Quantification of axonal loss in Alzheimer’s disease: an image analysis study

The density of axons in the optic nerve, olfactory tract and corpus callosum was quantified in non-demented elderly subjects and in Alzheimer’s disease (AD) using an image analysis system. In each fibre tract, there was significant reduction in the density of axons in AD compared with non-demented subjects, the greatest reductions being observed in the olfactory tract and corpus callosum. Axonal loss in the optic nerve and olfactory tract was mainly of axons with smaller myelinated cross-sectional areas. In the corpus callosum, a reduction in the number of ‘thin’ and ‘thick’ fibres was observed in AD, but there was a proportionally greater loss of the ‘thick’ fibres. The data suggest significant degeneration of white matter fibre tracts in AD involving the smaller axons in the two sensory nerves and both large and small axons in the corpus callosum. Loss of axons in AD could reflect an associated white matter disorder and/or be secondary to neuronal degeneration.

Attenuation of proteasome-induced proteolysis in skeletal muscle by beta-hydroxy-beta-methylbutyrate in cancer-induced muscle loss

Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) on the reduction of body weight loss and protein degradation in the MAC16 model of cancer-induced weight loss has been compared with that of eicosapentaenoic acid (EPA), a recognized inhibitor of protein degradation. HMB was found to attenuate the development of weight loss at a dose greater than 0.125 g/kg accompanied by a small reduction in tumor growth rate. When EPA was used at a suboptimal dose level (0.6 g/kg) the combination with HMB seemed to enhance the anticachectic effect. Both treatments caused an increase in the wet weight of soleus muscle and a reduction in protein degradation, although there did not seem to be a synergistic effect of the combination. Proteasome activity, determined by the "chymotrypsin-like" enzyme activity, was attenuated by both HMB and EPA. Protein expression of the 20S alpha or beta subunits was reduced by at least 50%, as were the ATPase subunits MSS1 and p42 of the 19S proteasome regulatory subunit. This was accompanied by a reduction in the expression of E2(14k) ubiquitin-conjugating enzyme. The combination of EPA and HMB was at least as effective or more effective than either treatment alone. Attenuation of proteasome expression was reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB. In addition, HMB produced a significant stimulation of protein synthesis in skeletal muscle. These results suggest that HMB preserves lean body mass and attenuates protein degradation through down-regulation of the increased expression of key regulatory components of the ubiquitin-proteasome proteolytic pathway, together with stimulation of protein synthesis.

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2(14k), has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2(14k) were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2(14k) mRNA and protein levels in gastrocnemius muscle with increases of 6-8-fold for C2 and two-fold for E2(14k) between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25-27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18-20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2(14k) mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss. © 2005 Cancer Research.

Safety and health in mines: the rise of bureaucracy in the coal mining industry and its results as evidenced by the public enquiry into an accident at Houghton Main Colliery

This thesis is concerned with certain aspects of the Public Inquiry into the accident at Houghton Main Colliery in June 1975. It examines whether prior to the accident there existed at the Colliery a situation in which too much reliance was being placed upon state regulation and too Iittle upon personal responsibility. I study the phenomenon of state regulation. This is done (a) by analysis of selected writings on state regulation/intervention/interference/bureaucracy (the words are used synonymously) over the last two hundred years, specifically those of Marx on the 1866 Committee on Mines, and (b) by studying Chadwick and Tremenheere, leading and contrasting "bureaucrats" of the mid-nineteenth century. The bureaucratisation of the mining industry over the period 1835-1954 is described, and it is demonstrated that the industry obtained and now possesses those characteristics outlined by Max Weber in his model of bureaucracy. I analyse criticisms of the model and find them to be relevant, in that they facilitate understanding both of the circumstances of the accident and of the Inquiry . Further understanding of the circumstances and causes of the accident was gained by attendance at the lnquiry and by interviewing many of those involved in the Inquiry. I analyse many aspects of the Inquiry - its objectives. structure, procedure and conflicting interests - and find that, although the Inquiry had many of the symbols of bureaucracy, it suffered not from " too much" outside interference. but rather from the coal mining industry's shared belief in its ability to solve its own problems. I found nothing to suggest that, prior to the accident, colliery personnel relied. or were encouraged to rely, "too much" upon state regulation.

Rural road accident investigation and prevention in Iran

The objectives are to examine rural road accident data in order to develop a method by which high accident rate locations and accident causes can be identified, and also to develop proposals for improvements at such locations and to identify measures which will improve road safety throughout the country. The problem of road safety in Iran is an important issue, because of the tragic and unnecessary loss of life, and the enormous cost of accidents in the country. The resources available to deal with the problems are limited and must be allocated on priority basis. This study represents an initial effort to identify the extent of the problem in order to take remedial measures. A study was made of all the available road accident data collected by agencies related to road safety in Iran, and the major organisations responsible for road safety development were visited. The Vice Minister of Roads and Transportation selected for this study a 280 Km rural road in South West Iran. Mainly because of the lack of suitable maps and plans of the roads, it was not possible to accurately identify the location of accidents. Accident scene data was subsequently collected by the highway police and personally by the author. The data for the study road was then analysed to identify 'high accident rate' locations, and also to determine, as far as was possible, the reasons for the accidents. The study suggests specific improvements for each of the high accident rate locations examined (eg. the building of dual carriageways with central guard rails to reduce the risk of collision with oncoming vehicles, pedestrian facilities to allow pedestrians to cross dangerous roadsl]. In addition recommendations are made to guide and assist the major organisations responsible for road safety in Iran. These recommendations are: (al for improving accident data collection and storage (bl for subsequent analysis for taking remedial measures with a view to accident prevention

A comparison of road accidents in developing countries with special reference to Jamaica

This research was originally undertaken to aid the Jamaican government and the World Bank in making funding decisions relative to improvement of road systems and traffic control in Jamaica. An investigation of the frequency and causes of road accidents and an evaluation of their impact on the Jamaican economy were carried out, and a model system which might be applied was developed. It is believed that the importance of road accident economic and manpower losses to the survival of developing countries, such as Jamaica, cannot be overemphasized. It is suggested that the World Bank, in cooperation with national governments, has a role to play in alleviating this serious problem. Data was collected from such organizations as the Jamaica Ministry of Construction, Police Department, the World Bank, and the World Health Organization. A variety of methodologies were utilized to organize this data in useful and understandable forms. The most important conclusion of this research is that solvable problems in road systems and in traffic control result in the unnecessary loss of useful citizens, in both developed and developing countries. However, a lack of information and understanding regarding the impact of high rates of road accident death and injury on the national economy and stability of a country results in an apparent lack of concern. Having little internal expertise in the field of road accident prevention, developing countries usually hire consultants to help them address this problem. In the case of Jamaica, this practice has resulted in distrust and hard feelings between the Jamaican authorities and major organizations involved in the field. Jamaican officials have found confusing the recommendations of most experts contracted to study traffic safety. The attempts of foreign consultants to utilize a technological approach (the use of coding systems and computers), methods which do not appear cost-effective for Jamaica, have resulted in the expenditure of limited funds for studies which offer no feasible approach to the problem. This funding limitation, which hampers research and road improvement, could be alleviated by such organizations as the World Bank. The causes of high accident rates are many, it was found. Formulation of a plan to address this serious problem must take into account the current failure to appreciate the impact of a high level of road accidents on national economy and stability, inability to find a feasible approach to the problem, and inadequate funding. Such a plan is discussed in detail in the main text of this research.

Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss

Atrophy of skeletal muscle is common in patients with cancer and results in increased morbidity and mortality. In order to design effective therapy the mechanism by which this occurs needs to be elucidated. Most studies suggest that the ubiquitin-proteasome proteolytic pathway is most important in intracellular proteolysis, although there have been no reports on the activity of this pathway in patients with different extents of weight loss. In this report the expression of the ubiquitin-proteasome pathway in rectus abdominis muscle has been determined in cancer patients with weight loss of 0-34% using a competitive reverse transcriptase polymerase chain reaction to measure expression of mRNA for proteasome subunits C2 and C5, while protein expression has been determined by western blotting. Overall, both C2 and C5 gene expression was increased by about three-fold in skeletal muscle of cachectic cancer patients (average weight loss 14.5 ± 2.5%), compared with that in patients without weight loss, with or without cancer. The level of gene expression was dependent on the amount of weight loss, increasing maximally for both proteasome subunits in patients with weight loss of 12-19%. Further increases in weight loss reduced expression of mRNA for both proteasome subunits, although it was still elevated in comparison with patients with no weight loss. There was no evidence for an increase in expression at weight losses less than 10%. There was a good correlation between expression of proteasome 20Sα subunits, detected by western blotting, and C2 and C5 mRNA, showing that increased gene expression resulted in increased protein synthesis. Expression of the ubiquitin conjugating enzyme, E214k, with weight loss followed a similar pattern to that of proteasome subunits. These results suggest variations in the expression of key components of the ubiquitin-proteasome pathway with weight loss of cancer patients, and suggest that another mechanism of protein degradation must be operative for patients with weight loss less than 10%. © 2004 Elsevier Ltd. All rights reserved.

In vitro assessment of the combined effect of eicosapentaenoic acid, green tea extract and curcumin C3 on protein loss in C2C12 myotubes

EPA has been clinically shown to reduce muscle wasting during cancer cachexia. This study investigates whether curcumin or green tea extract (GTE) enhances the ability of low doses of eicosapentaenoic acid (EPA) to reduce loss of muscle protein in an in vitro model. A low dose of EPA with minimal anti-cachectic activity was chosen to evaluate any potential synergistic effect with curcumin or GTE. Depression of protein synthesis and increase in degradation was determined in C2C12 myotubes in response to tumour necrosis factor-α (TNF-α) and proteolysis-inducing factor (PIF). EPA (50 μM) or curcumin (10 μg ml−1) alone had little effect on protein degradation caused by PIF but the combination produced complete inhibition, as did the combination with GTE (10 μg ml−1). In response to TNF-α (25 ng ml−1)-induced protein degradation, EPA had a small, but not significant effect on protein degradation; however, when curcumin and GTE were combined with EPA, the effect was enhanced. EPA completely attenuated the depression of protein synthesis caused by TNF-α, but not that caused by PIF. The combination of EPA with curcumin produced a significant increase in protein synthesis to both agents. GTE alone or in combination with EPA had no effect on the depression of protein synthesis by TNF-α, but did significantly increase protein synthesis in PIF-treated cells. Both TNF-α and PIF significantly reduced myotube diameter from 17 to 13 μm for TNF-α (23.5%) and 15 μm (11.8%) for PIF However the triple combination of EPA, curcumin and GTE returned diameters to values not significantly different from the control. These results suggest that either curcumin or GTE or the combination could enhance the anti-catabolic effect of EPA on lean body mass.

A comparative analysis of the characterization methods for submicron silicon waveguide propagation loss

An important parameter in integrated optical device is the propagation loss of the waveguide. Its characterization gives the information of the fabrication quality as well as the information of other passive devices on the chip as it is the basic building block of the passive devices. Although, over the last three decades many methods have been developed, there is not a single standard present yet. This paper presents a comparative analysis of the methods existing from the past as well as methods developed very recently in order to provide a complete picture of the pros and cons of different types of methods and from this comparison the best method is suggested according to the authors opinion. To support the claim, apart from the analytical comparison, this paper also presents a comparison performed with the experimental results between the suggested best method which is recently proposed by Massachusetts Institute of Technology (MIT) researchers based on undercoupled all-pass microring structure and the popular cut-back method.