Currently, in many countries - both in Europe and far beyond - existing insolvency legislation is being improved. These changes are often nurtured by the wish to prevent liquidation of companies as... Show moreCurrently, in many countries - both in Europe and far beyond - existing insolvency legislation is being improved. These changes are often nurtured by the wish to prevent liquidation of companies as much as possible. Legislation aimed at deferment or remission of payment is introduced or relaxed in order to give companies a chance to become viable again. A more efficient possibility - in the form of an informal reorganisation - seems to be often overlooked by the legislators. This phenomenon of Restructuring in the shadow of the law - during which a company, in cooperation with its direct interested parties, makes an attempt at reorganisation outside the legal frameworks - takes centre stage in this study. Relatively little is known about informal reorganisations. This can be explained by the fact that they often take place away from the public domain. By means of literary search, interviews, surveys and 35 case studies - carried out at so-called Intensive Care Departments of banks and at consultancy agencies - this book provides an insight into the practice of these rescue operations. It discusses causes of financial difficulties and measures which are taken within the framework of strategic and operational business and financial restructuring. Furthermore, it exposes bottlenecks and distinguishes success and failure factors. It also discusses international developments in the field of Voluntary rescue frameworks. It argues that considerable value can be created when companies reorganise in an informal manner. In order to remove bottlenecks in practice and to stimulate informal reorganisations, codes of conduct must be introduced - in the Netherlands at least - and mediation during informal reorganisations must be institutionalised. Relevant ideas are worked out (in greater detail) on the basis of the study results. Although it is based on the situation in the Netherlands, this study could be of interest to a large group of interested parties in international practice. Not only those involved with the daily prevention and solving of financial problems, but particularly also those who - intentionally or unintentionally - have been or are at times confronted with a deteriorated state of affairs in companies will find information of their interest. They may include accountants, auditors, management consultants, lawyers, politicians, civil servants, bankers, managers and entrepreneurs. Place of business hardly plays a role in this respect: after all, the laws of business economics are universal. Show less
This thesis explores the use of plea bargaining in the context of international crimes, and begins with a descriptive account of the plea bargaining that has taken place at the International... Show moreThis thesis explores the use of plea bargaining in the context of international crimes, and begins with a descriptive account of the plea bargaining that has taken place at the International Criminal Tribunal for the former Yugoslavia, the International Criminal Tribunal for Rwanda, and the Special Panels for Serious Crimes in East Timor. The thesis then turns to a normative justification of plea bargaining. In particular, because very limited resources are available for the prosecution of international crimes, most international offenders will not suffer criminal sanctions even in situations where the political will exists to bring them to justice. Because prosecuting only small numbers of (usually high-level) offenders does not advance the penological goals associated with international criminal prosecutions, the thesis argues that conventional plea bargaining - that is, the kind of plea bargaining practiced in national jurisdictions - is justified in the international context as a means of enhancing criminal accountability. The thesis goes on to construct an innovative guilty-plea system that incorporates restorative-justice principles, such as truth-telling, victim participation, and reparations. Such a restorative-justice guilty plea process serves not only to increase the number of offenders who can be prosecuted but also to advance reconciliatory goals more traditionally associated with non-prosecutorial mechanisms, such as truth commissions and reparations schemes. Show less
The main purpose of this book is to give a description of the Cholón language as represented in the Arte de la Lengua Cholona (ALC), a colonial grammar written in 1748 by a Franciscan friar, named... Show moreThe main purpose of this book is to give a description of the Cholón language as represented in the Arte de la Lengua Cholona (ALC), a colonial grammar written in 1748 by a Franciscan friar, named Pedro de la Mata. The ALC is kept in the British Library in London. Nowadays, the Cholón language is probably extinct. It was spoken in North Peru in the valley of the Huallaga river. Cholón formed a small language family together with the neighbouring language Híbito. The description of eighteenth-century Cholón, the linguistic part of the book, is preceded by a description of secondary sources and of theories about genetic relations (chapter 1), by an ethnohistorical sketch (chapter 2), and by an analysis of the manuscript (chapter 3). The linguistic part starts with an analysis of the orthography used in the ALC and of the observations about certain sounds, in order to reconstruct a tentative sound system (chapter 4). Chapter 5 deals with morphonology. In this chapter attention is paid to syllable structure, to phenomena like vowel suppression and harmonization, and to stem-initial consonant changes. Nominal and verbal morphosyntax are discussed in chapters 6 and 7, respectively. Cholón is an agglutinative language. Besides nouns and verbs, which are the most important word categories, Cholón has a small class of adverbs (chapter 8) and interjections (chapter 9). In chapter 10 discourse markers, such as question and exclamation markers, are treated. Chapter 11 is dedicated to the negation. In chapter 12, a survey of the different subordinate clauses is given. The linguistic part ends with a lexicon. Show less
Molecular biology offers new opportunities for experimental and clinical medicine. Promising clinical applications for patient care include identification of mRNA expression patterns (gene... Show moreMolecular biology offers new opportunities for experimental and clinical medicine. Promising clinical applications for patient care include identification of mRNA expression patterns (gene profiling) in diseased organs in correlation with diagnosis, prognosis, and responsiveness to different treatments. The development of novel technologies, such as microarray analysis and real-time PCR, allows study of gene expression networks, even in small renal biopsies. These technologies, in combination with the development of laser capture microdissection, enables specific gene expression analysis in a specific nephron segment. Chapter 2 describes a method to isolate RNA from purified glomeruli. Because the size of mouse glomeruli is similar to that of mouse tubules, mouse glomeruli cannot be isolated using relatively simple sieving techniques. The development of a purification method for mouse glomeruli is mandatory for extraction of mouse glomerular RNA (1-3). One of the major problems with RNA isolation is that mRNAs are very sensitive to degradation by endonucleases and exonucleases. In normal living eukaryotic cells, several pathways have been identified that play a role in mRNA degradation. One of these involves the exosome, a multi-protein complex that degrades transcripts in the 3’ to 5’ direction and that contains nucleases related to the enzymes of the bacterial degradosome (4). Another mechanism is de-adenylation–dependent decapping. This decapping is triggered by removal of the poly(A) tail by exonucleases, followed by cleavage of the 5’ cap by decapping enzymes. After decapping, which normally prevents the mRNA from being translated, the mRNA undergoes rapid exonuclease digestion starting at the 5’ end. Normally, mRNA degradation is strictly regulated by this multi-protein complex. However, after cell death, endonucleases such as RNase E and RNase III, which make internal cuts in RNA molecules, and RNase II, which is an exonuclease that removes nucleotides in the 3’ to 5’ direction are released from their regulatory complexes and rapidly degrade mRNA. In this study, we tested the feasibility of using a novel glomerular isolation method in combination with RNA extraction. To optimize this procedure, the necessity of using RNase inhibitors was investigated in combination with different RNA isolation methods. We found that including RNase inhibitors was not necessary for obtaining intact mRNA, despite the fact that the whole procedure takes 2 to 3 hours. We conclude that the cells survive the isolation method and thus, the RNA is protected against degradation. Indeed, in another study we demonstrated that it is possible to c Chapter 3 describes the distribution of alternatively spliced fibronectin isoforms in human renal disease with developing glomerulosclerosis. From animal studies it is known that fibronectin is one of the major components of sclerotic lesions in the kidney (7). Furthermore, it was found that the extent of glomerular fibronectin deposition correlated with the severity of glomerular structural abnormalities in human renal diseases (8). The EDA exon in the fibronectin molecule was found more often in skin wound healing compared to normal skin (9). In Chapter 3 we describe our immunohistochemical investigations into the distribution of the various fibronectin isoforms in glomerulosclerotic lesions and in regions of tubulointerstitial fibrosis in several progressive human renal diseases. In areas of glomerulosclerosis and interstitial fibrosis, we found increased deposition of total fibronectin. EDA- and EDB-positive fibronectin isoforms were found in significantly increased amounts in glomerulosclerotic lesions compared to normal glomeruli. In areas with interstitial fibrosis, an increase in the amount of EDA-positive fibronectin was found, but no EDB-positive fibronectin was deposited in the fibrotic interstitium. These results show that in renal disease, oncofetal fibronectin (FDC6) and EDA- and EDB-containing fibronectin isoforms are upregulated at specific locations within the renal tissue, suggesting a specific pathogenic role for these fibronectin isoforms during disease development. There were no statistically significant differences in the expression of the various fibronectin isoforms among any of the patient groups. This finding suggests that excessive fibronectin accumulation is a final common phenomenon in the development of glomerulosclerosis and interstitial fibrosis. Chapter 4 describes a study of alternatively spliced isoforms of fibronectin at the mRNA level in different animal models for immune-mediated glomerulosclerosis, and in human biopsies from patients developing glomerulosclerosis. Using cultured mesangial cells, we studied the effect of TGF-b and IL-4 on the splicing of fibronectin in the EDA and EDB regions. Using primers flanking the EDA or EDB regions, we performed RT-PCR on glomerular mRNA isolated from different animal models at several time points after induction of the disease, and on mRNA from renal biopsies from patients suffering from different glomerulopathies. Normal mice and rats did not express the oncofetal domains EDA and EDB. Induction of a-GBM nephritis, chronic serum sickness, or anti-Thy-1 nephritis resulted in inclusion of both the EDA and EDB domains in the fibronectin mRNA. However, induction of GvHD in mice had no effect on the splicing pattern of fibronectin mRNA. Culturing of glomerular mesangial cells in the presence of TGF-b led to inclusion of the EDA region, while IL-4–overexpressing mesangial cells showed a significant decrease in EDA+ fibronectin mRNA levels. This decrease may have resulted from reduced TGF-b levels in the IL-4–overexpressing cells. A relation between the presence of TGF-b mRNA and EDA+ mRNA was also found in the animal models for glomerulonephritis and in patients developing glomerulosclerosis. This finding suggests that TGF-b plays a role in the induction of EDA+ fibronectin in the kidney and thus in the development of glomerulosclerosis. On the other hand, GVH-diseased animals develop glomerulosclerosis containing large amounts of fibronectin without demonstrable increase of TGF-b or EDA inclusion. In an earlier study we have shown that in these mice, the accumulation of fibronectin is a result of specific trapping of plasma fibronectin from the circulation (7). In addition, mice with constitutive transgenic expression of IL-4 show progressive glomerulosclerosis with mesangial accumulation of collagen types I, I In Chapter 5, trapping of plasma fibronectin from the circulation during development was investigated. Earlier studies have shown that plasma fibronectin can accumulate from the circulation in sclerotic lesions. To obtain more insight into the molecular binding sites that play a role in the accumulation of fibronectin in pre-sclerotic lesions, fibronectin was cut into different fragments. The different fragments were separated on a heparin affinity column, resulting in two batches of fragments with either low or high affinity for heparin. The fragments were labeled with fluorescein isothiocyanate (FITC) and injected into chronic GVH mice developing glomerulosclerosis. These fragments were also pre-incubated with heparin or N-desulfated non-anticoagulant heparin to investigate the role of the heparin binding site in the accumulation of fibronectin in sclerotic lesions. Whole, labelled plasma fibronectin (pFN) molecules were injected intravenously into mice 10 to 12 weeks after induction of GVH disease in mice and accumulated in the glomerulosclerotic lesions. The pattern of trapped fibronectin was comparable to that seen in PAS-positive glomerulosclerotic lesions. Ex vivo pre-incubation of pFN-FITC with heparin resulted in a reduced accumulation of pFN-FITC upon injection. Injection of pFN pre-incubated with non-anticoagulant, N-desulfated heparin also prevented the accumulation of pFN-FITC in the glomerular lesions. There was no difference between the accumulation of pFN-FITC pre-treated with heparin or non-anticoagulant heparin. Intravenous injection of the digested FITC-conjugated pFN fragments with low affinity for heparin resulted in accumulation in sclerotic glomeruli. This accumulation did not occur when the low-affinity fraction was injected in control mice. The FITC-conjugated pFN fragments with high affinity for heparin did not accumulate in glomeruli of GvHD mice. From these results, we conclude that the protective effect of heparin treatment may be the result of steric interference with the specific Chapter 6 shows the results of gene expression profiling of glomeruli from human kidneys with DN. DN is a major cause of morbidity in patients with type II diabetes (10). Although several factors, including high glucose, insulin, AGEs, and high blood pressure, may be involved in the progression of DN, the precise mechanism is still unclear. Therefore, we investigated the gene expression profile of glomerular RNA isolated from morphologically and functionally normal kidneys and from kidneys of patients with DN. About 100 genes were upregulated in the diabetic glomeruli, and about 500 genes were downregulated. One of the downregulated genes was VEGF, which is one of the most important factors in endothelial repair and angiogenesis. Considerable research has focused on the pathogenesis of endothelial dysfunction in patients with diabetes, but the exact role for VEGF during the development of DN has remained unclear until now. In Chapter 7, we investigated expression of angiogenic factors identified by microarray analysis of kidneys from patients with DN or with normal kidneys. Endothelial cell loss and the role of VEGF in that loss determine development of renal disease and the progression to sclerosis. In human DN it has been suggested that VEGF is important in maintaining the glomerular endothelial cells and that a decrease in local VEGF levels accounts for abnormal remodeling of the glomerular capillaries (11,12). On microarray analysis, factors including CTGF, FGF2, and syndecan, which can induce new vessel formation (13,14), showed a decrease in patients with DN. We investigated the gene expression level of different angiogenic factors in renal biopsies from a larger patient group with DN. We found that VEGF and CTGF mRNA levels in both microdissected glomeruli and whole cortex were decreased in patients with DN compared to control kidneys. A negative correlation was found between glomerular VEGF mRNA and the extent of interstitial fibrosis. In other words, there is a relationship between progression of the disease and the reduction of glomerular VEGF mRNA. We also found a decreased number of endothelial cells both in glomerular and the tubulointerstitial tissue of patients with DN. From the results of this study, we speculate that loss of angiogenic factors contributes to the progression of DN. Podocyte injury resulting from the action of diabetic factors leads to loss of slit diaphragms and proteinuria. The resulting podocyte loss then leads to a reduction in expression of angiogenic factors, which are necessary for the normal maintenance of the endothelial cells. The reduced endothelial cell maintenance in combination with endothelial cell dysfunction leads to a loss of endothelial cells followed by a loss of glomerular capillaries (Fig. 1). On the other hand, it has been shown that urinary VEGF levels in patients with DN are increased. Although measurements of urine VEGF levels seem to be controversial in the literature, it has recently been demonstrated in a large patient group that urinary VEGF levels were increased and that this strongly correlated with 24-hour albumin excretion levels (15). In the same patients, plasma VEGF levels remained unchanged compared to a control group. The increase of urinary VEGF levels can be a result of VEGF synthesis in the kidney. The glomerular podocyte is the major site for renal VEGF synthesis, suggesting that the increased urinary VEGF excretion may be of glomerular origin. VEGF protein has also been found in proximal tubules of patients with late DN (16), suggesting that VEGF originating from renal tubules can also contribute to high levels of urinary VEGF. Based on our results and results from the literature, which show that both glomerular and tubularinterstitial VEGF mRNA levels decrease in DN (12,17), it is unlikely that the increased urinary VEGF levels result from increased VEGF production in the kidney. Because plasma VEGF levels remain unchanged in patients with DN, the explanations for higher urinary VEGF levels in patients with DN would be increased leakage of VEGF through the glomerular filtration barrier or a diminished absorption by proximal tubular epithelial cells. This increased leakage of VEGF through the filtration barrier may also explain the correlation found between urinary VEGF levels and urinary albumin excretion in patients with DN. The activity of VEGF is highly regulated by sFlt-1, a naturally occurring soluble form of VEGF receptor. More studies are necessary to define the exact role of VEGF, together with sFlt-1 and other angiogenic factors, in the development and progression of DN Show less
Following the general introduction regarding the epidemiology, aetiology, assessment and treatment of the frozen shoulder in Chapter 1 this thesis is divided into two parts: Part I describes the... Show moreFollowing the general introduction regarding the epidemiology, aetiology, assessment and treatment of the frozen shoulder in Chapter 1 this thesis is divided into two parts: Part I describes the results of the physiotherapeutic treatment of the frozen shoulder by means of mobilization techniques; Part II describes the clinical evaluation of the frozen shoulder and other shoulder disorders by various measurement instruments. Part I Physiotherapeutic treatment of the frozen shoulder. Chapter 2 shows a multiple-subject case study in 7 patients with a unilateral frozen shoulder treated with end-range mobilization techniques. Chapter 3 presents the results of a randomized controlled trial, comparing two treatment strategies with mobilization techniques in 100 patients with a unilateral frozen shoulder. In this trial we performed a cost-utility analysis comparing both mobilization techniques with respect to societal costs and quality-adjusted life years. Next a burden-of-illness study is presented estimating the impact of the frozen shoulder on costs and health. The results of this economic evaluation are presented in Chapter 4. Part II Clinical evaluation of the frozen shoulder and other shoulder disorders. Chapter 5 describes a new method of measuring shoulder positions by means of a three-dimensional electromagnetic tracking system. In a group of 15 healthy volunteers, two observers performed repeated measurements to examine the inter-trial, inter-day, inter-observer and intersubject reliability. In Chapter 6 the clinical application of the three-dimensional electromagnetic tracking device was tested on 10 patients with a unilateral frozen shoulder. The three-dimensional movement patterns of affected and non-affected shoulders were compared before and after 3 months treatment by means of end-range mobilization techniques. The translation, adaptation and validation of the Shoulder Rating Questionnaire into the Dutch language is discussed in Chapter 7 while the responsiveness of the Shoulder Function Assessment scale in 35 patients with rheumatoid arthritis suffering from shoulder complaints is presented in Chapter 8. Chapter 9 describes a comparison between two portable dynamometers in the assessment of shoulder and elbow strength in order to determine the practical applicability and the measurement properties of both devices. Finally, in Chapter 10, the findings and conclusions of the preceding chapters are summarized and indications for further research are discussed. Show less
This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in... Show moreThis research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family. Show less
Jager, M. de; Gooris, G.S.; Ponec-Waelsch, M.H.; Bouwstra, J.A. 2005
