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The Beauty of Food Turning Back The Clock

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ActinADPribosylating Toxins Cytotoxic Mechanisms of Clostridium botulinum C2 Toxin and Clostridium perfringens lota

Whereas most of the known bacterial ADP-ribosylating toxins modify GTP-binding proteins (Aktories and Just, 1993) (see chapter 1, 3 and 5), there is a family of clostridial toxins that ADP-ribosylates the ATP-binding protein actin (for review see (Aktories et ai, 1992 Considine and Simpson, 1991 Aktories and Just, 1990 Aktories and Wegner, 1992 Aktories and Wegner, 1989 Ohishi and DasGupta, 1987)). These toxins have proved to be a valuable tool in cell biology because they are most effective agents to induce depoylmerization of actin in intact cells. Therefore, they are used to study the role of the microfilament protein actin in various cell functions. The family of actin ADP-ribosylating toxins comprises Clostridium botulinum C2 toxin, C. perfringens iota toxin, C. spiroforme toxin and a transferase produced by certain strains of C. difficile. Besides their common eukaryotic substrate actin, these toxins are characterized by their binary structure. The toxins are constructed...

Purification Activation and Endocytosis of Botulinum C2 Toxin

Clostridium botulinum type C was firstly isolated by Bengston in 1922 identification of C2 toxin (Bengston, 1922). In 1935, Mason and Robinson reported that C. botulinum type C produced three different toxic factors, CI, C2 and D (Mason and Robinson, 1935), although it had been considered at that time that other types of C. botulinum, types A and B, produced only one antigenic type of the toxin. This was the first use of the term C2 toxin in the literature. Later on, Jansen applied this notion to the toxins produced by C. botulinum Ca and Cp strains, which had been classified by immunological cross-neutralization Ca produces CI, C2 and D toxins and Cp only C2 toxin (Jansen, 1971). Thus, C2 toxin had been thought of as a botulinum neurotoxin until it was purified and characterized in 1980 (Ohishi etal., 1980). Botulinum C2 toxin is produced by certain strains of C. botulinum structure of C2 toxin types C and D (Ohishi and Sakaguchi, 1982). The toxin is constructed with two unlinked...

With Clostridium botulinum C2 Toxin

Because C. botulinum C2 toxin is a real binary toxin, studies of its effects on intact cells depend on the presence of both the binding (C2II) and enzyme component (C2I) (Reuner eta ., 1987 Wiegers et al., 1991 Ohishi et al., 1984 Ohishi and Yanagimoto, 1992 Li et al., 1994 Prepens et al., 1996).

Botulinum Toxin Botox Injection

The neurotoxins produced by Clostridium botulinum exert physiologic effects by inhibiting release of acetylcholine from nerve terminals. These effects account for the utility of botulinum injections in alleviating blepharospasm or facial spasm but not necessarily pain. Analgesic effects of botulinum toxin type A may involve other neurotransmitter influences, including inhibition of glutamate and substance P. Botulinum toxin (both A and B types) has been invoked in the treatment of cervical dystonia, migraine headache, tension headache, temporomandibular joint disorders, and chronic back pain (Argoff2005). Multiple series of injections may be required to achieve maximal analgesia. Contraindications include pregnancy, concurrent aminoglycoside antibiotic use (e.g., gentamicin, tobramycin), myasthenia gravis, Eaton-Lambert syndrome, and known sensitivity to toxins. Clinical resistance brought on by development of antibodies to toxins may reduce clinical efficacy after repeated...

Muscle relaxants active at nerve endings Botulinum toxin

Botulinum is a product of the anaerobic bacterium, Clostridum Botulinum. Of the seven known immunologically distinct serotypes of these extremely potent neurotoxins, types A, B, C1, D, E, F, and G, types A and B are the only types available for routine clinical practice. Two type A preparations, Botox (Allergan, Inc. Irvine, CA) and Dysport (Ipsen Ltd., Berkshire, UK), have been developed for commercial use and while Dysport is currently being evaluated in the US, only Botox is available in the US at this time. Type B toxin is currently commercially available as Myobloc in the US and as Neurobloc in Europe. While each of these neurotoxins is similar in that they are proteins, they vary with respect to molecular weight, mechanism of action, duration of effect, and adverse effects. The bacteria synthesize each toxin initially as a single chain polypeptide. Bacterial proteases then nick both type A as well as type B proteins resulting in a di-chain structure consisting of one heavy and...

Clostridium botulinum ADPribosyltransferase C3

ADP-ribosyltransferase C3 is an exoenzyme produced by several strains of Clostridium botulinum. It was serendipitously detected during screening for high producer strains of C. botulinum C2 toxin (Aktories et al., 1987 Aktories et a ., 1988b). The novel ADP-ribosyltransferase was termed C. botulinum ADP-ribosyltransferase C3, because it proved to be distinct from C. botulinum neurotoxin CI and the actin ADP-ribosylating C. botulinum C2 toxin. C3 ADP-ribosylates members of the Rho protein family at asparagine-41 thereby inactivating the GTP-binding protein. Therefore, C3 ADP-ribosyltransferase has become a molecular tool to study the function of Rho proteins. The C3 ADP-ribosyltransferase gene was shown to be located on a DNA bacteriophage together with neurotoxin CI and D (Popoff eta ., 1991 Hauser et al., 1993). Various isoforms of the C3 transferase have C3 isoforms been described (Popoff et al., 1990 Nemoto et al., 1991 Popoff et al., 1991 Moriishi et al., 1991 Moriishi et al.,...

Clostridium botulinum C3 Exoenzyme and Studies on Rho Proteins

We and others have used the bacterial exoenzyme C3 ADP-ribosyltransferase from Clostridium botulinum to analyze the signaling pathways controlled by the Rho GTPase. The introduction of C3 transferase into a variety of cell types causes them to lose their actin stress fibers, round up, and eventually detach from the underlying substrate (Rubin etal., 1988 Chardin etal., 1989 Paterson etal., 1990). The targets of C3 in cells are the three isoforms of the Rho protein, RhoA, RhoB and RhoC (Narumiya et al., 1988) the enzyme catalyzes the transfer of an ADP-ribose group from NAD+ to an asparagine residue at codon 41 of Rho (Aktories et al., 1989 Sekine et al., 1989) and renders the protein inactive (Paterson et al., 1990). Other Rho family members such as Rae and Cdc42 are essentially not substrates for C3 in vitro (Ridley et al., 1992 Just et al., 1992), and microinjection of C3 into cells does not affect the activity of either Rae or Cdc42 (Ridley et al., 1992 Nobes and Hall, 1995). The...

Colloidal silver suspension for treating skin problems in tropical and decorative fish

Abstract This is a method of treating a wide range of skin lesions in tropical and decorative fish in which the animals to be treated are exposed to dilute suspensions of colloidal silver. During the course of treatment, colloidal silver is added periodically to the aquarium in which the fish lives. so that the water therein has a silver concentration on the order of 1 ppb. A suitable treatment procedure entails adding 1 teaspoon of colloidal silver which contains about 6 ppm of silver to 10 gallons of aquarium water every other day. This treatment has been found effective in healing some fish, ever those with rather large wounds in a matter of days. If a longer treatment period is required, then the colloidal silver addition is continued at the same rate and then 50 percent of the water is changed once a week, until the lesion(s) have healed. It was also found that bacteria and virus skin problems could be prevented by having silver colloidal concentrations of 0.3-0.5 ppb in the...

Skin Aging Photoaging

In addition to direct antioxidant activity, vitamin E modulates cell signaling and gene expression in skin. Aging of skin, whether intrinsic or due to environmental stress exposure, is associated with increased PKC activity, leading to induction of collagenase (MMP-1, a matrix metalloproteinase) and thus tissue degradation. Vitamin E is able to inhibit collagenase overexpression in aging skin fibroblasts via PKC inhibition (182). Moreover, Trolox inhibited UVA-induced collagenase expression in skin fibroblasts in vitro (183). These findings strongly suggest a beneficial role of vitamin E in the prevention of skin photoaging.

Botulinum toxin

Botulinum toxin is a product of the anaerobe Clostridium Botulinum and is indicated for the treatment of cervical dystonia, blepharospasm, hemifacial spasm, axillary hyperhidrosis, and glabellar wrinkles. A number of immu-nologically distinct serotypes exist of which type A and type B are the predominant forms in clinical practice. At least some of its effect is due to its ability to inhibit release of acetylcholine from cholinergic nerve terminals. In addition, it has been suggested that it may also inhibit glutamate release, as well as that of calcitonin gene-related peptide and substance P. Animal experimentation has shown that, as well as having muscle relaxant effects, botulinum toxin type A can have marked anti-allodynic effects after a single injection which persists for up to 3 weeks in a chronic nerve constriction It should be emphasized that some of the reports of successful use of botulinum toxin in these conditions report its use in a small number of patients and therefore...

Botulinum Toxins

Botulinum toxins from Clostridium botulinum are the most toxic proteins known to date but have, nevertheless, found widespread pharmaceutical and cosmetic use. Botulinum toxin type A (BTX-A) was approved in 1989 for the treatment of strabismus and in 2002 as a cosmetic against glabellar lines. Meanwhile, the use of BTX-A has been extended to the treatment of numerous other disorders resulting from hyperactive skeletal or smooth muscles, hypersecretory and painful disorders, and serotype B (BTX-B) was approved for treatment of cervical dystonia in 2000. Subcutaneous and intramuscular injections of BTX-A figure among the most popular cosmetic treatments worldwide (Lim and Seet 2007). by endocytosis. Upon reduction of the disulfide bond, the 50-kDa light chain escapes from endocytotic vesicles and proteolytically degrades SNAP 25. Other botulinum toxins, known as serotypes B-G, share the same two-chain structure and a similar route of cellular uptake but proteolyze different components...

Preface to the series

We are planning five books in the series Toxins and Signal Transduction, the first volume, presents selected mechanisms by which toxins affect molecular processes which transduce extracellular signals into intracellular messages regulating cell function. Secretory Systems and Toxins, the second volume, provides an updated state-of-the-art treatment of vesicle-mediated secretion with special emphasis on the specific action and recognition of the secretory organelle proteins and glycolipids by tetanus, botulinum, and a-latrotoxin neurotoxins. This third volume, Site-Selective Neurotoxicity, presents different neurotoxicological aspects with a unique mechanistic perspective of neurotoxicity. Chimeric Toxins Mechanisms of Action and Therapeutic Applications, the fourth volume, will focus on toxins affecting protein synthesis, their structure, genetic engineering, mechanism of action, and therapeutic application in medicine. The fifth volume, Pore Forming Peptides and Protein Toxins, will...

Quality Assurance of Herbal Ingredients

Food products such as cereals, beverage teas, potato chips, soups, and juices, as well as to sundry other products such as toilet paper, shampoos, hair conditioners, and skin care products. The quality assurance and assessment of botanical drugs, traditional or modern, requires that every available tool be accessible and applied as appropriate. Each analytical tool has its purpose and utility, and one is only superior to another in terms of the analytical goal.

Preventing Trauma During Electroshock Therapy

CONTROL OF MUSCLE SPASMS Agents that act in the CNS to block spasms are considered in Chapter 20. Two peripherally-acting agents are used, botulinum toxin (see Chapter 6) and dantrolene. Botulinum toxin A (BOTOX), by blocking ACh release, produces flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses. Inhibition lasts from several weeks to 3-4 months, and restoration of function requires nerve sprouting. Uses of BOTOX in dermatology and ophthalmology are described in Chapters 62 and 63.

Preparation of Inoculum and Incubation

C. botulinum type C strain 92-13, which was kindly provided by Prof. S. Nakamura, Kanazawa University, Kanazawa, Japan, is suitable for an inoculum, because it produces only C2 toxin. Prepare the inoculum by incubating the strain overnight at 37 C in cooked meat medium (Difco Laboratories) supplemented with 1 ammonium sulfate, 1 glucose, 1 yeast extract and 0.2 cysteine hydrochloride (pH 7.5). Transfer a 1-ml portion of the culture into 4 I of the toxin production medium in a flat-bottomed bottle (ca. 23 cm in diameter) and culture for 2 days at 37 C.

Assessment of sympathetic activity

Sympathetic hyperactivity may be present in some peripheral neuropathic pain states as part of complex regional pain syndrome (CRPS formerly known as cau-salgia or reflex sympathetic dystrophy see Chapter 27, Complex regional pain syndromes). The clinical aspects of sympathetic hyperactivity include a perception of burning-type pain soon (hours or days) after injury together with the demonstration of swelling, smooth glossy skin, and vasomotor instability. A characteristic localized osteoporosis may be observed in the extremities (Sudeck's atrophy) later on. These features may exist alone or in combination. Sweating may be affected, producing either wet or dry skin. Similarly, the skin may be cooler or warmer, depending on the degree of cutaneous vasoconstriction. In patients suspected of sympathetic dysfunction, tests can be useful to document the degree of sympathetic involvement. These include sweat testing, galvanic skin resistance, plethysmography, skin blood flow measurement...

Gel Filtration on Sephacryl S300

By these purification procedures, l-3mg of component I and 20-40 mg of component II are recovered from 4 I of culture of C. botulinum type C strain 92-13. The mixture of untrypsinized component I and trypsinized component II has high lethal activity in mice (specific activity is about 2xl04 mouse intraperitoneal 50 lethal doses per mg of protein), although each of these components alone shows very low activity even after trypsinization. The purified components I and II each show one band in SDS-PAGE, and their molecular weights as determined by the electrophoresis are 45kDa and 100 kDa, respectively.

Activation of Component II

The full biological activity of C2 toxin, a mixture of components I and II, is obtained by activation of the toxin with trypsin (Miyake and Ohi-shi, 1987 Ohishi et a ., 1980 Ohishi et a ., 1980 Ohishi, 1987). As described in Section 9.2 (Assay method for the toxin), the full activity of the toxin is produced by a mixture of untrypsinized component I and trypsinized component II. This indicates that activation of the toxin is brought about by the molecular cleavage of component II, but not of component I, by trypsin. Therefore, to study the biological activity of botulinum C2 toxin and the effect of ADP-ribosylation of cytoplasmic actin by C2 toxin on whole cells, it is essential to prepare activated component II (trypsinized component II).

Endocytosis of Two Nonlinked Protein Components in Cultured Cells

The two components of botulinum C2 toxin are functionally different proteins component II is a binding molecule, whereas component I is an ADP-ribosyltransferase, of which substrate is cytoplasmic actin monomers (Ohishi and Tuyama, 1986 Ohishi, 1986 Ohishi et a ., 1990). This indicates that the toxin binds to the cell surface and enters the cytoplasm. These steps, the binding of the two nonlinked components of C2 toxin to the cells and the endocytotic vesicles containing the components, can be visualized either directly by incubating the cells with the two differently fluorescently labeled components (Ohishi, 1992), or indirectly by immunofluorescence labeling of the two proteins with their specific antibodies. This endocytotic incorporation of the protein is not a specific feature of this toxin, but is common to all the proteins that enter cells by receptor-mediated endocytosis. However, the internalization of the toxin may be of an interest to those readers, who would like use this...

Reagents and Chemicals

Iwasaki M, Ohishi I, Sakaguchi G (1980) Evidence that botulinum C2 toxin has two dissimilar components. Infect. Immun. 29 390-394. Jansen BC (1971) The toxic antigenic factors produced by Clostridium botulinum types C and D. Onderstepoort J. Vet. Res. 38 93-98. Mason JH, Robinson EM (1935) The antigenic components of the toxins of C. botulinum types C and D. Onderstepoort J. Vet. Sei. Anim. Indus. 5 65-75. Miyake M, Ohishi I (1987) Reponse of tissue-cultured cynomolgus monkey kidney cells to botulinum C2 toxin. Microbial Pathogenesis, 3 279-286. Ohishi I, Iwasaki M, Sakaguchi G (1980) Purification and characterization of two components of botulinum C2 toxin. Infect. Immun. 30 668-673. Ohishi I, Iwasaki M, Sakaguchi G (1980) Vascular permeability activity of botulinum C2 toxin elicited by cooperation of two dissimilar protein components. Infect. Immun. 31 890-895. Ohishi I, Sakaguchi G (1982) Production of C2 toxin by Clostridium botulinum types C and D as determined by its vascular...

Identifying Potential Uses

Least the enzymatic component of the toxin, must be internalized. There is relatively little information on the underlying mechanism, although at least one study indicates that the toxin reaches the cell interior by receptor-mediated endocytosis (Simpson, 1989b). If this is correct, it would imply that the toxin must penetrate both the cell membrane and subsequently the endosome membrane. A sequence such as this is reminiscent of that utilized by other clostridial toxins, such as botulinum neurotoxin and tetanus toxin, as well as other microbial toxins (i.e., diphtheria toxin). As with the binding step, there is much that remains to be learned about the internalization step. Nevertheless, the fact that toxins possess the ability to penetrate biological membranes suggests that the mechanisms they use could have wide utility. To state the obvious, the ability to achieve efficient penetration of selected cell membranes would be highly advantageous in many areas of drug therapy.

Isolation and Purification

The components of C2 toxin can be isolated from culture superna-tants of type C and type D Clostridium botulinum. It is important to remember that these organisms are capable of producing type C and type D botulinum neurotoxin. Although there are no documented cases of type C or type D poisoning in adults, recent work has shown that the isolated human neuromuscular unction can be poisoned by type C toxin (Coffield and Simpson, unpublished). Therefore, extreme caution should be used when handling organisms that produce neurotoxin. A simple alternative that greatly diminishes the hazard of isolating type C2 toxin is to use organisms from which bacteriophages have been eliminated. Both type C and type D toxin are encoded in phages that infect Clostridium botulinum (Hatheway, 1990). Therefore, eliminating the phages from the organisms removes the hazard associated with production of neurotoxin, but it does not alter growth and reproduction of the organisms, or their ability to make C2...

Intracellular Step see Table

Representative Studies Reflecting the Use of Clostridium botulinum C2 Toxin as a Research Tool Table 1. Representative Studies Reflecting the Use of Clostridium botulinum C2 Toxin as a Research Tool The first area of investigation in which C2 toxin was used as a research tool was in the analysis of storage and release of chemical mediators (Considine and Simpson, 1991). This was a natural outgrowth of the fact that other clostridial toxins, and particularly botulinum neurotoxin and tetanus toxin, have profound effects on transmitter release (Simpson, 1989a Montecucco and Schiavo, 1994). It therefore seemed logical to determine whether clostridial binary toxins had similar effects. In addition, at the time that most of the original work on binary toxins and chemical mediators was done, there was a prevailing belief that the cytoskeleton played an integral role in governing the location and mobility of vesicles. Thus, it was reasonable to assume that any toxin that disrupted...

Molecular Mode of Action of the Toxins

In the past decade, toxins produced by various species of Clostridium were reported to disrupt the ACTSK by ADP-ribosylation of either actin, as does the C2-toxin from C. botulinum (Aktories et a ., 1986 Reuner et ai, 1987), or the small GTPase Rho, as does exoenzyme C3 from the same bacterium (Aktories et al., 1987 Chardin et ai, 1989). However, neither of the C. difficile toxins was found to have any ADP-ribosyltransferase activity (Florin and Thelestam, 1991 Just et al., 1994b Popoff eta ., 1988).

Modulation Of Presynaptic Glutamate Release By Nitric Oxide

III we reviewed the evidence showing that glutamate toxicity is mediated by NMDA glutamate receptors which, when activated, lead to Ca2+ entry which, in turn, activates the production of NO by NOS. Thus, it is the increase in NO concentration in the cell that would be responsible for many of the toxic effects of glutamate (6). On the other hand, recent observations also show that NO donors and peroxynitrite (ONOO ) stimulate a sustained increase of Ca2+ , in cerebellar granule cells, which can be prevented by inhibitors of NMDA receptors, such as MK-801, suggesting that NO and ONOO causes the release of glutamate (16), which then activates its receptors postsynaptically. In these studies, Leist et al. (16) showed that both the intracellular Ca2+ increase and apoptosis elicited by ONOO or the NO donors were prevented by blocking exocytosis with tetanus toxin or botulinum neurotoxin C.

Conclusions and Perspectives for the Future

Obviously the C. difficile toxins will become extremely useful tools applications for further studies of how the Rho subfamily proteins control the of C. difficile toxins ACTSK, as well as aspects of cell proliferation in different types of cells (Olson et al., 1995). These toxins will be easier to use for manipulation of small GTPases than the exoenzyme C3 from C. botulinum, because they are internalized into cells and are more potent. Their drawback compared with C3 is that they attack more than one target protein. Preparation of mutant toxins, fragments of toxins or hybrid toxins which discriminate between various GTPase targets might solve this problem and allow sophisticated studies of the cellular cross-talk between small GTPases (see further discussion in Chapters 10 and 15).

Surface binding and cell entry

The clathrin-dependent and clathrin-independent entry pathways converge within endosomes (Sandvig and van Deurs, 1996). All endocytosed toxins therefore enter endosomal compartments, and respond to this in one of two ways either they cross the endosomal membrane to enter the cytosol or they do not. DT translocates from endosomes, as do other bacterial toxins that do not act by directly inhibiting protein synthesis, including anthrax, botulinum and tetanus toxins.

Toxin B Action on Intact Cells

Toxin B is an intracellularly acting cytotoxin and enters the cell via a receptor-mediated endocytosis pathway to reach the endosomes, from which the toxin is translocated to the cytoplasm (Florin and Thelestam, 1986 Henriques etal., 1987). Because of this specific mode of entry, the toxin concentration needed for intoxication of cells is low (lOOng ml for about 4h). In contrast, Clostridium botulinum exoen-zyme C3 (23.5 kDa), which ADP-ribosylates the Rho subtype proteins RhoA, B and C only, enters the cells by a non-specific uptake process, possibly by pinocytosis. Therefore, C3 has to be applied in high concentrations (about 30ng ml) for 24 h or longer.

Toxin B a Tool in Cell Biology

Use of the ADP-ribosyltransferase C3 from Clostridium botulinum resulted in the identification of the involvement of the Rho proteins in the regulation of the microfilament system. The advantage of C3 (selective modification of RhoA, B and C) is offset by the disadvantage of poor cell accessibility. In contrast, toxin B can enter the cells by a specific mechanism. Therefore, the concentration needed is quite low and the incubation times are in a moderate range (2-6 h). However, toxin B glucosylates not only Rho subtype proteins, but also all members of the Rho subfamily (Rho, Rac and Cdc42). Although these GTPases are involved in the control of the actin cytoskeleton, each of them exhibits a specialized function in the regulation of the complex microfilament system. Furthermore, these Rho GTPases exhibit functions which are apparently not related to the cytoskeleton for example, they participate in the regulation of transcription factors (Minden etai, 1995 Hill etal., 1995 Coso etal.,...

The Origin of Clostridial Neurotoxins

Botulism, on the other hand, is characterized by a generalized muscular weakness. In its severe form, a generalized flaccid paralysis becomes evident in the victim and death results from respiratory failure (Hatheway, 1995). The causative agents of botulism are the neuro-toxigenic strains of Clostridium botulinum (van Ermengem, 1897), C. barati and C. butyricum (Hall et a ., 1985 Aureli et a ., 1986). So far, seven different serotypes of botulinum neurotoxin (BoNT), called A to G, have been identified. TeTx and BoNTs are the most potent toxins known. In fact, the 50 lethal dose (LD50) in mice, human and horses varies between 0.1 ng and 1 ng of toxin per kg of body weight. Interestingly, different animal species show a great range of sensitivity to TeTx and to BoNTs. While mice are exquisitely sensitive to TeTx, rats and birds are quite resistant, and turtles are completely insensitive to TeTx effects (Payling-Wright, 1955).

Structure of Clostridial Neurotoxins

The mechanism of activation of tetanus and botulinum neurotoxins. The toxins are produced as an inactive single polypeptide chain of 150 kDa, composed of three 50 kDa domains, connected by protease-sensitive loops. The toxins are activated by selective proteolytic cleavage which generates two disulfide-linked chains L (50kDa) and H (100kDa). The three domains play different functional roles in cell penetration Hc is responsible for cell binding and HN for cell penetration. Reduction takes place inside the nerve cells and liberates the metallo-protease activity of the L chain in the cytosol Fig. 1. The mechanism of activation of tetanus and botulinum neurotoxins. The toxins are produced as an inactive single polypeptide chain of 150 kDa, composed of three 50 kDa domains, connected by protease-sensitive loops. The toxins are activated by selective proteolytic cleavage which generates two disulfide-linked chains L (50kDa) and H (100kDa). The three domains play different...

Mice Carrying a Null Allele of the GR GRnulnuN Show Complete Penetrance of Perinatal Lethality

Analysis of GRnull null mice revealed only few differences compared to homozygous mutants carrying the hypomorphic allele. However, some of the phenotypes were more pronounced in GRnull null mice than in GRhypo hypo mice. As discussed earlier, this was especially obvious in the case of postnatal survival, but also in the case of the adrenal medulla. A major difference was observed for the skin, which is only altered in GRnull null mice. Whereas GRhypo hypo mice have normal skin at birth, the skin of GRnull null mice appears

Clostridial Neurotoxins How Do They Work

Clostridial neurotoxins are proteins that are produced by the anaerobic bacteria Clostridium tetani (tetanus toxin) and Clostridium botulinum (botulinum neurotoxins). Whereas tetanus toxin (TeTx) comprises a single molecular species, different strains of Clostridium botulinum produce seven different types of botulinum neurotoxin (desig- noted BoNT A , B, CI, D, E, F, and G) that were originally differentiated using immunological methods, and that represent different proteins. TeTx and BoNTs differ in their clinical manifestations, clinical symptoms Tetanus toxin poisoning produces tetanus, i.e. muscle contractions resulting in spastic paralysis. In contrast, botulinum neurotoxins cause botulism, which is characterized by flaccid paralysis. This difference reflects differences in the anatomical level of action of these toxins. TeTx acts primarily on the CNS where it blocks exocytosis from inhibitory glycinergic synapses in the spinal cord. Loss of inhibitory control results in...

Neuromuscular Junction Preparations

Most of the general aspects of the action of clostridial neurotoxin have been established using neuromuscular junction preparations as experimental model systems (Habermann and Dreyer, 1986). The neuromuscular endplate is the principal target in the natural poisoning process of botulinum neurotoxins. As little as 0.1 nM of BoNT A is sufficient to completely block acetylcholine release within 90min (Dolly et a ., 1984 Gansel et a ., 1987). With TeTx, higher concentrations are required to achieve the same result (Dreyer, 1989). Several different neuromuscular junction preparations have been used, such as mouse hemidiaphragm, the levator auris longus muscle, the triangularis sterni nerve-muscle of mice, or the extensor digitorum longus muscle from rat. The mouse hemidiaphragm preparation is one of the most widely used systems. Inhibition of transmitter release can be conveniently monitored by recording from the muscle fiber or by measuring the strength of contraction. Furthermore,...

Mitigation Of Effects

Nausea, vomiting, and diarrhea have been induced by ingestion of boron in humans. Some authors recommend reducing absorption of boron from the gastrointestinal tract by administration of emetics (e.g. syrup of ipecac) and cathartics (e.g. magnesium sulfate) (Stewart and McHugh 1990). Caution should be, however, taken not to induce further damage to the esophageal mucosa or to cause aspiration of the vomit into the lungs during emesis. There is disagreement regarding the efficiency of activated charcoal in preventing absorption of boron from the gastrointestinal tract following oral exposure (Ellenhorn and Barceloux 1988 Stewart and McHugh 1990). It has been suggested that activated charcoal be administered following gastric evacuation, but its effectiveness has not been established (Ellenhorn and Barceloux 1988). Administration of intravenous fluids may be required if severe dehydration or shock develop and local skin care may be necessary if skin desquamation occurs (Stewart and...

Regional Anesthesia and Other Interventions

In patients with moderate to severe TBI, the development of spasticity (especially extensor hypertonia of the lower limbs) can contribute to chronic pain. Tizanidine, cutaneous electrical stimulation, and cryotherapy have been beneficial in relieving spasticity in refractory cases, intrathecal baclofen and injections of botulinum toxin or alcohol neurolysis have been shown to be effective (Lahz and Bryant 1996, Branca et al. 2004).

Intrathecal drug delivery

There are no randomized prospective clinical trials of intrathecal medication for CRPS. Reported indications are for pain management and the usual pharmacology has been employed singly or, more commonly, in combination. Agents named in case reports and series include local anesthetics (usually bupivacaine), opioids (morphine, hydromorphone, fentanyl), adjuvants (clonidine, baclofen63 ), sodium channel blockers (ziconotide),64 V and botulinum toxins.65 V This route is discussed in more detail in Chapter 31, Intrathecal drug delivery in the Practice and Procedures volume of this series.

Sources for Clostridial Neurotoxins

Although the toxins are produced in large amounts by the relevant bacterial strains and are not difficult to purify, until recently most of them have been available only to a limited number of laboratories. The main reason for this is their extreme toxicity, particularly in the case of the botulinum neurotoxins.

Musculoskeletal pain

Guide clinicians in a rational approach to anti-spastic treatment for SCI.49 I A number of approaches are traditionally used. Oral baclofen may be sufficient to control the symptoms and is the first-line approach. Alternatively, diazepam may be used, but consideration must be given to the side effects associated with benzodiazepine use. Injection of botulinum toxin has also been suggested to be effective in the management of localized spasticity.50 Insertion of an intrathecal infusion device is invasive and is considered a second-line approach. However, there is good evidence to support the effectiveness of intra-thecal baclofen administered in this way for the relief of muscle spasm where there is poor control with oral administration.51,52,53 I

Intrathecal baclofen therapy

Figure 33.5 Severe traumatic brain injury. (a) The patient has had botulinum toxin injections to left biceps and brachialis. (b) The patient has had botulinum toxin to biceps and brachialis of both arms plus musculocutaneous nerve phenolization. Figure 33.5 Severe traumatic brain injury. (a) The patient has had botulinum toxin injections to left biceps and brachialis. (b) The patient has had botulinum toxin to biceps and brachialis of both arms plus musculocutaneous nerve phenolization.

Nonpharmacological Treatment

Physical treatment modalities, such as hot and cold packs, ultrasound and electrical stimulation, improvement of posture, relaxation, and exercise programs, have all been used. However, the majority of these treatments have not been properly evaluated, and most of the reported studies are not controlled. In one open-label study, the beneficial long-term effect of physical therapy was excellent,114 IV whereas a controlled study reported only a minor effect on headache frequency after eight weeks of standardized treatment.115,116 II A recent controlled study concluded that there was no significant effect of spinal manipulation on patients with episodic tension-type headache.98 II Likewise botulinum toxin plays no role in the treatment of tension-type headache or migraine.117,118 II

Management and prognosis

And placebo for the management of TMJ arthralgia.55 II A short-acting benzodiazepine (triazolam) has also been shown to improve sleep but failed to provide significant pain relief in myofascial TMD patients.56 II Cyclo-benzaprine (a muscle relaxant) has been shown to have a minor but significant effect on jaw-muscle pain upon awakening57 II and it has been suggested that flupirtine (another muscle relaxant), with its additional effects on potassium channels and membrane-stabilizing actions, may be useful in management of myofascial TMD pain.58 V A combination of paracetamol, codeine, and dox-ylamine succinate (antihistamine) provided significantly greater pain relief than placebo in another study on mixed TMD patients.59 III Also, low doses of tricyclic antidepressants (TCA) have been shown to provide significantly better pain relief than placebo.60 III Open studies later supported the usefulness of TCAs in the management of persistent TMD pain.61 IV Intraarticular morphine (0.1-1.0...

Uvinduced Photodamage And Photoprotection

Continuous exposure to UV irradiation (both UVA and UVB) leads to skin cancer and other photoaging complications, which are typically mediated by the reactive oxygen species (ROS), generated in the oxidative pathways (Dummermuth et al., 2003 Pallela et al., 2010). Normal skin cells

Etiology and management

Some studies have shown disappointing results when targeting chronic chest pain with therapies aimed at treating esophageal pain.95,96 These trials have not included PPI and the poor response rate may be related to the small proportion that has positive provocation studies in which a smooth muscle relaxant may prove beneficial. This benefit is seen in long-term follow up and the physiological benefit of a reduction in spasm of the esophageal wall does not always translate into a reduction in reported chest pain.95 Another drug that has been used as part of diagnostic esophageal tests is the spasmomimetic agent edrophonium, but this appears to produce chest pain symptoms, as well as alterations in esophageal motility.97 Other patients have other esophageal motor disorders that do not fit into any diagnostic categories. One study reported that in 72 percent of these patients, botulinum toxin injections at the gastroesophageal junction can be beneficial for up to 18 months. The mean...

Trigger Point Injections

Eliminating the positive feedback arc.10 No RCTs specifically looked at chronic pelvic pain and trigger point injections. One small RCT compared trigger point injections in patients with myofascial syndrome with bupiva-caine 0.5 percent, etidocaine 1 percent, or saline. Subjective improvement was noted with the local anesthetic treatment over saline.146 II Slocumb10 III studied the response of 122 women with abdominal pelvic pain characterized by dermatome hypersensitivity and trigger points 89.3 percent reported relief or improvement in pain, such that no further therapy was required over the duration of the study (3-36 months). Further management of myofascial pain is described in Chapter 12, Diagnostic procedures in chronic pain. Botulinum toxin injections were effective in reducing pain in patients with myofascial pain syndrome but the difference in pain between the two modes was not significantly different.147 II

Therapeutic Interference with Coiled Coil Interactions

Among the structurally and functionally diverse coiled-coil proteins discussed so far, SNARE proteins (Sect. 2.2) and viral fusion proteins (Sect. 3) are of particular therapeutic relevance because they both represent targets of approved and widely employed drugs, botulinum toxins and fusion inhibitors. However, the specificity and reversibility of their association and the crucial roles they play in many central cellular processes suggest that many other coiled coils might also be considered promising targets for pharmacological interference.

The Treatment Of Pruritus

The term pruritus is derived from the Latin prurire, which means to itch. Pruritus is a symptom unique to skin that occurs in a multitude of dermatologic disorders, including dry skin or xerosis, atopic eczema, urticaria, and infestations. Itching also may be a sign of internal disorders, including

Doseresponse Relationships Risk Assessment

There are marked differences in the LD50 values of various chemicals. Some result in death at extremely low doses (LD50 for botulinum toxin 10 pg kg) others may be relatively harmless in doses of several grams or more (e.g., penicillin). Even a single chemical may be safe at low doses and quite toxic at higher doses, or safe acutely but harmful over time. Thus, it is not possible to categorize all chemicals as either safe or toxic. The real concern is the risk associated with use of the chemical. Depending on the use and disposition of a chemical, a very toxic compound ultimately may be less harmful than a relatively nontoxic one.

Examples of Translocated Peptides and Proteins

The Clostridium botulinum exoenzyme C3 is able to ADP-ribosylate the small G-protein, rho, in a cell free system, but is unable to enter cells (except at very high concentrations) because it lacks a B-moiety. Constructs where exoenzyme C3 was linked to the N-terminal end of diphtheria toxin or to toxin where the N-terminal part of the Afragment had been deleted, were able to translocate the exoenzyme-containing fusion protein into the cytosol and interfere with the organization of actin filaments (Aullo et a ., 1993).

Dosing of NMDA antagonists

The dose of dextromethorphan in children over the age 12 years is 30 mg every six to eight hours up to a maximum dose of 120 mg 24 hours. The adult recommended dose of memantine is 5 mg 24 hours, up to a maximum dose of 20 mg 24 hours. Future studies are needed to demonstrate the efficacy and safety of botulinum toxins for pediatric tension headache and other complementary therapies of magnesium, riboflavin, feverfew, and butterbur.112 V

Clinical trials in tensiontype headache

Prophylactic treatment of chronic tension-type headache, antidepressant drugs and botulinum toxin have been investigated. After positive open studies, botulinum toxin has been studied in chronic tension-type headache but the conclusion of these RCT is that botulinum toxin is not more effective than placebo 89 .Thus in the most recent large RCT including 298 randomized patients, botulinum toxin A admistered in doses from 50 U to 150 U was not different from placebo 90 .

Release Of Acetylcholine And Its Modulation By Toxins

Kotter Change Model Penguins

The release of ACh and other neurotransmitters by exocytosis is inhibited by botulinum and tetanus toxins from Clostridium. Botulinum toxin acts in the nerve ending to reduce ACh vesicular release (see Chapters 9 and 63 for therapeutic uses of botulinum toxin). FIGURE 6-3 A cholinergic neuroeffector junction. The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent carrier. This uptake can be blocked by hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyltransferase (ChAT). ACh is transported into the storage vesicle by a carrier that can be inhibited by vesamicol. ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP. Release of ACh and the Co-T occurs following depolarization of the membrane, which allows the entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated Ca2+ in promotes fusion of the...

Skin whitening activity

Skin whitening has been in practice around the world with Asia as the largest market. As much Asian female preferred more fair skin tone, skin whitening product has become and continues to be the best selling skin care products in Asia (Wang et al., 1997). Tyrosinase inhibition is the most common approach to achieve skin hypo-pigmentation as this enzyme catalyzes the rate-limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to show induced effects in clinical trials. In this chapter, we review some potential marine organisms with its effects on pigmentation of skin focusing mainly on tyrosi-nase inhibitors. Hence, development of novel tyrosinase inhibitors from natural resources continues to arouse great attention, and in recent years, marine algae have attracted great attention in the search of natural tyrosi-nase inhibitor agents (Solano et al., 2006).

Neurotoxin From Conus Snails

Neurotoxin From Conus Snails

Investigations of marine toxins during the past few decades have provided a remarkable diversity of molecules new to science. Besides stimulating chemical interest in unique structures posing many synthetic challenges, these substances often possess such unique targets that they can serve not only as useful research tools, but in some cases can either be useful drug candidates in their naturally occurring forms or as leads for designing analogs that possess even more selective actions. Traditionally, small, non-peptide molecules (MW < 500) have served as lead compounds for drug design, due to their superior bioavailability and ease of synthesis, but this approach is rapidly being enlarged to include much larger molecules including peptides and nucleic acids. Who would have thought that an extremely lethal, large bacterial protein like botulinum toxin would become a very useful drug for treating various muscle spasms (Cooper 2007). Similarly a sea anemone peptide of 35 residues (ShK,...

Receptor binding domain

The DT-based fusion toxins can also be used to determine the minimum requirements for binding and internalization of their respective ligands. Studies are currently underway using a DT-based fusion toxin with differently sized fragments from the C-terminus of Botulinum toxin A as targeting ligands (Ratts and Murphy, unpublished). Kreitman et al. (1994) mutated the IL-4 portion of a Pseudomonas exotoxin A-based fusion protein, such that the N-terminal 38 amino acid residues of IL-4 were moved to the C-terminus. The resulting construct bound to the IL-4 receptor with 10-fold better affinity. Permutations are currently being created in the IL-7 portion of DAB389IL-7 to determine if a protein with greater affinity for the IL-7 receptor can be produced (vanderSpek, unpublished).

Other Agents That Suppress Motility

Smooth muscle relaxants such as organic nitrates and Ca2+ channel antagonists (see Chapter 31) often produce temporary, if partial, relief of symptoms in motility disorders such as achalasia, in which the lower esophageal sphincter fails to relax, resulting in a functional obstruction to the passage of food and severe difficulty in swallowing. Another approach relies on the use of botulinum toxin, injected in doses of 80 200 units directly into the lower esophageal sphincter via an endoscope. This agent inhibits ACh release from nerve endings (see Chapter 9) and can produce partial paralysis of the sphincter muscle, with significant improvements in symptoms and esophageal clearance. However, its effects dissipate over a period of several months, requiring repeated injections. Botulinum toxin also is being used increasingly in other GI conditions such as chronic anal fissures.

Drugs and Biological Agents Used in Ophthalmic Surgery

Botulinum toxin type a in the treatment of strabismus, ble-pharospasm, and related disorders Botulinum toxin type A (botox) is used to treat strabismus, blepharospasm, Meige's syndrome, spasmodic torticollis hemifacial spasm, facial wrinkles, and certain migraine headaches (see also Chapter 9). By preventing acetylcholine release at the neuromuscular junction, botulinum toxin A usually causes a temporary paralysis of the locally injected muscles. The variability in duration of paralysis may be related to the rate of developing antibodies to the toxin, upregulation of nicotinic cholinergic postsynaptic receptors, and aberrant regeneration of motor nerve fibers at the neuromuscular junction. Complications related to this toxin include double vision (diplopia) and lid droop (ptosis).

Application of the Snare Hypothesis to Insulin Exocytosis

Several of the proteins which, it has been suggested, regulate neurotransmitter release have recently been identified in the (3-cell, and for a number of them a function in insulin exocytosis has been established. The ubiquitous fusion factor NSF is present in the insulin-secreting cell line HIT-T15. In addition, aSNAP, also present in these cells, appears to be one of the factors in cytosol required for Ca2+-triggered insulin exocytosis (Kiraly-Borri et at., 1996). The v-SNARE VAMP-2 was localized to insulin secretory granules (Jacobsson et a ., 1994). It is also expressed on the SLMVs in the (3-cell, as demonstrated by its colocalization with synaptophysin, a synaptic vesicle membrane protein (Regazzi eta ., 1995). Clostridial neurotoxins have been used to investigate the functional importance of several of the SNARE proteins. As insulin-secreting cells do not express the ganglioside receptors for the clostridial neurotoxins on the cell surface, the toxins were introduced into the...

Different Classes Of Heterotrimeric G Proteins And Their Coupling Properties

Olfative Pathway

Interestingly, the constitutively active Ga12 and Ga13 forms are oncogenic. Overexpression of these proteins leads to the transformation of cultured fibroblasts (64). The growth-promoting activity and oncogenicity of the activated forms is dependent on Rho signaling because their capability to form foci is inhibited when the Rho-sensitive Clostridium botulinum toxin C3 exoenzyme is present (65). The link between Ga12 13 and Rho signaling has occurred through RhoGEFs such as p115-RhoGEF, PDZ-RhoGEF, and leukemia-associated RhoGEF (LARG). Ga12 13 can physically interact with these RhoGEFs through their RGS domain and may stimulate their guanine nucleotide exchange activity toward Rho (66). Nevertheless, Ga12 and Ga13 display distinct signaling pathways toward Rho. Activated Ga13 can stimulate the GEF activity of p115-RhoGEF, whereas Ga12 cannot. The difference is also shown in Ga13 knockout mice. The Ga13-deficient mice show embryonic lethality resulting from defects in the vascular...

Exceptions To The Rules

Preferred treatment for Gaucher's disease is enzyme replacement therapy. Another medical application of proteins is the injection of botulinum toxin type A (trade name Botox) for cosmetic applications, severe underarm sweating, cervical dystonia, uncontrollable blinking, and misaligned eyes. The toxin is a 900 kDa protein consisting of two protein strands linked by a disulfide bridge. In all of these applications, the injection partially paralyzes the tissue. The large size of the protein prevents it from migrating throughout the body and causing unwanted effects elsewhere.

Cholinergic System

This figure depicts the cholinergic pathways in the brain (A) and various regulatory processes involved in cholinergic neurotransmission (B). Choline crosses the blood-brain barrier to enter the brain and is actively transported into cholinergic presynaptic terminals by an active uptake mechanism (requiring ATP). This neurotransmitter is produced by a single enzymatic reaction in which acetyl coenzyme A (AcCoA) donates its acetyl group to choline by means of the enzyme choline acetyltransferase (ChAT). AcCoA is primarily synthesized in the mitochondria of neurons. Upon its formation, acetylcholine (ACh) is sequestered into secretory vesicles by vesicle ACh transporters (VATs), where it is stored. Vesamicol effectively blocks the transport of ACh into vesicles. An agent such as B-bungarotoxin or AF64A is capable of increasing synaptic concentration of ACh by acting as a releaser and a noncompetitive reuptake inhibitor, respectively. In turn, agents such as botulinum toxin are able to...

Electrical Barrier

Dry skin offers high impedance to the flow of an electrical current (18). Stripping the skin by successively removing layers of the stratum corneum with an adhesive tape reduces the electrical resistance about sixfold, which tells us that the horny layer is the skin's prime electrical insulator. Its high impedance complicates the measurement of body potentials, as is done in electroencephalograms and electrocardiograms. Consequently, electrodes having large contact areas are used to monitor the brain's and the heart's electrical rhythms. Granular salt suspensions or creams and pastes containing high percentages of electrolytes are placed between the electrode surface and the skin to assure that the electrical conductance is adequate to make the measurements.

Surface Effects

Of the many possible dermatological targets mentioned above, the skin surface is clearly the easiest to access. Surface treatment begins at the fringe of cosmetic practice. Special cosmetics are available to hide unsightly blemishes and birthmarks. These lessen self-consciousness and are psychologically uplifting. Applying a protective layer over the skin is sometimes desirable. For example, zinc oxide pastes are used to create a barrier between an infant and its diaper that adsorbs irritants found in urine, ameliorating diaper rash. These same pastes literally block out the sun and at the same time hold in moisture, protecting the ski enthusiast from facial sun and windburns on the high slopes. Transparent films containing ultraviolet light-absorbing chemicals are also used as sunscreens. Lip balms and like products lay down occlusive (water-impermeable) films over the skin, preventing dehydration of the underlying stratum corneum and thereby allaying dry skin and chapping. The...

Adpribosylation

Fer of the ADP-ribosyl group of NAD+ to a protein acceptor, producing the modified protein and free nico-tinamide. The reaction scheme catalyzed by the cholera toxin A subunit and a rabbit muscle protein has been determined to be random1. The amino acyl residues that have been reported to have been modified in these reactions include a cysteinyl residue (e.g., via pertussis toxin2), an arginyl residue (via cholera toxin A), an asparaginyl residue (via botulinum toxin), and a modified histidyl residue (via diphtheria toxin). In addition, the subunit structure appears to have a role in substrate specificity13.

Laminarin

Another constituent has been found to assist with this process via a tumor angiogenesis blocking mechanism. Last but not least, L. japonica is great for the hair, skin, and nails, taken either internally or applied topically in masks and creams. Because of its high mineral content and polysacchar-ides, the seaweed helps by adding important nutrients to the skin, and by removing toxins. In its extract form, this seaweed can be easily incorporated into a range of skin care products to help give the skin a silky smoothness.

In Cultured Cells

Cell line derived from human colon carcinoma, and cultured in vitro as a polarized epithelium, forms the tight junctions essential for epithelial barrier function. Both ToxA and B caused the disintegration of these tight junctions, measured as a loss of barrier function correlated with disruption of actin filaments (Hecht et al., 1988, 1992). This event occurred even at low toxin concentrations which did not cause rounding of the cells. Indeed, recent work with C. botulinum exoenzyme C3 demonstrated that Rho regulates the tight junctions and perijunctional actin organization in T-84 cells (Nusrat et al., 1995). This is consistent with the notion that the C. difficile toxins may disrupt epithelial barrier function due to glucosylation, and thereby inactivation, of Rho.

Homeopathy

The homeopathic physician must take a different kind of history from the patient than an allopathic physician would. The homeopathic history is a detailed inquiry into the symptom complex and the environment and mind of the patient with respect to the symptoms. The purpose of this is to individualize the selection of remedies to match the symptoms. Classification of diseases and pathophysiology are not as important as the nature of the symptoms. Thus, diabetic neuropathy is not as relevant to a homeopathic assessment as burning, sensitive skin, interference with sleep, etc. This construct becomes useful to the allopathic practitioner, particularly when the pathophysiology of symptoms, such as chronic pain, may be obscure.

Maria A Blasco

Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. In addition, we have recently shown that telomere length is regulated by a number of epigenetic modifications, thus pointing to a higher-order control of telomere function. A key process in organ homeostasis is the mobilization of stem cells out of their niches. Defects in organ homeostasis are present both in cancer and in aging-related diseases. Here we will discuss that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of epidermal stem cells. On one hand, we will show that telomere shortening in the absence of telomerase negatively impacts on the mobilization of epidermal stem cells. On the other...

Juan Guinea Viniegra

The proto-oncogene c-fos is a major nuclear target for signal transduction pathways involved in the regulation of cell growth, differentiation, and transformation. To investigate the function of c-fos in skin development and skin tumor formation, we achieved specific conditional deletion of c-fos in the epidermis. Mice lacking c-fos in the keratinocytes (c-fos) show normal skin and no obvious phenotype. In vitro treatment of c-fos f f or c-fos keratinocytes with Ca2+ or with the promoting agent, TPA, induced premature differentiation of the keratinocytes in the absence of c-fos. A similar phenotype was observed in newborn and adult mice treated topically with TPA. The observed premature keratinocyte differentiation in the c-fos mice is due to an increased Notch1 activation, which induces an increase in p21 and Caspase 3 protein expression. In the context of oncogenic signals driven by H-RasV12, c-fos keratinocytes overexpressing Ras show again premature differentiation. In the absence...

Invertebrate Neurons

Large neurons A major advantage of some invertebrate model synapses is the large size of the neurons, allowing easy access with microelectrodes to pre-and postsynaptic cells. For instance, in the buccal ganglion of Aplysia californica two large cholinergic neurons contact the same postsynaptic neuron and form a chloride-dependent inhibitory synapse. With this preparation it is possible to microinject toxin into one neuron while the second neuron serves as a control for the excitability of the postsynaptic neuron (Tauc eta ., 1974 Poulain etal., 1986). This preparation is almost as sensitive to botulinum toxins as the vertebrate neuromuscular junction, and the mechanism of poisoning has been extensively investigated (Poulain et a ., 1989). Recently, toxins have also been shown to be active when microinjected into presynaptic compartments of the leech Retzius cell and the squid giant synapse (Bruns and Jahn, 1995, Bruns and Jahn, in preparation Hunt et a ., 1994 Llinas etal., 1994)....

Precautions

When using these toxins, one should be aware that these are the most potent known poisons. Exposure is less a problem for TeTx since protection through immunization is easily available (most people in developed countries are immunized) and since the toxin is not taken up by the gastrointestinal tract. Care should be used in manipulating these toxins (particularly botulinum toxins, which can resist the acidic and protease-rich environment within the gastric juice when com-plexed with the hemagglutinating and non-toxic proteins) and in handling the material that has been in contact with them. Always use gloves, protective goggles and appropriate clothes.

Cancers Of The Skin

Y In normal skin, the main reservoir of proliferating keratinocytes consists of basal cells from which the upper protective layers of the skin are formed by terminal differentiation. This 'transient amplifying' fraction of cells can be replenished from stem cells. Normally, hedgehog activity is restricted to precursor cells. Its

General Remarks

In contrast to neuronal cells, a number of toxins, which provide interesting tools for the investigation of cell function, do not cross the cell membrane. Controlled cell permeabilization allows the intracellular application of these molecules in a system which retains the exocy-totic response to stimulating or inhibiting agents. This can be achieved by the use either of detergents or of pore-forming toxins (Holz et a ., 1992, Ahnert-Hilger et a ., 1993). The detergent digitonin solubilizes membranes according to their cholesterol content and is therefore in general suitable for the creation of pores, mainly in the plasma membrane. Although this approach has often been used successfully in chromaffin cells (Holz et a ., 1994, Holz et a ., 1992), we did not find it a reliable method for insulin-secreting cells (Wollheim and Ullrich, unpublished). An alternative approach has been described, i.e., intracellular application of toxins by electrophoresis (Boyd et a ., 1995). This method is...

Dystonia

The gene for DRD was mapped to a locus on chromosome 14.20 The use of botulinum toxin A (Botox, Dysport) injections for focal and segmental dystonia has greatly improved the therapeutic possibilities in this type of disorder.21,22 Unfortunately, botulinum toxin injections cannot be used to treat segmental and generalized dys-tonias, because of the greater number of muscles involved and the larger doses that would be needed. Very large doses may stimulate antibody formation or even induce generalized weakness. Even doses used to treat cervical dystonia have been found to produce blocking antibodies in some patients. A list of medications used for the treatment of this disorder is presented in Table 33.2.

Oral

Skeletal muscle relaxants have no analgesic effect for pure bone fracture pain. However, muscle spasm is a frequent accompaniment of any fracture, can be painful by itself, but most importantly increases fracture pain by compounding the mal-alignment of fractured bone. Fracture reduction and stabilization may by themselves reduce or remove muscle spasm, but where it remains troublesome, a skeletal muscle relaxant drug may be indicated. Baclofen has a fairly rapid onset of action and a favorable side effect profile and can be used in adults at a dose of 15-60 mg daily in three divided doses. Where muscle spasm becomes chronic, then other agents such as dantrolene or tizanadine may be considered. Alternatively, if the spasm is confined to a well-defined muscle or muscle group, then botulinum toxin injection may become an option.

Injection therapies

Overall, there are conflicting or poor quality studies to support the use of epidural, facet joint, sacroiliac joint, radiofrequency procedures, intradiscal electro-thermotherapy (IDET), botulinum toxin injections, pro-lotherapy, trigger point injections, or spinal cord stimulation for patients with CLBP.15 IV Proper patient selection and wise counseling to set realistic expectations for these procedures is important. They should only be performed with the intent to move along the rehabilitation process, after proper screening for contraindications, and executed in experienced hands. Patients should

Chronic Neck Pain

In chronic neck pain, there is no solid evidence that the use of the following is effective traction, use of cervical collar, TENS, acupuncture, botulinum toxin injections, conventional physical therapy, and manipulation therapy. Exercises appear to be as effective as manual therapy or physical therapy in reducing pain. There is evidence that percutaneous radiofre-quency neurotomy for cervical facet pain provides pain relief for chronic neck pain. Pain from the facet joints can be diagnosed by diagnostic blocks of the medial branches that innervate the joints.

Retinoids

The usual dosing regimen of orally administered ATRA is 45 mg m2 day until remission is achieved. ATRA as a single agent reverses the hemorrhagic diathesis associated with APL and induces a high rate of temporary remission. In combination with an anthracycline, ATRA achieves > 70 relapse-free, long-term survival. ATRA reaches a plasma concentration of 400 ng ml and is cleared by CYP-mediated elimination with a t 2 of < 1 hour. Treatment with CYP inducers increases drug metabolism and may result in resistance to ATRA. Remission rate and time to remission induction improve with the inclusion of other chemotherapy. When used as a single agent, especially in patients with > 5000 leukemic cells per mm3 in the peripheral blood, ATRA induces an outpouring of cytokines and mature appearing neutrophils of leukemic origin. These cells can clog small vessels in the pulmonary circulation and elsewhere, resulting in the retinoic acid syndrome characterized by fever, respiratory distress,...

Biological Factors

Beyond considering the solvent perse, formulators must also consider the biology and state of the skin, and whether transient or sustained delivery is desired. Generally, semisolid formulations are selected for increased residence on the skin, and liquid formulations for a rapid short-term input of permeant into the skin. In both the clinical and cosmetic domains, skin type can affect the choice of formulation base in that usually for normal to oily skin types, gels are preferred but for normal to dry skin types lotions are usually selected and for dry skin, creams are often the preferred base. As well as skin type, the skin site to be treated can affect vehicle selection. For example, for hairy areas lotions, gels or sprays are usually preferable as these spread better whereas for intertriginous areas, creams or lotions are usually employed.

Bioassay

This assay is based on injection of toxin into live mammals (usually mice) and is used to check the potency (lethality) of a given toxin preparation. It has also been applied to the study of substances that antagonize the effect of the toxin by interfering with the initial steps of poisoning (Bakry etal., 1991 Simpson etal., 1990). Normally, the LD50 or the time to death is measured (Boroff and Fleck, 1966) and compared with non-treated control animals. It is also possible to inject small amounts of toxin into mammals (mainly BoNT A) to produce local paralysis which, may result in long term morphological and functional changes (Angaut-Petit et a ., 1990). The highly localized and long-lasting action of the botulinum neurotoxins led to the widespread use of BoNT A in the symptomatic treatment of local muscle spasms (Hughes, 1994).

Proctalgia fugax

No etiology or method of treating preventing proctalgia fugax has been universally accepted. The brief nature of most episodes makes most reactive pharmacologic treatments inadequate since the episode resolves spontaneously prior to the onset of treatment effects. Inhaled salbutamol, clonidine, nitroglycerine, antispasmodics, botulinum A toxin, and calcium channel blockers have all been reported as effective in either reactive or preventive fashions, but none in controlled trials. Heat or pressure applied to the perineum, food drink consumption, dilation of the anal sphincter, assumption of a knee-to-chest

Trityl1Himidazoles

It combines good skin penetration with broad-spectrum activity against dermatophytes, yeasts, 2.367 Aspergillus, Malassezia furfur, and inhibits Corynebacte-rium minutissimum, Staphylococci, Streptococci which all may accompany myco-tic infections. In the treatment of tinea infections and cutaneous candidiasis of skin and mucous membranes such as vaginal candidiasis, clotrimazole can be used as a single dose. 2.366

Regulated Exocytosis

It has been suggested that stimulators of exocytosis cause a remodeling of the microfilamentous cell web, which could act as a barrier, interfering with the access of the secretory granules to the plasma membrane (Burgoyne, 1990). There is, however, no evidence in insulin-secreting cells that Ca2+ and or cAMP are capable of changing the arrangement of actin filaments. We found that drastic reduction of F-actin following treatment of HIT-T15 cells or rat pancreatic islets with C. botulinum C2 exotoxin mainly affects the recruitment of secretory granules to the plasma membrane (Li et a ., 1994). It is unlikely, therefore, that stimulators or inhibitors of insulin exocytosis act primarily on the composition of the cytoskeleton.

Non Hodgkins lymphoma

The predominate T-cell variant of non-Hodgkin's lymphoma is CTCL, which is also known as mycosis fungoides. As described by Broder and Bunn (1980), CTCL is a low grade epidermotropic disease mediated by CD4+ T cells which invade the skin. Skin lesions associated with this disease usually progress through patch, plaque, and tumor phases. Patch lesions are flat, scaly, erythrematous macules which are often pruritic. Plaques are generally raised, red to purple in color, thick and scaly, and pruritic. Nodules, which predominate in the face and intertriginous areas of the body, are susceptible to ulceration. Once the disease progresses beyond 10 of the total body surface area, spontaneous remission rarely occurs and the disease is invariably fatal. Patients are compromised by both the breakdown of the normal skin barrier and a depression in cell-mediated immunity, predisposing them towards infection (Axelrod et al., 1992). In addition to epidermotropic spread, disease progression leads to...

Mange mites

Barth and Preston (1988) concluded from the results of three trials that it is apparent that the topical formulation of ivermectin administered to healthy skin is fully effective against sarcoptic mange, but that its efficacy was impaired when the drug was applied over severe lesions caused by the parasite. This presumably results from reduced absorption of ivermectin at these thickened and encrusted areas, resulting in lower plasma levels of ivermectin, which would also reduce the efficacy of the drug against internal parasites.

Hypervitaminosis

Niacin, in doses that range above the DRI but below that required for dyslipidemias, is unlikely to produce adverse effects. However, adverse effects of niacin are seen when this vitamin is used at pharmacological doses above 1 g day in the treatment of dyslipidemia. Notable adverse effects include flushing because of vasodilation dermatological effects including dry skin, pruritus and hyperkeratosis gastrointestinal effects including peptic ulcer, stomach pain, nausea, and diarrhea elevations in serum uric acid and glucose (in Type 2 diabetics) and rare hepatotoxic-ity.159-161 Traditionally, hepatotoxicity has been more associated with the sustained release as compared to the immediate release formulations however, recent analysis of niacin-ER adverse events suggests the opposite may be true for this formulation.162

The Trpm Subfamily

1.4.1.1 Cancer TRPM1 is possibly a tumor suppressor. The melanocyte-specific gene trpm1 is exclusively expressed in melanoma cells and is down-regulated during the development of metastasis in cutaneous malignant melanoma. Malignant melanoma is a tumor developing from moles or normal-looking skin, as well as in eyes and the meninges, and constitutes the most aggressive skin tumor (Duncan et al., 2001). The inverse correlation between TRPM1 transcript expression and metastatic potential represents one of the most reliable differential diagnostic markers to discriminate between non-metastatic and metastatic melanomas. TRPM1 has at least five splice variants. A potential, but disputed, mechanism of the regulation of TRPM1 may involve a short cytosolic variant (TRPM1-S) binding to, or interacting with, the full-t ength variant (TRPM1-L) to suppress its translocation to the plasma membrane. Upon a specific yet unidentified stimulus, TRPM1-S might dissociate from TRPM1-L and might enable...

Gefitinib

Gefitinib (iressa quinazoline) was discovered by screening a library for compounds that inhibited EGFR tyrosine kinase activity. Gefitinib is a specific inhibitor of the EGFR tyrosine kinase that competitively inhibits ATP binding. Gefitinib is 100 times less potent against highly related tyrosine kinases such as HER2 (ErbB2 neu) and does not inhibit a variety of serine threonine kinases. The predominant problem with the clinical use of gefitinib has been relatively low response rates. Levels of EGFR expression do not correlate with clinical responses however, patients whose non-small cell lung tumors have point mutations in the EGFR respond dramatically to gefitinib, similar to imatinib response in GIST with KIT mutations (see above). Thus, primary resistance could result from tumors that are not uniquely dependent on EGFR activity for survival. Although target inhibition by gefitinib has been demonstrated in normal skin, it is possible that poor tumor penetration of the drug could...

Types of Emulsions

On the basis of the nature of the dispersed phase and the dispersion medium, two types of macroemulsions can be distinguished (i) If the continuous phase is an aqueous solution, and the dispersed phase an oil, the system is called an o w emulsion. Such an o w emulsion is generally formed if the aqueous phase constitutes more than 45 of the total weight, and if a hydrophilic emulsifier is used. (ii) Conversely, if the aqueous phase is dispersed within the oil, the system is called a w o emulsion. w o emulsions are generally formed when the aqueous phase constitutes less than 45 of the total weight and if a lipophilic emulsifier is used. Generally, o w emulsions are more popular than w o emulsions in the pharmaceutical field, especially when they are designed for oral administration. In the cosmetic industries, lotions or creams are either of the o w or w o type, depending on their applications. o w emulsions are most useful as water-washable drug bases and for general cosmetic...

Radiation Barrier

Exposure to ultraviolet light, UVA or UVB, from sunlight has substantial effect on the skin, causing premature skin aging, skin cancer, and other skin changes. Ultraviolet wavelengths of 290 to 310 nm from the UVB band of radiation and of 320 to 400 nm from the UVA constitute the principal tissue-damaging rays of the sun that are not fully atmospherically filtered. An hour's exposure to the summer sun and its damaging rays can produce a painful burn with a characteristic erythema. The skin has natural mechanisms to prevent or minimize such sun-induced trauma, but it takes time to set these into place. Upon stimulation by ultraviolet rays, particularly longer, lower-energy rays above 320 nm, melanocytes at the epidermal-dermal junction produce the pigment melanin. Melanin's synthesis begins in the corpus of the melanocyte, with forming pigment granules migrating outward to the tips of the long protrusions of these starlike cells. Adjacent epidermal cells endocytotically engulf these...

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