Hirsh

Hirsh, J., Dalen, J. E., Deykin, D., Poller, L., and Bnssey, H., 1995. Oral anti-coagnlants Mechanism of acdon, clinical effectiveness, and optimal dier-apentic range. Chest 108 231S-246S. 

Hirsh, R. F. (1989). Technology and Transformation in the American Electric Utilivy Industry. Cambridge, Eng. Cambridge University Press. 

Hirsh, R. F. (1999). Power Loss The Origins of Deregulation and Restructuring in the American Electric Utility Systenr. Cambridge, MA MIT Press. 

Weitz JI, Hirsh J (2001) New anticoagulant drags. Chest 119(Suppl.) 95S-107S... 

Hirsh J, Dalen JE, Anderson DR et al (2001) Oral anticoagulants mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119 (Suppl.) 8S-21S... 

Hirsh J, Warkentin TE, Shaughnessy SG et al (2001) Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119(Suppl.) 64S-94S... 

Bachmann F (1994) The plasminogen-plasmin enzym system. In Colman RW, Hirsh J, Marder VJ, Salzman EW (eds.) Hemostasis and thrombosis. Lippincott JB Comp., Philadelphia, pp 1592—1622... 

M much needed authoritative guide to a complex subject, wendy hirsh... 

Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 126 204S-233S. 

The author would like to thank Dr. Kenneth Hirsh and Dr. William Ryder for reading an earlier edition of this chapter, written in 1983, and offering many helpful comments. 

The author wishes to acknowledge the chapters of Drs. Kenneth Hirsh David W. Yesair, Alan R. Branfman and Marianne M. Callahan Bertil B. Fredholm and Eliot Spindel in The Methylxanthine Beverages and Foods Chemistry, Consumption and Health Effects (Alan R. Liss, 1984) that have been a valuable resource in writing this chapter. 

Hirsh, K., Central nervous system pharmacology of the dietary methylxanthines,... 

Hirsh, K., Central nervous system pharmacology of the dietary methylxanthines. In The Methylxanthine Beverages and Foods Chemistry, Consumption, and Health Effects, Edited by Spiller, G.A., New York Allan R. Liss, Inc., 1984. 

WR Perkins, I Ahmad, X Li, DJ Hirsh, GR Masters, CJ Fecko, JK Lee, S Ali, J Nguyen, J Schupsky, C Herbert, AS Janoff, E Mayhew. Novel therapeutic nano-particles (lipocores) trapping poorly water soluble compounds. Int J Pharm 200(l) 27-39, 2000. 

Hirsh J., Fuster V. Guide to anticoagulant therapy. Part 1 Heparin. Circulation 1994 89, 1449-68. 

Figure 2. Temporal profile of DDC enzyme activity during Drosophila development. Note the major peaks of DDC induction during late embryo-genesis, at pupariation, and at the time of eclosion of the adult from the pupal case. At these developmental times when there is extensive synthesis and hardening of cuticle, the induced DDC in the hypoderm is involved in this process. Levels of DDC in the CNS show much less developmental variation (Hirsh, 1986). Figure adapted from Hirsh, 1986.

Drosophila Ddc is expressed primarily in the CNS and the hypoderm, the epithelial layer of the fly that secretes the cuticle. In the CNS, Ddc is expressed in a small subset of neurons that produce either dopamine or serotonin (Budnik and White, 1988 Valles and White, 1988). In the hypoderm, Ddc expression leads to synthesis of dopamine, which is further metabolized into quinones that have a vital function in the cross-linking, hardening, and pigmentation of the fly cuticle (Wright, 1987). The developmental profile of DDC activity in these two tissues is quite different (Hirsh, 1986). DDC is first detected during late embryo-... 

Figure 3. Sketch of DDC-expressing neurons in the Drosophila larval CNS. The CNS consists of brain lobes and a segmented ventral ganglion. Filled circles represent dopamine cells open circles represent serotonin cells grayed circles represent DDC cells that contain no detectable tyrosine hydroxylase or serotonin immunoreactivity, indicating that these cells may produce neither transmitter (Lundell and Hirsh, 1994). M, medial dopamine neurons VL, ventrolateral serotonin neurons DL, dorsolateral dopamine neurons. The hatched rectangle shows the region of the ventral ganglion that is shown in Figures 4 and 6.

The majority of DDC-expressing cells in the brain lobes are dopamine cells. Most of these dopamine cells have axons that project into a common axonal fiber extending anteriomedially within the brain lobe and then separating into finer fibers that cross between the lobes. The dopamine cells occur in small clusters of two to six cells, which suggests that these cells might share common lineages. The serotonin cells within the lobes are also found in pairs, and each pair projects axons into closely associated tracts. The pathways of the serotonin tracts often parallel those of the dopamine cells but are distinct (Lundell and Hirsh, 1994). 

Within the proximal promoter are found five sequence elements that are conserved between D. melanogaster and D. virilis (Scholnick et al., 1986) (Fig. 5). The 16-bp element I sequence is perfectly conserved between D. melanogaster and D. virilis (Bray and Hirsh, 1986). Inactivation of element I by deletion or point mutation leads to a selective loss of Ddc expression within the CNS (Scholnick et al., 1986 Bray et al., 1988) (Fig. 6A), without significantly affecting hypodermal Ddc expression. This demonstrates that element I is required specifically for expression of Ddc within the CNS. 

The distal enhancer also contains five sequence elements that are conserved between D. melanogaster and D. virilis (Johnson et al., 1989 Lundell and Hirsh, 1992) (Fig. 5). Both tissue-specific and cell-specific regulatory functions have been attributed to these elements. Here we will... 

The second cell-specific regulatory element within the distal enhancer is named SER. Loss of this element, which is at the extreme distal edge of the enhancer, leads to a selective loss of DDC expression in the ventral lateral serotonin cells (Johnson et al., 1989 Lundell and Hirsh, 1992) (Fig. 6C). This element has been delimited to about 40 bp and shows unexpected complexity, consisting of two functionally redundant elements. These two subelements, SERl and SERr, are each sufficient to allow normal DDC expression in the ventral lateral serotonin neurons if the other is deleted. In spite of this functional similarity, no sequence similarity is apparent between the two regions. The region of conservation between D. melanogaster and D. virilis is limited to SERl. 

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