Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats

Background Alcoholism imposes a tremendous social and economic burden. There are relatively few pharmacological treatments for alcoholism, with only moderate efficacy, and there is considerable interest in identifying additional therapeutic options. Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions. Thus, positive SK modulators such as chlorzoxazone (CZX), a US Food and Drug Administration–approved centrally acting myorelaxant, might enhance SK function and decrease neuronal activity, resulting in reduced alcohol intake. Methods We examined whether CZX reduced alcohol consumption under two-bottle choice (20% alcohol and water) in rats with intermittent access to alcohol (IAA) or continuous access to alcohol (CAA). In addition, we used ex vivo electrophysiology to determine whether SK inhibition and activation can alter firing of nucleus accumbens (NAcb) core medium spiny neurons. Results Chlorzoxazone significantly and dose-dependently decreased alcohol but not water intake in IAA rats, with no effects in CAA rats. Chlorzoxazone also reduced alcohol preference in IAA but not CAA rats and reduced the tendency for rapid initial alcohol consumption in IAA rats. Chlorzoxazone reduction of IAA drinking was not explained by locomotor effects. Finally, NAcb core neurons ex vivo showed enhanced firing, reduced SK regulation of firing, and greater CZX inhibition of firing in IAA versus CAA rats. Conclusions The potent CZX-induced reduction of excessive IAA alcohol intake, with no effect on the more moderate intake in CAA rats, might reflect the greater CZX reduction in IAA NAcb core firing observed ex vivo. Thus, CZX could represent a novel and immediately accessible pharmacotherapeutic intervention for human alcoholism. Key Words: Alcohol intake; intermittent; neuro-adaptation; nucleus accumbens; SK potassium channel

Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Abstract Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

An empirical study of applying ISO 9001 elements in large size Indonesian contractors

The effective implementation of such an ISO 9001 Quality Management System (QMS) in construction companies requires a proper and full implementation of the system to allow companies to improve the way they operate, by this means increasing profitability and market share, producing innovative and sustainable construction products, or improving employee and customer satisfaction. In light of this, this paper discusses the current status of QMS implementation, particularly related to the twenty elements of ISO 9001 within the grade 7 (G-7) category of Indonesian construction companies. A survey was conducted involving 403 respondents from 77 companies, to solicit an evaluation of the current implementation levels of the ISO 9001 elements. The survey findings indicated that for a large percentage of the sector surveyed they had ‘not so fully implemented’ the elements. Scrutiny of the data had also indicated elements that are ‘minimally implemented’, whilst none of the elements fell in the category of ‘fully implemented’. Based on these findings, it is suggested that the G-7 contractors may need to fully commit to practicing control of customer-supplied product and statistical techniques in order to enhance an effective implementation of ISO 9001 elements for ensuring better quality performance. These two elements are recognized as the least implemented of the quality elements.

Size effects on tensile and fatigue behaviour of polycrystalline metal foils at the micrometer scale

Tensile and fatigue properties of as-rolled and annealed polycrystalline Cu foils with different thicknesses at the micrometer scale were investigated. Uniaxial tensile testing results showed that with decreasing foil thickness the uniform elongation decreases for both as-rolled and annealed foils, whereas the yield strength and ultimate tensile strength increase for as-rolled foils, but decrease for the annealed foils. For both the as-rolled or annealed foils, bending fatigue resistance decreases with decreasing the foil thickness. Deformation and fatigue damage behaviour of the free-standing foils were characterised as a function of foil thickness. In addition, the fatigue strength of various small-scale Cu foils was compared to understand they physical mechanisms of size effects on mechanical properties of the metallic material at micrometer scales.

A study on acoustic emission signal propagation of a small size multi-cylinder diesel engine

Acoustic emission has been found effective in offering earlier fault detection and improving identification capabilities of faults. However, the sensors are inherently uncalibrated. This paper presents a source to sensor paths calibration technique which can lead to diagnosis of faults in a small size multi-cylinder diesel engine. Preliminary analysis of the acoustic emission (AE) signals is outlined, including time domain, time-frequency domain, and the root mean square (RMS) energy. The results reveal how the RMS energy of a source propagates to the adjacent sensors. The findings lead to allocate the source and estimate its inferences to the adjacent sensor, and finally help to diagnose the small size diesel engines by minimising the crosstalk from multiple cylinders.

Corporate governance mechanisms and earnings management in transitional countries – evidence from Chinese listed firms

The objective of this thesis is to investigate whether the corporate governance practices adopted by Chinese listed firms are associated with the quality of earnings information. Based on a review of agency and institutional theory, this study develops hypotheses that predict the monitoring effectiveness of the board and the audit committee. Using a combination of univariate and multivariate analyses, the association between corporate governance mechanisms and earnings management are tested from 2004 to 2008. Through analysing the empirical results, a number of findings are summarised as below. First, board independence is weakened by the introduction of government officials as independent directors on the boards. Government officials acting as independent directors, claim that they meet the definition of independent director set by the regulation. However, they have some connection with the State, which is the controlling shareholder in listed SOEs affiliated companies. Consequently, the effect of the independent director’s expertise in constraining earnings management is mitigated as demonstrated by an insignificant association between board expertise and earnings management. An alternative explanation for the inefficiency of board independence may point to the pre-selection of independent directors by the powerful CEO. It is argued that a CEO can manipulate the board composition and choose the "desirable" independent directors to monitor themselves. Second, a number of internal mechanisms, such as board size, board activities, and the separation of the roles of the CEO and chair are found to be significantly associated with discretionary accruals. This result suggests that there are advantages in having a large and active board in the Chinese setting. This can offset the disadvantages associated with large boards, such as increased bureaucracy, and hence, increase the constraining effects of a large and resourceful board. Third, factor analysis identifies two factors: CEO power and board power. CEO power is the factor which consists of CEO duality and turnover, and board power is composed of board size and board activity. The results of CEO power show that if a Chinese listed company has CEO duality and turnover at the same time, it is more likely to have a high level of earnings management. The significant and negative relationship between board power and accruals indicate that large boards with frequent meetings can be associated with low level of earnings management. Overall, the factor analysis suggests that certain governance mechanisms complement each other to become more efficient monitors of opportunistic earnings management. A combination of board characteristics can increase the negative association with earnings management. Fourth, the insignificant results between audit committees and earnings management in Chinese listed firms suggests that the Chinese regulator should strengthen the audit committee functions. This thesis calls for listed firms to disclose more information on audit committee composition and activities, which can facilitate future research on the Chinese audit committee’s monitoring role. Fifth, the interactive results between State ownership and board characteristics show that dominant State ownership has a moderating effect on board monitoring power as the State totally controls 42% of the issued shares. The high percentage of State ownership makes it difficult for the non-controlling institutional shareholders to challenge the State’s dominant status. As a result, the association between non-controlling institutional ownership and earnings management is insignificant in most situations. Lastly, firms audited by the international Big4 have lower abnormal accruals than firms audited by domestic Chinese audit firms. In addition, the inverse U-shape relationship between audit tenure and earnings quality demonstrates the changing effects of audit quality after a certain period of appointment. Furthermore, this thesis finds that listing in Hong Kong Stock Exchanges can be an alternative governance mechanism to discipline Chinese firms to follow strict Hong Kong listing requirements. Management of Hong Kong listed companies are exposed to the scrutiny of international investors and Hong Kong regulators. This in turn reduces their chances of conducting self-interested earnings manipulation. This study is designed to fill the gap in governance literature in China that is related to earnings management. Previous research on corporate governance mechanisms and earnings management in China is not conclusive. The current research builds on previous literature and provides some meaningful implications for practitioners, regulators, academic, and international investors who have investment interests in a transitional country. The findings of this study contribute to corporate governance and earnings management literature in the context of the transitional economy of China. The use of alternative measures for earnings management yields similar results compared with the accruals models and produces additional findings.

What determines real-world meal size? Evidence for pre-meal planning

The customary approach to the study of meal size suggests that ‘events’ occurring during a meal lead to its termination. Recent research, however, suggests that a number of decisions are made before eating commences that may affect meal size. The present study sought to address three key research questions around meal size: the extent to which plate cleaning occurs; prevalence of pre-meal planning and its influence on meal size; and the effect of within-meal experiences, notably the development of satiation. To address these, a large-cohort internet-based questionnaire was developed. Results showed that plate cleaning occurred at 91% of meals, and was planned from the outset in 92% of these cases. A significant relationship between plate cleaning and meal planning was observed. Pre meal plans were resistant to modification over the course of the meal: only 18% of participants reported consumption that deviated from expected. By contrast, 28% reported continuing eating beyond satiation, and 57% stated that they could have eaten more at the end of the meal. Logistic regression confirmed pre-meal planning as the most important predictor of consumption. Together, our findings demonstrate the importance of meal planning as a key determinant of meal size and energy intake.

‘I could eat a horse’! : meal planning determines meal size

Evidence that our food environment can affect meal size is often taken to indicate a failure of ‘conscious control’. By contrast, our research suggests that ‘expected satiation’ (fullness that a food is expected to confer) predicts self-selected meal size. However, the role of meal planning as a determinant of actual meal size remains unresolved, as does the extent to which meal planning is commonplace outside the laboratory. Here, we quantified meal planning and its relation to meal size in a large-cohort study. Participants (N= 764; 25.6 yrs, 78% female) completed a questionnaire containing items relating to their last meal. The majority (91%) of meals were consumed in their entirety. Furthermore, in 92% of these cases the participants decided to consume the whole meal, even before it began. A second major objective was to explore the prospect that meal plans are revised based on within-meal experience (e.g., development of satiation). Only 8% of participants reported ‘unexpected’ satiation that caused them to consume less than anticipated. Moreover, at the end of the meal 57% indicated that they were not fully satiated, and 29% continued eating beyond comfortable satiation (often to avoid wasting food). This pattern was neither moderated by BMI nor dieting status, and was observed across meal types. Together, these data indicate that meals are often planned and that planning corresponds closely with amount consumed. By contrast, we find limited evidence for within-meal modification of these plans, suggesting that ‘pre-meal cognition’ is an important determinant of meal size in humans.

Body composition and appetite : fat-free mass (but not fat mass or BMI) is positively associated with self-determined meal size and daily energy intake in humans

The idea of body weight regulation implies that a biological mechanism exerts control over energy expenditure and food intake. This is a central tenet of energy homeostasis. However, the source and identity of the controlling mechanism have not been identified, although it is often presumed to be some long-acting signal related to body fat, such as leptin. Using a comprehensive experimental platform, we have investigated the relationship between biological and behavioural variables in two separate studies over a 12-week intervention period in obese adults (total n 92). All variables have been measured objectively and with a similar degree of scientific control and precision, including anthropometric factors, body composition, RMR and accumulative energy consumed at individual meals across the whole day. Results showed that meal size and daily energy intake (EI) were significantly correlated with fat-free mass (FFM, P values ,0·02–0·05) but not with fat mass (FM) or BMI (P values 0·11–0·45) (study 1, n 58). In study 2 (n 34), FFM (but not FM or BMI) predicted meal size and daily EI under two distinct dietary conditions (high-fat and low-fat). These data appear to indicate that, under these circumstances, some signal associated with lean mass (but not FM) exerts a determining effect over self-selected food consumption. This signal may be postulated to interact with a separate class of signals generated by FM. This finding may have implications for investigations of the molecular control of food intake and body weight and for the management of obesity.