aphasia reflects a combination of acoustic-phonological and semantic control deficits: A case-series comparison of Wernicke’s aphasia, semantic dementia and semantic aphasia

Wernicke’s aphasia (WA) is the classical neurological model of comprehension impairment and, as a result, the posterior temporal lobe is assumed to be critical to semantic cognition. This conclusion is potentially confused by (a) the existence of patient groups with semantic impairment following damage to other brain regions (semantic dementia and semantic aphasia) and (b) an ongoing debate about the underlying causes of comprehension impairment in WA. By directly comparing these three patient groups for the first time, we demonstrate that the comprehension impairment in Wernicke’s aphasia is best accounted for by dual deficits in acoustic-phonological analysis (associated with pSTG) and semantic cognition (associated with pMTG and angular gyrus). The WA group were impaired on both nonverbal and verbal comprehension assessments consistent with a generalised semantic impairment. This semantic deficit was most similar in nature to that of the semantic aphasia group suggestive of a disruption to semantic control processes. In addition, only the WA group showed a strong effect of input modality on comprehension, with accuracy decreasing considerably as acoustic-phonological requirements increased. These results deviate from traditional accounts which emphasise a single impairment and, instead, implicate two deficits underlying the comprehension disorder in WA.

Revealing and quantifying the impaired phonological analysis underpinning impaired comprehension in Wernicke’s aphasia

Wernicke’s aphasia is a condition which results in severely disrupted language comprehension following a lesion to the left temporo-parietal region. A phonological analysis deficit has traditionally been held to be at the root of the comprehension impairment in WA, a view consistent with current functional neuroimaging which finds areas in the superior temporal cortex responsive to phonological stimuli. However behavioural evidence to support the link between a phonological analysis deficit and auditory comprehension has not been yet shown. This study extends seminal work by Blumstein et al. (1977) to investigate the relationship between acoustic-phonological perception, measured through phonological discrimination, and auditory comprehension in a case series of Wernicke’s aphasia participants. A novel adaptive phonological discrimination task was used to obtain reliable thresholds of the phonological perceptual distance required between nonwords before they could be discriminated. Wernicke’s aphasia participants showed significantly elevated thresholds compared to age and hearing matched control participants. Acoustic-phonological thresholds correlated strongly with auditory comprehension abilities in Wernicke’s aphasia. In contrast, nonverbal semantic skills showed no relationship with auditory comprehension. The results are evaluated in the context of recent neurobiological models of language and suggest that impaired acoustic-phonological perception underlies the comprehension impairment in Wernicke’s aphasia and favour models of language which propose a leftward asymmetry in phonological analysis.

Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2

The E3 ubiquitin ligase c-Cbl ubiquitinates the G protein-coupled receptor protease-activated receptor 2 (PAR(2)), which is required for postendocytic sorting of activated receptors to lysosomes, where degradation terminates signaling. The mechanisms of PAR(2) deubiquitination and its importance in trafficking and signaling of endocytosed PAR(2) are unknown. We report that receptor deubiquitination occurs between early endosomes and lysosomes and involves the endosomal deubiquitinating proteases AMSH and UBPY. Expression of the catalytically inactive mutants, AMSH(D348A) and UBPY(C786S), caused an increase in PAR(2) ubiquitination and trapped the receptor in early endosomes, thereby preventing lysosomal trafficking and degradation. Small interfering RNA knockdown of AMSH or UBPY also impaired deubiquitination, lysosomal trafficking, and degradation of PAR(2). Trapping PAR(2) in endosomes through expression of AMSH(D348A) or UBPY(C786S) did not prolong the association of PAR(2) with beta-arrestin2 or the duration of PAR(2)-induced ERK2 activation. Thus, AMSH and UBPY are essential for trafficking and down-regulation of PAR(2) but not for regulating PAR(2) dissociation from beta-arrestin2 or PAR(2)-mediated ERK2 activation.

Nonlocal office investors: anchored by their markets and impaired by their distance

Nonlocal investors purchase and sell investment property in a distant metropolitan area. In this study, we identify capital value underperformance for nonlocal investors on both sides of the transaction, when they purchase and when they sell. The commercial real estate transactions data include a national sample of office property occurring in more than 100 U.S. markets. Using propensity-score matched sample to control for selection bias, we find that nonlocal investors overpay on the purchase by an estimated 13.8 % and sell at an estimated 7 % discount. These disadvantages relative to local investors expand with the geographic distance separating investor and asset. Nonlocal investors fundamentally overvalue similar assets sold to each other relative to assets transacted between locals, and are less patient as sellers. The positive bias in overpayment is directly tied to office rent differentials between the asset and investor markets.

Distraction control processes in free recall: benefits and costs to performance

How is semantic memory influenced by individual differences under conditions of distraction? This question was addressed by observing how visual target words—drawn from a single category—were recalled whilst ignoring spoken distracter words that were either members of the same, or members of a different (single) category. Working memory capacity (WMC) was related to disruption only with synchronous, not asynchronous, presentation and distraction was greater when the words were presented synchronously. Subsequent experiments found greater negative priming of distracters amongst individuals with higher WMC but this may be dependent on targets and distracters being comparable category exemplars. With less dominant category members as distracters, target recall was impaired – relative to control – only amongst individuals with low WMC. The results highlight the role of cognitive control resources in target-distracter selection and the individual-specific cost implications of such cognitive control.

Imbalanced functional link between executive control network and reward network explain the online-game seeking behaviors in Internet gaming disorder

Literatures have shown that Internet gaming disorder (IGD) subjects show impaired executive control and enhanced reward sensitivities than healthy controls. However, how these two networks jointly affect the valuation process and drive IGD subjects' online-game-seeking behaviors remains unknown. Thirty-five IGD and 36 healthy controls underwent a resting-states scan in the MRI scanner. Functional connectivity (FC) was examined within control and reward network seeds regions, respectively. Nucleus accumbens (NAcc) was selected as the node to find the interactions between these two networks. IGD subjects show decreased FC in the executive control network and increased FC in the reward network when comparing with the healthy controls. When examining the correlations between the NAcc and the executive control/reward networks, the link between the NAcc - executive control network is negatively related with the link between NAcc - reward network. The changes (decrease/increase) in IGD subjects' brain synchrony in control/reward networks suggest the inefficient/overly processing within neural circuitry underlying these processes. The inverse proportion between control network and reward network in IGD suggest that impairments in executive control lead to inefficient inhibition of enhanced cravings to excessive online game playing. This might shed light on the mechanistic understanding of IGD.

Microalbuminuria is associated with impaired arterial and venous endothelium-dependent vasodilation in patients with Type 2 diabetes

Background: Microalbuminuria in Type 2 diabetes is associated with arterial endothelial dysfunction, but the venous bed was never evaluated. Aim: To study the endothelial function in the venous and arterial bed in patients with Type 2 diabetes with normoalbuminuria or microalbuminuria. Material and methods: We evaluated 28 patients with Type 2 diabetes, glycated hemoglobin (Hbak(1c)) <7.5%, who were classified as normo- (albuminuria <30 mg/24 h; no.=16) or microalbuminuric (albuminuria 30-300 mg/24 h; no.=12). Venous and arterial endothelial function were assessed by the dorsal hand vein technique (venodilation by acetylcholine) and brachial artery flow-mediated vasodilation, respectively. Results: Patients were normotensive (systolic arterial pressure: 131.1 +/- 10.6 mmHg) and on good metabolic control (HbA(1c): 6.6 +/- 0.6%). Microalbuminuric patients presented impaired venous (32.9 +/- 17.4 vs 59.3 +/- 26.5%; p=0.004) and arterial vasodilation (1.8 +/- 0.9 vs 5.1 +/- 2.4; p<0.001), as compared to normoalbuminuric patients. There was a negative correlation between acetylcholine-induced venodilation and albuminuria (r=-0.62; p<0.001) and HbA(1c) (r=-0.41; p=0.032). The same was observed between flow-mediated arterial vasodilation and albuminuria (r=-0.49; p=0.007) and HbA(1c) (r=-0.44; p=0.019). Venous and arterial vasodilation was positively correlated (r=0.50; p=0.007). Conclusions: Both venous and arterial endothelial function are impaired in Type 2 microalbuminuric diabetics, in spite of good metabolic control, suggesting that other factors are involved in its pathogenesis. (J. Endocrinol. Invest. 33: 696-700, 2010) (C) 2010, Editrice Kurtis

EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats

Objectives: Early weaning (EW) increases proliferation of the gastric epithelium in parallel with higher expression of transforming growth factor alpha and its receptor epidermal growth factor receptor (EGFR). The primary objective of the present study was to examine involvement of EGFR signalling in regulating mucosal cell proliferation during the early weaning period. Materials and methods: Fifteen-day-old rats were split into two groups: suckling (control) and EW, in which pups were separated from the dam. Animals were killed daily until the 18th day, 3 days after onset of treatment. To investigate the role of EGFR in proliferation control, EW pups were injected with AG1478, an EGFR inhibitor; signalling molecules, proliferative indices and cell cycle-related proteins were evaluated. Results: EW increased ERK1/2 and Src phosphorylation at 17 days, but p-Akt levels were unchanged. Moreover, at 17 days, AG1478 administration impaired ERK phosphorylation, whereas p-Src and p-Akt were not altered. AG1478 treatment reduced mitotic and DNA synthesis indices, which were determined on HE-stained and BrdU-labelled sections. Finally, AG1478 injection decreased p21 levels in the gastric mucosa at 17 days, while no changes were detected in p27, cyclin E, CDK2, cyclin D1 and CDK4 concentrations. Conclusions: EGFR is part of the mechanism that regulates cell proliferation in rat gastric mucosa during early weaning. We suggest that such responses might depend on activation of MAPK and/or Src signalling pathways and regulation of p21 levels.