"Safe 100mcg rhinocort, treatment 4 allergy".

Y. Elber, M.A., M.D., M.P.H.

Co-Director, Michigan State University College of Osteopathic Medicine

The considerable auxin- and cytokininenhanced ethylene emission is causally related with the development of the enlarged xylem 566 Roni Aloni and Cornelia I. The phloem sieve element/companion cell complex is well coupled to the tumor parenchyma by numerous plasmodesmata. Spatio-temporal analysis of the activity of sucrose degrading enzymes and of sugar accumulation confirm symplastic metabolite phloem unloading. In conclusion, predominantly auxin and cytokinin-induced ethylene have a key role for successful tumor establishment by tumor vascularization and, together with cuticular disruption, by redirecting of water flow and symplastic phloem unloading of carbohydrate, amino acid and anion import. The detection of particular tissue structures in plant tumors, namely the continuous vascular bundles, made them a unique model system to study phytohormone-controlled vascular bundle development, including membrane pumps, channels, specific carriers within vascular bundles and hence xylem and phloem long distance transport mechanisms related to tumor adaptations of water relations and carbohydrate metabolism. Some benign human tumors are related to bacteria such as Bartonella (Rochalimaea) henselae which belongs to the same -2 subgroup of proteobacteria as Agrobacterium tumefaciens. It is expected that comparison of plant, animal and human tumor development may provide further insights into general principles of cancer pathogenesis and eventually leads to new strategies for tumor prevention or therapy. Since the tumors reach diameters of up to 30 cm special structural and physiological pathways for efficient nutrient and water supply extending up to the rapidly growing periphery were suspected (Malsy et al. Due to their prominent lignified structures they are much easier to recognize than sieve elements. Furthermore, because of the complicated three-dimensional organization and tree-like architecture of the tumor bundles, in thin tissue sections the tracheary elements appear as if they were idioblasts without connection to the host bundle (Agrios, 2004), or only scarcely connected to the main host bundle (Kupila-Ahvenniemi and Therman, 1968; Beiderbeck, 1977). This sophisticated structure became apparent as soon as 2 to 3 d after infection with Agrobacterium tumefaciens C58 or A281. Both vessels and sieve tubes differentiate with the growing tumor in all studied host plant species, i. Apparently, strong vascularization is a precondition of crown gall tumor proliferation in plants just as neovascularization is essential for development of animal and human tumors (Folkman, 1971; Gimbrone et al. Moreover, the induction of a neoangiogenic process by a bacterium is not restricted to Agrobacterium and higher plants. While leaf tumors are characterized by a dense net of single-stranded vessels and sieve elements (Malsy et al. Longitudinal diagram with vascularization pattern (thick lines) and phloem anastomoses (dotted lines and arrowheads) in crown gall tumor and host stem. The three diagrams of cross sections illustrate the symmetric structure of a healthy vascular stem system above the tumor (A), the pathological host xylem (arrow) with multiseriate rays in a median position (B), and the asymmetrically enhanced vascular differentiation below the tumor (C). Asterisks mark regenerative phloem fibres restricted to the upper and lower basal regions of the tumor. Bundles extend close to the tumor surface and are interconnected by a dense net of phloem anastomoses (Figure 15-1, Figure 15-2 A and C and Aloni et al. The vascular bundles are either of tree-like or of circular structure, the latter most probably induced by pathological circular flow of auxin (Aloni et al. Amazingly, fibres are almost absent from the tumors, or are produced only at the border between the tumor and the host (Aloni et al. Tumor-induced ethylene also inhibits fibre formation; in the ethylene insensitive Never ripe tomato mutant therefore fibres are produced also inside crown galls (Aloni et al. Usually tumors do not differentiate shoots and roots, indicating high inhibitory and mutually interacting concentrations of auxin and cytokinin. When tumors on Trifolium runners get into contact with humid soil numerous roots proliferate (Schwalm et al. Voluminous organs like crown galls are supposed to be endangered by anaerobiosis and hence to posses prevailing glycolytic metabolism, as known from animal and human tumors (Warburg, 1930; Aisenberg, 1961; Pedersen, 1978). To encounter this, plant tumors develop a dense net of vessels with oxygen-transporting water flow. Ethylene is known to promote cell enlargement of cells and to dissolving middle lamellae thus inducing large lacunae, which provide better aeration for the otherwise compact tissue. Less vascularized and compact inner tumor parts and also the phloem are probably predominantly energized by glycolysis since several genes of the glycolytic pathway such as pyruvate decarboxylase and alcohol dehydrogenase were found to be upregulated (Deeken et al. However, expression of these genes has not yet been attributed to defined locations or analyzed for their time dependence during tumor development As a general feature, the structures of the host stem xylem and phloem in the host/tumor interface and below are substantially different. The stem diameter considerably increases adjacent and below galls due to vigorous xylem enhancement; vessel diameters are much smaller, rays remain unlignified and become multiseriate (Figure 15-2d and Aloni et al.

Natural oils affect the human skin integrity and the percutaneous penetration of benzoic acid dose-dependently. Enhancing effect of essential oils on the penetration of 5fluorouracil through rat skin. Constituents Policosanol consists of a mixture of alcohols with octacosanol being the major component. This finding therefore suggests that policosanol is unlikely to induce or inhibit the metabolism of other drugs that are substrates of hepatic enzymes. P Use and indications Policosanol is isolated from sugar cane wax and, because of its lipid-lowering and antiplatelet properties, is mainly used for cardiovascular disorders. Interactions overview Policosanol has antiplatelet effects, which may be additive with other antiplatelet drugs, and could theoretically increase the risk of bleeding in patients taking anticoagulants. Policosanol may also enhance the blood pressure-lowering effects of some antihypertensives. Pharmacokinetics Policosanol did not alter the metabolism of phenazone 323 324 Policosanol Policosanol + Anticoagulants the interaction between policosanol and anticoagulants is based on a prediction only. Experimental evidence Policosanol 200 mg/kg did not prolong the bleeding time of warfarin 200 micrograms/kg given for 3 days in rats. Policosanol + Beta blockers Policosanol appears to increase the blood pressure-lowering effects of beta blockers. Clinical evidence In a randomised study in patients (aged 60 to 80 years) taking beta blockers, the addition of policosanol 5 mg tablets daily (titrated to a dose of 2 to 4 tablets) found that the average blood pressure was reduced from about 141/83 mmHg to 131/81 mmHg after one year, and 126/79 mmHg after 3 years. The efficacy of policosanol was not reduced and adverse effects were actually slightly lower in the policosanol group. Importance and management Policosanol increased the blood pressure-lowering effects of beta blockers and the clinical study suggests that the effect is gradual and beneficial. It therefore appears that, as with other conventional antihypertensives, policosanol may increase the effects of the beta blockers and so some caution is warranted, but no adverse effects such as first-dose hypotension would be expected. P Policosanol + Antiplatelet drugs Policosanol has antiplatelet effects, which may be additive with those of other antiplatelet drugs. Clinical evidence In a randomised study, four groups, each containing 10 or 11 subjects, were given placebo, policosanol 20 mg daily, aspirin 100 mg daily or both drugs together, for 7 days. Adrenaline-induced platelet aggregation was reduced in the group given aspirin and policosanol by about 35% more than in the group given aspirin alone: the effects of aspirin and policosanol were approximately additive. Furthermore, collagen-induced platelet aggregation was reduced in the group given aspirin and policosanol by about 10% more than in the group given aspirin alone. Importance and management the concurrent use of two conventional antiplatelet drugs is not uncommon, and so concurrent use of policosanol and aspirin need not be avoided. However, because platelet aggregation was reduced significantly, and a bleeding event was experienced, caution is perhaps warranted when taking policosanol supplements with aspirin or any other antiplatelet drug. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Policosanol + Nifedipine Policosanol does not appear to affect the blood pressurelowering effects of nifedipine. Clinical evidence A 3-year study, primarily designed to assess the safety and efficacy of policosanol in patients taking beta blockers, included 28 patients taking calcium-channel blockers (unnamed). Importance and management There appears to be no reason to avoid taking policosanol supplements with nifedipine. However, additive blood pressurelowering effects seem possible, see beta blockers, page 324. Policosanol + Sodium nitroprusside the interaction between policosanol and sodium nitroprusside is based on experimental evidence only. Experimental evidence A study found that the antiplatelet and hypotensive effect of sodium nitroprusside was greater in rats that had been pre-treated with a single 200-mg/kg oral dose of policosanol, than in animals that had not received policosanol. Policosanol reduces vascular resistance and has been shown to enhance the blood pressure-lowering effects of other antihypertensives. Importance and management the clinical significance of this finding is unclear, but bear it in mind in case of an unexpected response to treatment.

Remarkably, despite their age (the penicillins were first produced commercially in the late 1940s), Table 1. Metabolite Penicillins Cephalosporins Griseofulvin Fusidin Ciclosporins Zearalenone Gibberellins Ergot alkaloids and related compounds Fungal source Penicillium chrysogenum Acremonium chrysogenum Penicillium griseofulvum Fusidium coccineum Tolypocladium spp. Fusidic acid (from various fungi) has been used to control staphylococci that have become resistant to penicillin, and there is renewed interest in a range of other natural fungal products for treating the systemic fungal infections of humans (Chapter 17). Ciclosporins from various fungi (but principally from species of Tolypocladium) are used as immunosuppressants to prevent organ rejection in transplant surgery. Another powerful immunosuppressant is the antibiotic gliotoxin (from Trichoderma virens), which is better known for its role in biological control of plant pathogenic fungi (Chapter 12). As a final example, the ergot alkaloids and related toxins of the ergot fungus, Claviceps purpurea (Chapter 14), have many important pharmacological applications (Keller & Tudzynski 2002). The fourmembered ring structure of the d-lysergic acid derivatives of ergot alkaloids mimic the ring structures of neurotransmitters (dopamine, epinephrine (adrenaline), and serotonin. However, at present many of the ergot derivatives are too nonspecific in their modes of action to meet their true potential in treating human disorders. Even these few examples raise fascinating questions about the roles of fungal secondary metabolites. What functions do they serve in fungi and what competitive advantage do they confer In recent years many of the genes encoding the secondary biosynthetic pathways have been identified and sequenced. This should lead both to an understanding of their roles and to the potential construction of transgenic strains that overproduce valuable metabolites. Pullulan is an -1,4-glucan (polymer of glucose) produced as an extracellular sheath by Sydowia polyspora (formerly Aureobasidium pullulans), one of the sooty moulds. A potential new market could develop from the discovery that fungal wall polymers or their partial breakdown products can be powerful elicitors of plant defense responses (Chapter 14) so they might be used to "immunize" plants. So too does chitosan, the de-acetylated form of chitin in fungal cell walls (Chapters 3 & 7). At present, chitosan is used on a large scale in Japan for clarifying sewage, but the source of this chitosan is crustacean shells. Enzymes and enzymic conversions Saprotrophic fungi and some plant-pathogenic fungi produce a range of extracellular enzymes with important commercial roles (Table 1. The pectic enzymes of fungi are used to clarify fruit juices, a fungal amylase is used to convert starch to maltose during breadmaking, and a fungal rennet is used to coagulate milk for cheese-making. A single fungus, Aspergillus niger, accounts for almost 95% of the commercial production of these and other bulk enzymes from fungi, although specific strains of the fungus have been selected for particular purposes. The methanol-utilizing yeasts (Candida lipolytica, Hansenula polymorpha, and Pichia pastoris) have potential commercial value because they produce large amounts of alcohol oxidase, which could be used as a bleaching agent in detergents. In addition to these examples of "bulk" enzymes, fungi have many internal enzymes and enzymic pathways that can be exploited for the bioconversion of compounds such as pharmaceuticals. For example, fungi are used for the bioconversion of steroids, because fungal enzymes perform highly specific dehydrogenations, hydroxylations and other modifications of the complex aromatic ring systems of steroids. Precursor steroids are fed to a fungus, held at low nutrient level either in culture or attached to an inert bed, so that the steroid is absorbed, transformed and then released into the culture medium from which it can be retrieved. In particular, this fungus is genetically quite different from other fungi and other eukaryotes, including its use of different codons for some amino acids, so it does not always correctly read the introduced genes. For this reason attention has switched to some other fungi, such as the fission yeast Schizosaccharomyces pombe and the filamentous fungus Emericella (Aspergillus) nidulans, for both of which the genomes have now been sequenced. Furthermore, yeast has a well-characterized secretory system for exporting gene products into a culture medium.

Stating your central point, hypothesis, or interpretation is also a good way to begin: Workers do not organize unions; unions organize workers. Population growth coupled with loss of arable land poses a threat to North African food security in the next decade. Obviously some projects are too complex and some conceptualizations too subtle for such telegraphic messages to capture. But even if you adopt this strategy, do not fail to leave the reviewer with something to remember: some message that will remain after reading many other proposals and discussing them for hours and hours. Adam Przeworski and Frank Salomon, the Art of Writing Proposals 2 1988, 1995 Aim for Clarity Remember that most proposals are reviewed by multidisciplinary committees. A reviewer studying a proposal from another field expects the proposer to meet her halfway. You should avoid jargon as much as you can, and when technical language is really needed, restrict yourself to those new words and technical terms that truly lack equivalents in common language. An archeologist should argue the concepts latent in the ceramic typology more than the typology itself, a historian the tendency latent in the mass of events, and so forth. When additional technical material is needed, or when the argument refers to complex ancillary material, putting it into appendices decongests the main text. Establish the Context Your proposal should tell the committee not only what will be learned as a result of your project, but what will be learned that somebody else does not already know. It is essential that the proposal summarize the current state of knowledge and provide an up-to-date, comprehensive bibliography. They need not constitute a review of the literature but a sharply focused view of the specific body or bodies of knowledge to which you will add. Committees often treat bibliographies as a sign of seriousness on the part of the applicant, and some members will put considerable effort into evaluating them. Proposal writers with limited library resources are urged to correspond with Adam Przeworski and Frank Salomon, the Art of Writing Proposals 3 1988, 1995 colleagues and libraries elsewhere in the early stages of research planning. Resource guides such as Dissertation Abstracts International and Social Science Periodical Index are highly recommended. Some disciplines have bibliographically-oriented journals, for example Review of Economic Literature and Contemporary Sociology. There are also valuable area studies-oriented guides: Handbook of Latin American Studies, International African Bibliography, etc. Disciplinary norms and personal tastes in justifying research activities differ greatly. Between two identical projects, save that one concerns Egypt and the other the Sudan, reviewers are likely to prefer the latter. Citing the importance of the events that provide the subject matter is another and perhaps less dubious appeal. Turning points, crucial breakthroughs, central personages, fundamental institutions, and similar appeals to the significance of the object of research are sometimes effective if argued rather than merely asserted. Among many Adam Przeworski and Frank Salomon, the Art of Writing Proposals 4 1988, 1995 social scientists, explicit theoretical interest counts heavily as a point of merit. Theoretical exposition need not go back to the axiomatic bases of the discipline, proposal readers will have a reasonable interdisciplinary breadth, but it should situate the local problem in terms of its relevance to live, sometimes controversial, theoretical currents. Help your reader understand where the problem intersects the main theoretical debates in your field and show how this inquiry puts established ideas to the test or offers new ones. Use a Fresh Approach Surprises, puzzles, and apparent contradictions can powerfully persuade the reviewer whose disciplinary superego enforces a commitment to systematic model building or formal theorizing: Given its long-standing democratic traditions, Chile was expected to return to democracy before other countries in the Southern Cone, and yet. Is it because these traditions were already extinct by 1973 or because the assumption on which this prediction was based is false Everyone expected that One Big Union-the slogan of the movement-would strike and win wage increases for workers. It is often worthwhile to help readers understand how the research task grows from the intellectual history or current intellectual life of the country or region that generated it. Council committees strive to build linkages among an immense diversity of national and international intellectual traditions, and members come from various countries and schools of thought. In fact, the chance to see intellectual history in the making is another reason people accept committee membership. Adam Przeworski and Frank Salomon, the Art of Writing Proposals 5 1988, 1995 It pays to remember that topics of current salience, both theoretical and in the socalled real world, are likely to be a crowded field. The competitors will be more numerous and the competition less interesting than in truly unfamiliar terrain.

In summary, decreased glucose uptake appears to be common in some "epileptic" tissues, but there is little knowledge about the metabolism of this major fuel. Given the anticonvulsant efficacy of dietary treatments, such as the ketogenic and modified Atkins diets, there is a critical need for more knowledge about glycolysis in epilepsy. For example, in the mouse pilocarpine epilepsy model, we found lower forebrain levels of malate, aspartate, and acetyl- and propionyl-CoA during the chronic epileptic stage compared with mice without seizures (Willis et al. Thus, we tested the metabolic effects and anticonvulsant profile of triheptanoin treatment as an anaplerotic approach, which at that time had already been explored in a few animal models and in patients with various genetic metabolic disorders. The 13C-carbons were largely found in brain glutamine, but not glutamate, indicating that astrocytes primarily metabolize heptanoate and its C5 ketone metabolites. While the even medium chain triglyceride altered the levels of various metabolites, no significant changes were found with triheptanoin, indicating that it would have few metabolic side effects. Efficacy in this model suggests efficacy against drugresistant seizures, based on the finding that a similar second hit rat model is resistant to valproate, phenytoin, and phenobarbital (Blanco et al. Effects in other acute seizure models have been variable, for example, in the 6-Hz model the threshold to motor seizures was only elevated in some experiments, but not others (McDonald et al. This lack of consistent effects in acute mouse models is not surprising, because energy metabolism in healthy mice is likely to be optimal and unlikely to require additional fuel and/ or anaplerosis. Currently, there are three clinical trials of triheptanoin in adult and children with medically refractory epilepsy in Australia. Patients who took part in this trial have been invited to continue in an open-label extension study of oral triheptanoin as an add-on treatment. Taken together, all studies are consistent with the brain being able to metabolize heptanoate or "C5 ketones," and improvements in cases of impaired energy metabolism could be detected. It was found to be anticonvulsant in various mouse seizure models (McDonald et al. Protective effects of various compounds in kindling models correlate well with efficacy in humans against absence seizures. The treatments for this disorder are discussed in an other chapter in this book (Klepper, chapter 5). The use of dietary or body fat as energy sources is preempted in these disorders, which can result in severe clinical problems, such as cardiomyopathy, intermittent rhabdomyolysis, hypoglycemia, and sudden death. Treatment with traditional medium chain triglycerides has been unsatisfactory in the past, while triheptanoin as an alternatively medium chain and anaplerotic fuel, which is also gluconeogenic, can decrease hospitalizations due to major clinical manifestations and incidences in hypoglycemia (Roe and Brunengraber, 2015; Roe and Mochel, 2006; Roe et al. Another metabolic disorder that may benefit from triheptanoin is pyruvate carboxylase deficiency (Breen et al. In three neurological disorders models, oral triheptanoin feeding was found to prevent neuronal cell death, and it is conceivable that increased energy levels can protect cells from degeneration. The pediatric leukodystrophy Canavan disease is caused by mutations in aspartoacylase, an enzyme that is largely found in oligodendrocytes and catalyzes the hydrolysis of neuronally derived N-acetylaspartate to provide acetyl groups for lipid synthesis. In nur7 mutant mice containing a nonsense mutation in the aspartoacylase gene, early triheptanoin treatment prevented the loss of oligodendrocytes, dysmyelination, and impairments in motor function (Francis et al. Within the last decade new research has shown promising effects of triheptanoin in a variety of human disorders and their animal models, including epilepsy. Moreover, improvements in muscle function were found in skeletal muscle in a Rett syndrome model (Park et al. The mutant mice also showed increased adiposity and lower glucose tolerance and insulin sensitivity, which all improved with triheptanoin treatment, indicating that this medium chain triglyceride can counteract obesity and normalize glucose metabolism. It had been known for some time that propionate is an anaplerotic substrate for the heart, for example (Martini et al. Recently, the effects of triheptanoin in a rat model of cardiac hypertrophy were assessed.