Xylose, a sugar not metabolised by brain, and glucose may be transported into brain by a common mechanism (Gilbert, 1965). In the present studies the effects of some anticonvulsant drugs on the uptake of xylose by the non-raffinose compartment of cerebral cortex slices have been examined. The slices were pre-incubated for 30 minutes in oxygenated bicarbonate media, containing pyruvate as nutrient, and raffinose, before transfer to similar media containing xylose. Employing an incubation time of 9 minutes, and a xylose concentration in the medium of 50 mM, it was found that the anticonvulsant drugs acetazolamide, 20 μM, and ethosuximide, 500 μM, caused an increase in xylose uptake, while diphenylhydantoin, 100μM, was without effect in this respect,-SH group blocking agents (5,5- dithiobis (2~nitobenzoic acid), 100μM, or iodoacetamide, 100 μM), did not appear to affect 'basal' xylose uptake by the slices, but prevented stimulation of xylose uptake by acetazolamide or ethosuximide. Studies of the initial velocity of xylose uptake by the slices, over a range of medium xylose concentrations, indicated that the xylose uptake process appeared to conform to Michaelis-Menten kinetics; the apparent Km (under control conditions) for xylose being 87 mM, and the Vmax. being 30 millimole, 1iter of intracellular water-1minute-1. Acetazolamide increased both the Km and Vmax. of the xylose transport process. Both these parameters were decreased by ethosuximide. The effect of phenobarbitone on the kinetics of xylose uptake by cerebral cortex slices has been found (Gilbert, Ortiz, and Millichap, 1966) to resemble that recorded here for ethosuximide. The anticonvulsants which have been shown to be capable of increasing xylose uptake by brain slices also increased brain glucose content 'in vivo' (Gilbert, Gray, and Heaton, 1971), - probably as a consequence of a stimulation of glucose transport into brain rather than a depression of cerebral metabolism. The uptake of glucose may, under certain conditions, be the rate - limiting factor in its metabolism by brain (Joanny, Gorriol, a Hillman, 1969; Buschiazzo, Terrell, and Regen, 1970), Glucose may also have a direct stabilizing effect on brain cells (Goldman and Good, 1969)* The stimulation of sugar uptake 'brought about by the drugs might thus contribute to their anticonvulsant effect However, the interaction of these drugs with cerebral membranes may, in addition to affecting permeability to sugars, result in other effects more directly responsible for their anticonvulsant efficacy.

Nitric oxide is a recognised dilator of vascular smooth muscle and therefore is central in the control of blood flow. A lack of blood flow in humans can have very important implications in a number of disorders of both cutaneous tissue and internal circulation. In this thesis we look at the synthesis of new nitric oxide donors, their stabilities and their possible medicinal usage. These donors have been based on the S-nitrosothiol group, connected to sugar moieties, simple amino acids or linked glycoaminoacids. The donors prepared have been used to investigate the skin blood flow and localised responses to nitric oxide, proving that NO has an important role in the maintenance of healthy skin. These will be further investigated as possible treatments for disorders involving a lack of cutaneous blood flow, such as connective tissue disorders and the repeated ulceration often seen in diabetic patients. A set of clinical trials have been carried out comparing the responses of healthy patients and sufferers of Raynaud's Phenomenon to exogenous nitric oxide. In this we have highlighted a number of differences and have helped to determine a possible cause of the disorder. We have prepared a number of slow release NO donors which have been shown to produce a sustained vasodilatory response in blood vessels with removed or damaged endothelial cells. These show promise for use in the treatment of patients with circulatory disorders, especially for subjects following treatment for atherosclerosis. Basic studies investigating the stabilities of these compounds have been carried out, in order to aid our understanding of their mode of breakdown.

1) Transverse hippocampal slices were prepared from rats and maintained in a recording chamber. Intracellular recording techniques were used to measure the amplitudes of the resting potentials (mean -63.4mV), the action potentials (mean 72.5mV), and the input resistance (mean 16.5M?) of neurones in the CA1 region of the hippocampus. Impalements of neurones could be maintained for up to 9.5hrs. 2) Impaled neurones in the CA1 region of the hippocampus were identified as pyramidal neurones after injection of the fluorescent dye Lucifer Yellow CH and subsequent microscopical examination of the slices. The projections of the apical and basal dendrites were complete and in some cases the axon could be identified and traced toward the subiculum. Injections of pyramidal neurones in the CA3 region and of granule cells in the area dentata demonstrated the different morphologies of the three types of neurone. 3) CA1 neurones were hyperpolarised by up to 10mV by serotonin applied locally by iontophoresis. This response was slow on onset and lasted between 30s and 3min. In contrast, glutamic acid and acetylcholine depolarised these neurones. 4) The amplitude of the hyperpolarisation induced by serotonin was dependent on the amplitude and duration of the iontophoresis current. A decreased input resistance of the neurones was associated with and followed the same time course as the potential change induced by serotonin. 5) The serotonin response was reversed at membrane potentials more negative than the reversal potential which was between -81mV and -104mV. This high reversal potential indicated that the response might be mediated by efflux of potassium ions from the neurones. 6) In ion substitution experiments, the serotonin response was shown to be dependent on the extracellular potassium ion concentration, but was independent of the chloride ion concentration. 7) The serotonin response was blocked by the putative serotonergic antagonist methysergide (100μM). However, the responses of the neurones to serotonin were not affected by cyproheptadine, methergoline, mianserin, and 1-propranolol which have also been proposed to be antagonists of serotonin in the central nervous system. 8) The significance of these results is discussed with reference to previous investigations by other workers.

Tumour-associated arteries are a potential target for therapeutic strategies aimed at reducing or stopping tumour growth and metastases. However, the tumour vasculature exists in a state of 'near maximal vasodilation' and is markedly hyporesponsive to vasoactive agents generally. The role of nitric oxide (NO) in the growth and maintenance of solid tumours is unclear. Recent evidence suggests that it may be responsible for some of the characteristics of angiogenically- derived vessels found within the tumour and also for those of 'normal' vessels which become incorporated into the surrounding host tissue. A marked hyporesponsiveness to vasoactive agents also characterises vessels from animals in endotoxin-induced shock. One aim of the present study then was to compare the properties of arteries which formerly supplied an implanted solid tumour (tumour epigastric artery, or TEA) with arteries taken from experimental animals (rat tail artery, or RTA) injected with bacterial lipopolysaccaride (LPS). The extent of endotoxaemia resulting from LPS treatment was assessed by (a) monitoring arterial blood pressure, using the tail cuff method; (b) measuring accumulated plasma nitrite and nitrate; (c) monitoring the development of hyporesponsiveness of RTAs to phenylephrine (PE); (d) detecting expression of inducible nitric oxide synthase (iNOS) by Western blot and immunocytochemical analysis; and (e) monitoring the loss of sensitivity of pre-contracted vessels from LPS-treated rats exposed to the vasodilator S-nitroso-N-acetylpenicillamine. RTAs from LPS-treated rats and TEAs were less sensitive to PE than control arteries. This difference was abolished by non-selective NOS inhibitors (L-NAME and L-NMMA) and by the isoform-selective inhibitor aminoguanidine (AG). Furthermore, the protein synthesis inhibitor cycloheximide also reversed the hyporesponsiveness to PE of both types of vessel. The 'restoring' effect of cycloheximide was abolished when given after indomethacin, a specific cyclooxygenase inhibitor. Chronic, oral administration of L-NAME or AG to tumour-bearing rats (via the drinking water) significantly slowed tumour growth. When L-NAME treatment was halted, tumour growth resumed at pre-L-NAME (control) rates. A single i.p. injection of LPS also impaired tumour growth: this was dependent upon the time of injection, with no effect seen 24hrs prior to tumour implantation and the maximum delaying effect at 11 days post-implantation. LPS potentiated the growth retarding effects of L-NAME but abolished those of AG. These results provide evidence for the involvement of iNOS-derived NO in regulating the tone of arteries supplying a solid tumour and also of those from animals in septic shock. They suggest that NO may assist tumour growth by helping to maintain an adequate flow of blood into the tumour and they highlight the L-arginine/NO pathway as a potential target for the design of improved therapeutic interventions.

Ethanol production by Zymomonas mobilis CP4 under chemostatic and continuous transient reactor. Ethanol production by Zymomonas mobilis CP4 under chemostat and continuous transient operation has been investigated. Under carbon limitation with simple chemostatic operation, glucose, fructose and sucrose were tested at 35° C. At 2%(w/v) carbon source medium, glucose was more efficiently utilised. Ethanol production values for glucose, fructose and sucrose were respectively; volumetric productivity 2.5, 1.8 and 2.5 g/1/h; conversion to ethanol efficiency 96, 88 and 76% at values of dilution rate of 0.35, 0.21 and 0.32 h-1 which represent approximately 85% of Dm. With 5%(w/v) glucose values of volumetric productivity of 5 g/l/h and conversion to ethanol efficiency of 85% were achieved. However, under nitrogen limitation with glucose 5% (w/v), approximately 25% of feed glucose medium was being washed out while conversion to ethanol efficiency was around 60% at a dilution rate of 0.17 h-1 Under alternating glucose concentrations of 2 and 5%(w/v) medium and at a fixed dilution rate of 0.2 h-1, continuous transient operation achieved values of ethanol conversion higher than 80%. However, both continuous transient (utilising high alternating glucose concentration of 8 and 11% and 8 and 16%(w/v)) and simple chemostatic operation running with 9.5 and 12%(w/v) glucose medium were less satisfactory as conversion efficiency values were as less satisfactory as conversion efficiency values were as low as 40 and 29% for the former and 48 and 45% for the 1atter. Pulsing the culture with mineral salts (NH+4, Mg++,K+) and ethanol, the culture showed no effect with mineral salts and a strong inhibitory effect on growth for ethanol.

The stability constants of some lead(II)-ligand anion complexes already measured have been recalculated and others of some lead(II) and zinc(II) complexes have been measured by glass and chloride electrode potentiometry. These constants have been used in computer models of biological systems in order to assess the suitability of current and proposed therapeuticals as lead(II) sequestering agents in vivo. Glutathione is proposed as the most promising ligand for the treatment of plumbism. Thermodynamic functions for some lead(II)-ligand anion complexes have been determined, by calorimetry and temperature variation of formation constants, and from these some complex structures in aqueous solution have been suggested. The interaction of bovine serum albumin with lead(II) and copper(II) has been studied potentiometrically. The effect of some antirheumatoid arthritis drugs on the copper(II)-bovine serum albumin interaction has been observed by visible spectroscopy and molecular filtration. It is concluded that some of these drugs have the ability to release copper(II) from this protein bound situation. A contribution has been made to an interlaboratory potentiometric study of the nickel(II)-glycinate complexing system and a comparison of results from several laboratories is presented.

During embryogenesis, the inherited information on the spatial arrangement of a particular tissue results in the deposition of extracellular matrix components. The overall tissue architecture is the responsibility of the embryonic cells which use the physico-chemical properties of the synthesised matrix components to assure local stability and form. Trelstad and Birk (1984) have postulated that embryonic cells are inherently polarised in both structure and function and that the quality, quantity and orientation of the extracellular matrix is under cellular control. They have shown that the cellular polarity and matrix patterning in embryonic chick tendon and corneal matrix is very similar to that proposed in this thesis for the morphogenesis of the elastic fibre. During matrix secretion, epithelial cells in the cornea are observed to undergo a reversal of their polarity with up to 80% of the cells relocating their Golgi to the basal cell pole. Discrete packets of collagen are then transported to the cell surface where the vacuoles are brought into register with the orientation of the underlying matrix by the alignment of ordered filaments and/or microtubules in the basal cell cytoplasm. The fact that elastin appears in the extracellular matrix at a later stage in development than most other connective tissue macromolecules suggests that elastogenic cells require a highly structured or 'mature' extracellular matrix upon which to organise the complex elastic fibre and that only late in gestation is the matrix suitable for the fibre organisation. Accordingly, a component of the extracellular matrix such as the microfibrils may provide the information that signals the appropriate time for elastin synthesis and secretion. This view is supported by the cellular polarity and the presence of both secretory vesicles and aligned microtubules (Chapter Two) observed when elastin-producing cells are in close proximity to the microfibrillar component of developing elastic fibres. The belief that elastin-associated microfibrils play a crucial role in the morphogenesis of the elastic fibre has until recently been based primarily on electron microscopic studies of the development of elastic tissue. In Chapter Three, purified 35k-GP was shown by immunoblotting and immunochemical techniques to be a constituent of elastin-associated microfibrils in developing elastic tissues within the ear, skin, aorta and ligamentum nuchae of the foetal calf. No binding of anti-35k-GP was detected in adult bovine ligamentum nuchae, aorta or ear which suggests that this glycoprotein plays an important but transient role in the development of elastic tissue. It is proposed that the role of 35k-GP in the function of microfibrils is to induce the adhesion and morphogenetic movements of elastogenic cells during elastic fibre formation. The preliminary results described in Chapter Four support this view and we now plan to undertake a more detailed study with the following objectives in mind:- 1.(a)To examine by immunofluoresence the involvement of cytoskeletal structures such as microtubules and microfilaraents in the interaction of elastogenic cells with 35k-GP. (b)To determine the type and duration of the 35k-GP induced adhesion by time-lapse video interference reflection microscopy to discover whether a substrate specific focal contact is occuring resulting in cytoskeletal reorganisation and ultimately in the synthesis and extracellular deposition of elastin. 2. A study of the ability of 35k-GP fragments to induce cell adhesion and spreading. This will allow the elucidation of a possible specific cell-binding region of the molecule. 3. An investigation into the identity of a specific cell receptor, the presence of which appears essential to the primary recognition event in the binding of 35k-GP and the possible existence of additional cell surface molecules to the cell-substratum attachment mechanism. 4. In conjuction with the above, a gene library from human foetal aortic smooth muscle cells is being created with the intention of developing cDNA probes to 35k-GP specific mRNA from this tissue.

ANGLICKÝ ABSTRAKT This master's thesis analyses European legal framework on handling chemical substances. Primary focus of this thesis is on the Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals, establishing a European Chemicals Agency. A part of the thesis is dedicated to comparing analyses between American and Europeans legal framework and part is also dedicated to an attempt of monetary cost-benefits evaluation of this regulation. The thesis covers also the nanoparticles regulation and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures. Powered by TCPDF (www.tcpdf.org)

Darbe analizuojama cheminių medžiagų tvarkymo valdymo Lietuvoje problemų sprendimo eiga nuo 1991 iki 2010 metų ir nagrinėjami kai kurie sveikatos ir aplinkos apsaugos politikos aspektai. Lietuvoje po Nepriklausomybės atkūrimo nebuvo cheminių medžiagų tvarkymo sistemos. Pereinamuoju laikotarpiu buvo palikti galioti dokumentai, priimti iki Nepriklausomybės atkūrimo paskelbimo datos, ir jau įsigaliojo nauji dokumentai, patvirtinti nepriklausomos Lietuvos Respublikos valstybės institucijų. Analizuojant nepriklausomos Lietuvos Respublikos cheminių medžiagų valdymo raidą, akivaizdžiai matyti, kad teisė turinio prasme buvo nuolat kintantis procesas ir didžiausi buvo jos esmės pokyčiai. Lietuvoje pagrindinės pavojingų cheminių medžiagų ir preparatų valdymo koordinatorės yra Aplinkos ministerija ir Sveikatos apsaugos ministerija, kadangi šių ministerijų esminė misija yra apsaugoti aplinką ir gyventojų-vartotojų sveikatą nuo galimo kenksmingo cheminių medžiagų poveikio. Cheminių medžiagų valdymo ir tvarkymo Lietuvoje problemų sprendimo eigos pagal įvykimo laiką analizė remiantis oficialiais dokumentais rodo, kad sveikatos ir aplinkos saugos plėtra nagrinėjamoje specifinėje srityje, nuo problemos suformavimo iki jos sprendimo pradžios užtruko apie 10 metų. Darbe pateikiamos ir analizuojamos dvi schemos – Pavojingų cheminių medžiagų valdymo Lietuvoje 2000–2005 m. sistema pagal Cheminių medžiagų ir preparatų įstatymą ir Nuodingųjų medžiagų kontrolės įstatymą, ir Pavojingų cheminių... [toliau žr. visą tekstą] / The graduating paper analyses the process of solution of problems related to chemicals management in Lithuania from the year 1991 to 2010; deals with certain aspects of practical development of health and environment protection. Since restoration of independance in 1991 Lithuania has no chemicals management system; during transitional period both old USSR legal acts and new legal acts, adopted by independant Lithuanian Government, were in force. Legislation development analysis leads to conclusion that changes were continuous process and the changes were essential. Main chemicals management coordinators in Lithuania were Ministry of Environment and Ministry of Health, as their main field of administration is to protect human health and the environment from risks posed by chemicals. Analysis of official documents shows that transitional period from task formulation until beginning of solution in this specific field lasts about 10 years. Course of resolvement of chemicals handling and management issues in Lithuania from 2000 till 2010 is analysed and certain practical features of health and environmental protection development are considered in the article. Two schemes are presented and analysed in it. One is on Dangerous Chemicals Management System in Lithuania in 2000–2005 based on the Law on Chemical Substances and Preparations and the Law on Poisonous Substances Control (LPSC), another one – Dangerous Chemicals Management System in Lithuania from the second half of the... [to full text]

The ever-changing industrial processes which are becoming more globalised as well as the merging of markets in different economies, led to an increased focus on the health and safety of workers in the industries and the mining sector over the past decades. Occupational exposure limits (OELs) have been used for more than half a century as a risk management tool for the prevention of work-related illnesses which may arise from the exposure to a wide variety of hazardous chemical substances in the working environment. Aim: The aim of this study is to analyse comparatively occupational exposure limits (OELs) of hazardous chemical substances from selected groups contained in the Hazardous Chemical Substance Regulations (HCSR) and the Mine Health and Safety Regulations (MHSR) with those of selected developed countries and organisations. Method: The two lists of OELs from South Africa – HCSR and MHSR – were compared with 11 different developed countries and/or organisations namely: Canada (British Colombia), United Kingdom (Health and Safety Executive, HSE), Australia (National Occupational Health and Safety Commission, NOHSC), New Zealand (Ministry of Business, Innovation and Employment), Japan (Japan Society for Occupational Health, JSOH), Finland (Ministry of Social Affairs and Health), Germany (Deutsche Forschungsgemeinschaft-DFG), Sweden (Swedish Work Environment Authority) and United States of America (American Conference of Governmental Industrial Hygienists, ACGIH, Occupational Safety and Health Administration, OSHA and National Institute for Occupational Safety and Health, NIOSH). The selection of these countries and organisations was done on the basis of their dominance in the literature as well as the availability of the lists containing OELs. The OELs from each country and/or organisation, depending on the nature and characteristics of the said element and/or compound, were categorised into one of four groups, namely: pesticides, metals, dusts and fibres. The geometric means of each country and/or organisation were calculated from the ratios of each list by using the HCSR and MHSR as the denominator respectively. Results: It became evident that South Africa performed poorly when compared to other countries and/or organisations, indicated in this study. OSHA overall had the highest set OELs, in five out of the six comparisons that could be made, thus being less stringent than South Africa’s. Countries and organisations such as Sweden, Japan and Finland have the lowest overall set OELs for the different groups respectively. Conclusion: South African OELs legislated by both the HCSR and MHSR, are overall higher (less stringent) when compared to those of developed countries and/or organisations. The less stringent nature of South African OELs may be attributed to infrequent rate at which they are updated. The failure to incorporate recent scientific knowledge into OELs may impact on the health of workers. South Africa should follow international best practice and increase the frequency at which OELs are updated. Recommendations: The effectiveness of having two sets of OELs within a country; each applicable to its own industry should be investigated. Attention with regards to the groups lacking attention, i.e. fibres and pesticides should be given priority when revised. Although the other groups should not be disregarded. Duplicate OELs identified in the HCSR should be removed. To prevent duplicate OELs from being established it would be prudent to utilise CAS numbers when referring to substances in addition to their common and chemical names, thus this supports the recommendations made in an earlier study. / MSc (Occupational Hygiene), North-West University, Potchefstroom Campus, 2015