Morphometric Study of Cerebral Arterioles in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL) is the most common hereditary small vessel disease (SVD) leading to vascular dementia. The cause of the disease is mutations in NOTCH3 gene located at chromosome 19p13.1. The gene defect results in accumulation of granular osmiophilic material and extracellular domain of NOTCH3 at vascular smooth muscle cells (VSMCs) with subsequent degeneration of VSMCs. This arteriopathy leads to white matter (WM) rarefaction and multiple lacunar infarctions in both WM and deep grey matter (GM) visible in magnetic resonance imaging. This thesis is focused on the quantitative morphometric analysis of the stenosis and fibrosis in arterioles of the frontal cerebral WM, cortical GM and deep GM (lenticular nucleus (LN), i.e. putamen and globus pallidus). It was performed by assessing four indicators of arteriolar stenosis and fibrosis: (1) diameter of arteriolar lumen, (2) thickness of arteriolar wall, (3) external diameter of arterioles and (4) sclerotic index. These parameters were assessed (a) in 5 elderly CADASIL patients with the mean age of onset 47 years and of death 63 years, (b) in a 32-year-old young CADASIL patient with the first ischemic episode at the age of 29 years and (c) a very old CADASIL patient aged 95 years, who suffered the first stroke at the age of 71 years. These measurements were compared with age-matched controls without stroke, dementia, hypertension, and cerebral amyloid angiopathy. Morphometric analyses disclosed that in all age groups of CADASIL patients compared to corresponding controls there was significant narrowing of arteriolar lumen (stenosis) and fibrotic thickening of the walls (fibrosis) in the WM arterioles, although the significance of stenosis in the very old patient was marginal. In the LN arterioles there was only significant fibrosis without stenosis. These results suggest that the ischemic lesions and lacunar infarcts in the cerebral WM are mainly attributable to the stenosis of arterioles, whereas those in the LN are probably mainly due to hemodynamic changes of the cerebral blood flow. In conclusion: The SVD of CADASIL is characterized by narrowing of lumina and fibrotic thickening of walls predominantly in the cerebral WM arterioles. On the other hand, in the LN the ischemic lesions and lacunar infarcts are most probably hemodynamic due to impaired autoregulation caused by the rigidity of fibrotic arterioles. The pathological cerebral arteriolar alterations begin to develop already at a relatively young age but the onset may be delayed to a remarkably old age. This underlines the well known great variability in the clinical picture of CADASIL. The very late onset of CADASIL may cause its underdiagnosis, because the strokes are common in the elderly and are attributed to common risk factors.

Intellectual Property Protection in China in the Cases of Outsourcing and own Manufacturing

The intellectual property (IP) environment in China is still very immature. There are several problems in legal, political, economic, social-cultural, competitive and labor environment which have hindered IP legal enforcement. Under such circumstances, IP misappropriation is a major concern especially for foreign small and medium-sized enterprises (SMEs) doing business in China. These circumstances require foreign companies, no matter whether they are multinational corporations (MNCs) or SMEs and have own manufacturing in China or not, to take strong IP actions. Therefore, the purpose of this study is to discuss how IP can be protected in China in the case of outsourcing and in the case of own manufacturing. The comparison will consider the process of outsourcing and own manufacturing consisting two stages: preparation stage and operation stage. In order to clarify the conceptual arguments, two illustrative case studies were studied. The case data bases on two semi-structured interviews of the managing directors, field notes and archival data. The findings propose that attention in IP protection should be given to following issues: integrating IP strategy into the company’s business strategy, protecting the most critical knowledge, regarding IP steps as a whole in the protection mechanism and making IP strategy as proactive as possible. The major difference between outsourcing and own manufacturing in IP protection is in the operation stage. Besides, the findings also provide managerial advice on IP protection, e.g. foreign managers should be prepared for IP risks in China, they should establish an own IP protection mechanism which matches the company’s situation and they should consider IP protection as an on-going process.