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Protect the hair from excessive exposure to sunlight discount xenical online mastercard, by wearing a loose-tting hat or scarf order xenical 60 mg without prescription. If a fracture occurs transversely through the node buy discount xenical 120mg online, the end of the hair resembles a small paintbrush. However an assessment of what is pathological needs to also consider the patient s racial background. Vigorous attempts to straighten curly hair may cause nodes to occur sooner and closer to the root. In contrast, Caucasian and Asian hair is stronger than African hair and even the most vigorous abuse tends to produce distal rather than proximal acquired trichorrhexis nodosa. Trichorrhexis nodosa is the most common defect of the hair shaft leading to hair breakage (1). Treatment of trichorrhexis nodosa (congenital or acquired) involves the avoidance of mechanical or chemical injury to hair. When severe, the entire scalp is affected and patients are totally bald or more often have a sparse covering of short, twisted, broken and lusterless hairs. Follicular keratosis and abnormal hairs are found most frequently on the nape and occiput but may affect the entire scalp. Occasionally there is no keratosis pilaris, suggesting that the follicular hyperkeratosis is not important in the genesis of the beaded hairs. The most pathogenic mutations in hHb6 affect either the start of the rod domain at the helix initiation motif or the end of the rod domain at the helix termination motif (2). Both these sites in the rod domain contain a sequence that is very susceptible to point mutation. In fact, patients with autosomal recessive monilethrix appear to have more severe disease than those with an autosomal dominant aetiology with more extensive alopecia and papular rash. Retinoids (4) have been used with variable success and improvement in the condition may be related to resolution of the keratosis. Minoxidil has also been used but the condition may also spontaneously improve over time. Intermittently placed nodes form and the internodes tend to be the site of transverse hair fracture. Excessive weathering of the hairs with uting and disruption of the cuticle is most marked at the internodes. There are case reports of rare associations with mental and physical retardation, abnormal dentition, cataract, syndactyly and koilonychia. The beading is produced as an artifact of mounting hairs on glass slides and is of no signicance. On scanning electron microscopy, the widened beads can be seen to be an optical illusion. They merely represent art factual indentations of the shaft viewed in cross section. In the twisting hair dystrophy known as pilitori, or corkscrew hair, there is irregular thickening of the outer root sheath and attened hairs rotate completely through 180 degrees at irregular intervals. The twists can resemble beads on light microscopy and may be confused with monilethrix. These incomplete twists may occasionally occur in normal hair (seen in African hair and in the pubic/axillary hairs of other races). In pili torti, hair is often normal at birth, but is gradually replaced by abnormal twisted hairs that may be detected as early as the third month. Affected hairs are brittle, fracture easily, and do not grow to any considerable length. Patients present with a sparse and short coarse stubble over the entire scalp and may have a few circumscribed bald patches. A late-onset variant of isolated pili torti that rst pres- ents after puberty with patchy alopecia has also been described. The affected child typically has pale, lax skin and intellectual or neurological impairment secondary to degeneration of cerebral, cerebellar, and connective tissue. Affected males have pili torti, growth retardation and progressive psychomotor retardation. Affected females demonstrate patchy areas of short, broken, and twisted hairs, along Blaschko s lines on their scalp. It is unknown why the abnormality in copper metabo- lism makes the hair twist and defects in copper metabolism have not been demonstrated in other forms of pili torti. Without treatment Menke s patients slowly deteriorate and die within the rst few years of life. Partially treated males may develop long unruly hair that resembles uncombable hair. Trichorrhexis invaginata (also called bamboo hair ) occurs due to intussusception of the distal portion of the hair shaft (which is fully keratinized and hard) into the proximal portion (which is incompletely keratinized) (7). Netherton s syndrome is usually diagnosed in the rst few days after birth with widespread erythema and scaling. These characteristic lesions are seen in three-quarters of reported cases but their extent and persistence is variable. The patient may present primarily with either cutaneous changes or with sparse and fragile hair. Erythroderma and exfoliation may lead to complications of secondary infection, dehydration, or failure to thrive during the rst year. The hair defect may be very obvious on hair microscopic examination or so infrequent that examination of hundreds of hairs is needed to make a diagnosis. If hair-shaft examination is negative but clinical suspicion remains, further hair-shaft examinations at a later date are appropriate. Apart from trichorrhexis invaginata, golf-tee hairs where the distal portion of the bamboo hair fractures, leaving a cupped proximal ragged end is also a feature of Nether- ton s syndrome. It cannot grow to normal lengths, especially in areas most susceptible to friction. In adults, the scalp hair may improve slowly and the bamboo defects may only appear in the eyebrows or limb hair. Shapiro and Callender D D 188 Eyelashes D Alopecia is the clinical manifestation of many diverse causes. This chapter does not address the various etiologies of alopecia nor its varied clinical morphologies. It addresses alternative treat- ments for alopecia since many patients become frustrated with usual therapeutic regimens. In patients with alo- pecia, in whom scarring is evident clinically or histologically, improvement becomes progres- sively unattainable. The lay literature and Internet are replete with suggestions, advertisements, and promises that encourage and often eventually disappoint patients. It is important to be aware of possible alternative treatments and pitfalls in discussing treatments with our patients affected by alopecia. This chapter discusses herbal remedies, dietary supplements and other modalities used for alopecia.

It is also for this reason that genetic screening of adults is unlikely to completely eliminate occurrence of the disease discount xenical 120mg with visa. Morpholino generic xenical 120mg with visa, and other related compounds ( oligos ) discount generic xenical canada, are chemically more stable derivatives of oligonucleotides, and have been extensively investigated as agents for promoting exon skipping. Indeed, several have demonstrated ecacy using in vivo models such as the mdx mouse. Hence they can be viewed as a development from anti-sense gene silencing strategies. While progress has been encouraging, with activity of morpholinos seen in clinical trials, a number of challenging technological questions remain, and have hampered the wider applicability of the strategy. Foremost amongst them relates to how to achieve the most eective and systematically widespread delivery of drug to patients, because the compounds evaluated clinically to date are not orally available molecules and thus far have had to be injected directly to the site of the aected muscle in both pre-clinical experiments using animals,80 as well as in clinical studies. This also suggests that there will be limited opportunity to treat cardiac muscle using this strategy, although one can imagine combination therapy with other therapeutic paradigms being explored. Micro- encapsulated derivatives have shown encouraging data, but nonetheless wider systematic bioavailability is still a problem. Ultimately, exon-skipping strategies should allow production of functional dystrophin protein in individuals who carry the mutation in that particular exon, although importantly the dystrophin protein produced is shorter. In an extension of this strategy, a screening approach was employed by Miceli and co-workers to search for small molecules that could enhance exon skipping. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 279 Data from both in vitro assays (mdx and human muscle cells), and func- tional tests in mdx mice indicated the eects of anti-sense were augmented by dantrolene, and although the precise mechanisms in play are not clear at this time, the results were encouraging in their own right and provide precedent for the use of drug combinations. Encouraging increases in dystrophin levels were seen in patient biopsies, and no series safety issues were noted. Increases in dystrophin protein have been seen in preclinical87 and clinical studies. Results from Phase 1 and 2 clinical trials for this agent were published recently. The advantage of the class was that the drugs had already been evaluated in humans as antibiotics (which was in fact where the ground-breaking observation of their stop codon read-through ability was originally made),95 and therefore had a known toxicological prole. Thus, in a way they could also be seen as a very early example of the reproling approach paying therapeutic dividends. The net result is that the usual discrimination which takes place in reading of codons during translation is relaxed somewhat, and allows for incorporation of an amino acid, rather than termination of translation occurring. Specically, the expression of dystrophin in cultured mdx muscle cells as well as in vivo in the mdx mouse itself was initially demonstrated using genta- micin 11. Encouragingly, gentamicin appeared to be well toler- ated in patients, with no signs of toxicity. At the end of the study, muscle biopsies revealed that dystrophin levels in several of these patients increased signicantly, from <5% to over 15%. This is particularly striking, because protein levels have reached a point that is thought to be therapeu- tically relevant based on the ecacy results previously noted for other read- through agents. Of more concern was the observation that in one subject an immune system T-cell response was noted, although whether this was related to the expression of dystrophin was unclear. It does highlight, however, that careful monitoring of subjects for propensity of immunological adverse events is critical in this paediatric patient population (both pre- and post-trial), particularly due to the chronic dosing anticipated for the agents. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 283 premature stop codon, vide infra); both of these latter concerns would be circumvented by the use of orally available small-molecule drugs. Compounds that were able to promote read- through of this premature stop codon would therefore result in an increased amount of luciferase expression, and more luminescence. The result of this screen was identication of a series of hit compounds based on an oxadiazole core, which were subsequently optimised further using conventional library- based medicinal chemistry synthesis techniques. All in all, following the high-throughput screen, approximately 3500 compounds were synthesised and evaluated in follow-up biological tests. Given the putative mode of action of the compound, it might be antici- pated that any compounds discovered using this paradigm would similarly have the potential to nd utility as a therapeutic agent for use in other diseases caused by premature stop codons. In terms of target plasma concentration for ecacy, detailed information on the plasma levels required to see a therapeutic eect were not available, but the pre-clinical ecacy models used had suggested that maintaining plasma 1 concentrations between 2 and 10 mgmL would prove ecacious. Accord- ingly, these were the trough levels targeted during the clinical studies for the compound. In addition, a qualitative assessment of drug taste (palatability) of the orally delivered liquid suspension was included in the trial design, again to cater for the intended paediatric patients. Based on the dose dependence of these events, the investigators concluded that the occurrences were linked to Cmax plasma levels of drug. In line with the investigators expectations, no toxicological issues were encountered. Critically, given the compound mode of action, analysis of blood samples for evidence of non- selective read-through of stop codons was also undertaken by looking for extended length marker proteins. Although the drug was well tolerated and this latter result was encouraging, it was not statisti- cally signicant, and the study was discontinued. Further- more, the confounding activity in the rey luciferase assay was conrmed. The assay protocol was validated using ataxia-telangiectasia as a disease model, and in separate experiments also established that the treatment of mdx cells with the compounds resulted in the restoration of dystrophin expression. Although a detailed evaluation of the compound s pharmacokinetics was not reported, bioanalysis of 11. Interestingly no parent compound was detectable in plasma at any time point following intraperi- toneal injection, although levels up to around 3 mM were detected in most muscles sampled, including the heart. This observation is of particular relevance for a muscular dystrophy therapeutic where cardiac muscle has historically proven dicult to target with drugs. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 287 observed when various types of muscle were analysed for dystrophin-positive bres. More importantly, these positive histological data translated to functional benet following treatment with 11. Although these data are clearly encouraging, it is important to place this project in context. A more detailed analysis of the compound/class pharmacokinetics will be essential, as well as concomitant delineation of structure activity relationships in order to translate the intraperitoneal dosing regimen into (ideally) an orally delivered agent. For reasons that are not yet clear, utrophin expression decreases signicantly with maturity during foetal development, and is replaced almost exclusively by dystrophin. As well as having structural similarity, utrophin has been established as playing a functionally equivalent role to dystrophin, this having been conclusively demonstrated by Davies et al. The potential of both biologics and low molecular weight biochemicals to upregulate the production of utrophin has good precedent, with agents such as heregulin128 and L-arginine129 having been shown to ameliorate the dystrophic phenotype when dosed to mdx mice. Heregulin is thought to work by activation of the utrophin A promoter, with the mode of action of L-arginine being postulated as being through activation of the nitric oxide pathway, indirectly activating utrophin. It was discovered during a collaborative programme with scientists from the University of Oxford s Chemistry, Physiology, Anatomy and Genetics Departments.

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Fol- lacunata but this organism is rarely isolated licles under the upper lids are especially charac- from cases nowadays purchase line xenical. The examination of a severe case of conjunc- Untreated generic 120mg xenical with visa, the cornea also becomes infected order xenical master card, tivitis of unknown cause is not complete until leading to perforation of the globe and perma- Common Diseases of the Conjunctiva and Cornea 47 should be taken before starting treatment. Commonsense precautions against spread of the infection should also be advised, although they are not always successful. Attempts to culture bacteria from the conjunc- tival sac of cases of chronic conjunctivitis do not yield much more than commensal organisms. One particular kind of chronic conjunctivitis in which the inammation is sited mainly near to the inner and outer canthi is known as angular conjunctivitis with follicles on the superior tarsal conjunctiva. The clinical picture has been recognised in associa- tion with infection by the bacillus M. Purulent discharge, redness Often, zinc sulphate drops and the application and severe oedema of the eyelids are features of of zinc cream to the skin at the outer canthus the condition, which is generally known as oph- are sufcient treatment in such cases. The disease is notiable and Chlamydial Conjunctivitis any infant with purulent discharge from the eyes, particularly between the second and The chlamydia comprise a group of large twelfth day postpartum, should be suspect. At viruses that are sensitive to tetracycline and one time, special blind schools were lled with erythromycin and that cause relatively minor children who had suffered ophthalmia neonato- disability to the eyes in northern Europe and the rum. Inclusion conjunctivitis careful cleansing of the infant s eyes and the ( inclusion blenorrhoea ) is the milder form of instillation of silver nitrate drops. The condition but there is still a low incidence of ophthalmia is usually, but not always, sexually transmitted. Those affected require treatment The conjunctivitis typically occurs one week with both topical medication (e. Both parents of the usually self-limiting but often has a prolonged child should also be assessed. The diagnosis Pink eye is the name given to the type of acute depends on the results of conjunctival culture purulent conjunctivitis that tends to spread and examination of scrapings and the associa- rapidly through families or around schools. The tion of a follicular conjunctivitis with cervicitis eyes begin to itch and within an hour or two or urethritis. In children and adults, disease is mild, it can be treated by cleaning tetracycline ointment should be used at least away the discharge with cotton-wool, and it four times daily. In adults, the treatment can be does not usually last longer than three to ve supplemented with systemic tetracycline, but days. More severe cases might warrant the pre- this drug should not be used systemically in scription of antibiotic drops instilled hourly pregnant mothers or children under seven years during the day for three days followed by four of age. A conjunctival culture biotics are known to be particularly effective 48 Common Eye Diseases and their Management in treating systemic chlamydial infection; azithromycin can be given conveniently as a one-off dose. A referral to genitourinary med- icine is advisable on presentation, as a screening measure, because reinfection from partners can trigger a recurrent infection. The ecially under the upper lid where scarring and affected eye becomes red and discharges; distortion of the lid can result. The inam- characteristically, the eyelids become thickened matory reaction spreads to inltrate the cornea and the upper lid can droop. If such opacities by improved hygienic conditions long before the are situated in the line of sight, the vision can be introduction of antibiotics. There is no known effective treatment but it is usual to treat with an antibiotic drop to prevent secondary infection. Adenoviral Conjunctivitis From time to time, epidemics of viral con- junctivitis occur and it is well recognised that Acute viral conjunctivitis is common. Usually, the eye spread can result from the use of improperly sterilised ophthalmic instruments or even con- taminated solutions of eye drops, and poor hand-washing techniques. Herpes Simplex Conjunctivitis This is usually a unilateral follicular conjunc- tivitis with preauricular lymph node enlarge- ment. Common Diseases of the Conjunctiva and Cornea 49 Other Infective Agents keratoconjunctivitis have a higher risk than normal for the development of herpes simplex The conjunctiva can be affected by a wide keratitis; the condition is also associated with variety of organisms,some of which are too rare the corneal dystrophy known as keratoconus or to be considered here, and sometimes the conical cornea. They are likely to develop skin infected conjunctiva is of secondary importance infections and chronic eyelid infection by to more severe disease elsewhere in the rest of staphylococcus. It be avoided if possible because of their side can be accompanied by conjunctivitis when effects. The infec- predisposed individuals and aggravate herpes tion is usually easily eliminated by curetting simplex keratitis. Infection from Phthirus pubis (the pubic louse) involving the lashes and Vernal Conjunctivitis (Spring Catarrh) lid margins can initially present as conjunc- Some children with an atopic history can tivitis but observation of nits on the lashes develop a specic type of conjunctivitis charac- should give away the diagnosis. The child tends to develop Allergic Conjunctivitis severely watering and itchy eyes in the early spring, which can interfere with schooling. Several types of allergic reaction are seen on the Eversion of the upper lid reveals the raised conjunctiva and some of these also involve the papillae, which have been likened to cobble- cornea. Occasionally, the cornea is also involved, initially by punctate keratitis but sometimes it This is simply the commonly experienced red can become vascularised. It is often necessary and watering eye that accompanies the sneezing to treat these cases with local steroids, for bouts of the hay fever sufferer. The eyes are itchy example, prednisolone drops applied if needed and mildly injected and there might be con- every two hours for a few days,thus enabling the junctival oedema. The dose can then be vasoconstrictors, such as dilute adrenaline or reduced as much as possible down to a main- naphazoline drops, can be helpful; sodium tenance dose over the worst part of the season. Atopic Conjunctivitis Unfortunately,patients with asthma and eczema can experience recurrent itching and irritation of the conjunctiva. Less severe cases can respond well to spreads into the cornea, drawing a triangular sodium cromoglycate drops; these can be band of conjunctiva with it. The eye becomes useful as a long-term measure and in prevent- irritable because of associated conjunctivitis ing but not controlling acute exacerbations. Pterygium Secondary Conjunctivitis is more common in Africa, India, Australia, Inammation of the conjunctiva can often China and the Middle East than in Europe. It is be secondary to other more important pri- rarely seen in white races living in temperate cli- mary pathology. Treatment is by surgical excision if the possible underlying causes of this type of cornea is signicantly affected with progression conjunctivitis: towards the visual axis; antibiotic drops might be required if the conjunctiva is infected. Non- Lacrimal obstruction infective inammation of pterygium is treated Corneal disease with topical steroids. Examples of this are the red eye unilateral purulent conjunctivitis and it is of renal failure and gout, and also polycythemia important to consider this possibility in recal- rubra. The association of conjunctivitis, arthri- citrant cases because early resolution can be tis and nonspecic urethritis makes up the triad achieved simply by syringing the tear ducts. Some diseases cause Corneal ulceration from a variety of causes is abnormality of the tears and these have already often associated with conjunctivitis and here been discussed with dry eye syndromes, the the treatment is aimed primarily at the cornea. Thyrotoxicosis is a more common ecially in the case of entropion, when the defor- mity is not present all the time. A special type of degenerative change is seen in the conjunctiva, which is more marked in hot, dry, dusty climates. It appears that the com- bination of lid movement in blinking, dryness and dustiness of the atmosphere and perhaps some abnormal factor in the patient s tears or tear production can lead to the heaping up of subconjunctival yellow elastic tissue, which is often inltrated with lymphocytes. The lesion is seen as a yellow plaque on the conjunctiva in the exposed area of the bulbar conjunctiva and usually on the nasal side.

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Clinical features Primary varicella infection presents with fever and a rash starting on the head and spreading to the trunk and extremities buy 60mg xenical overnight delivery. The eruption evolves from maculopapular to vesicular generic xenical 120 mg amex, then pustular discount xenical 60mg with amex, and nally scabs over. Most common complication of primary varicella is bacterial superinfec- tion, usually by Staphylococcus or Streptococcus. Herpes zoster (shingles) is usually localized to a single unilateral der- matome, but bilateral zoster has been reported [2]. Early lesions are papules on an erythematous base progressing to vesicles and pustules that crust over. Diagnosis Diagnosis of varicella and herpes zoster is generally made with clinical his- tory and exam. Treatment Treatment of primary varicella infection is usually symptomatic, but acy- clovir has been approved for decreasing the duration and severity of vari- cella if used within 24 72 hours of the onset of symptoms [15]. Small petechiae on the hard and soft palates are visible in a third of the patients. Macules, papules, vesicles, and petechiae or purpura occur in 3 16% of patients [2]. Diagnosis Elevated heterophil antibodies or peripheral smear showing atypical lym- phocytes are used for diagnosis. Treatment of Burkitt s lymphoma includes con- comitant chemotherapy and rituximab. In cases of congenital infection, the blue- berry mufn rash petechial rash is characteristic. Exanthema subitum most commonly occurs in children and is characterized by the abrupt onset of high fever followed by the rose red maculopapular exathem with a white halo [19]. It is a zoonotic retrovirus whose transmission requires contact with blood or bodily uid. A morbilli- form eruption is present in 40 80% of patients; mucocutaneous oral or genital ulcers are also common [23]. Human T-cell lymphotrophic virus Epidemiology Human T-cell lymphotrophic virus type I is a human retrovirus discovered in 1980; transmission can be vertical, sexual, or blood borne [25]. Japan, Africa, the Caribbean, and Central and South America are areas with the highest prevalence of infection [25]. Patients have extensive eczematous dermatitis and recurrent infections with Staphylococcus aureus or -hemolytic Streptococcus [26]. It is treated with long-term systemic antibiotics, although the disease is often recalcitrant [26, 27]. Clinical features Verruca vulgaris (common warts) appear as hyperkeratotic papules, some- times with verrucous features on virtually any cutaneous surface of the body. If untreated and nonresolving, genital warts can go on to develop into precancerous lesions and eventually neoplasia [2]. Diagnosis Diagnosis is generally based on clinical appearance, but can be aided by histological examination via a biopsy. Treatment Therapy includes topical acidic preparations such as trichloroacetic acid, and destructive procedures such as cryotherapy and electrodessication. The vac- cines are recommended in males and females ages 9 26 for the prevention of genital warts, and cervical and/or vaginal cancer. Endemic disease was eradicated from the United States in 2000, and Europe s current goal is 2015 [30]. In the United States from 2001 to 2008, 88% of the 557 reported cases were either directly imported or related to imported cases; the remaining 12% were from unknown sources [31]. Furthermore, there have been more reported cases per year in 2009 2010 than combined from 2001 to 2008. The pathognomonic koplik spots can be seen soon afterward, appearing as bluish-white spots on an erythematous base on the buccal mucosa opposite premolar teeth. The rash may involve the palms and soles and may desquamate; it typically resolves in 4 6 days [2,31,32]. However, since measles is now rare in the Western world, con- rmation with detection of IgM antibody is recommended [31]. Parvovirus B19 Parvovirus B19 is the only member of the family Paroviridae known to infect humans. Transmission is normally via aerosolized respiratory droplets and rarely via blood transfusion [33]. Clinical features The most characteristic cutaneous manifestation is in erythema infectio- sum (fth disease), which presents as a slapped cheek appearance of the face, and a pink lacy eruption comprised of reticulated macules and papules on the trunk and extremities [2,33]. IgM antibody detection is used for conrmation of acute disease, while IgG indicates past infection [2]. Smallpox Epidemiology Smallpox is caused by the variola virus and is highly contagious and deadly. The most recent outbreak in the United States occurred in Texas in 1949 and the last endemic case of smallpox was reported in Somalia in 1977 [34]. Smallpox is transmitted through inhalation of aerosolized virus particles or contact with bodily uid or fomites. The erup- tion is initially maculopapular turning into well-circumscribed vesicles, and then pustules in a centrifugal distribution. Diagnosis Diagnosis is conrmed via a rise in antibody titer (equal to or more than fourfold) or uorescent antibody staining of smears taken from lesions [2, 35]. Patients must be quarantined and health ofcials contacted for proper infection control. Vaccinia/cowpox/monkeypox Clinical features Vaccinia virus is a constituent of the smallpox vaccine. Papules can appear a few days after vaccination followed by erythematous pustules. Cow- pox infects cows, rodents, and humans who come into contact with the infected animals. Infected individuals develop papules at the inoculation site followed by vesicles. Monkeypox can be transmitted via handling or consuming the meat of wild monkeys or via close contact with infected humans. Symptoms are similar to smallpox except for more pronounced cervical and/or inguinal lymphadenopathy. Viral Diseases 145 Treatment No specic treatment exists for vaccinia or cowpox; however, cidofovir is used in severe cases of monkeypox. A vaccine exists that can be used as prophylaxis or within 4 days of exposure to monkeypox.

Remove the bigger bristles with a forceps and 292 Imported Skin Diseases the smaller ones with adhesive tape purchase xenical 120mg free shipping. As stated in the introduction the eld of the aquatic dermatology is a growing one and it is not possible to highlight all the aquatic dermatoses buy discount xenical line. For that reason a brief overview of the most frequently encountered aquatic dermatoses has been presented order 60mg xenical visa. These tables can be consulted, and can be helpful in establishing a diagnosis (Tables 25. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have care- fully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; E-mail: humana@humanapr. The fee code for users of the Transactional Reporting Service is: [0-89603-804-1/01 $10. The past decade has seen the identification of new mutation mecha- nisms, such as triplet repeat expansions, and new genes causing familial forms of common neurodegenerative diseases, such as Parkinson s and Alzheimer s diseases. Cellular and animal models based on this genetic information are now available and, importantly, common mechanisms are rapidly emerging among diseases that were once considered unrelated. The field is poised for the development of new therapies based on high throughput screenings and a bet- ter understanding of the molecular and cellular mechanisms leading to neurodegeneration. Molecular Mechanisms of Neurodegenerative Diseases reviews recent progress in this exploding field. In the first chapter, Bill Klein reviews the role of A` toxicity in the patho- physiology of Alzheimer s disease. This controversial issue is further exam- ined in the context of transgenic models of Alzheimer s disease by LaFerla and colleagues. Sue Griffin and Robert Mrak, and Caleb Finch and collabora- tors, then examine the role of glial cells and inflammation in Alzheimer s disease; a review of the role of proteolysis in the generation of abnormal pro- tein fragments by Hook and Mende-Mueller follows. Therapeutic opportuni- ties offered by a better understanding of Alzheimer s disease pathophysiology are examined by Perry Molinoff and his colleagues at Bristol-Myers Squibb. The chapter on proteolysis by Hook and Mende-Mueller identifies one of the recurring themes that is appearing among neurodegenerative diseases: the formation of abnormal protein fragments, whose misfolding may lead to a cas- cade of cellular defects, ultimately leading to cell death. Joel Perlmutter and his colleagues review the information we have recently gained on the progression of the disease from brain imaging studies. Chesselet and Levine compare the different mouse models of Huntington s disease, MacDonald and colleagues review the role of proteins interacting with huntingtin, and George Jackson discusses the potential of fly genetics to iden- tify the molecular mechanisms of neurodegenerative diseases. Despite their differences in focus, many chapters of Molecular Mecha- nisms of Neurodegenerative Diseases overlap, presenting the variety of view- points that pervade this dynamic field. Evidently, since new data appear every day, the chapters in a book can only provide the basis for understanding ongo- ing research. Penney, who dedicated his life to finding a cure for neurodegenerative diseases and whose untimely death prevented him from contributing to this book. Alzheimer s research provided the first direct evidence that dementia is the consequence of neurodegenerative mechanisms, not a simple fact of aging. A less diagnostic but equally apt description of the disease also came from Alzheimer s care of Auguste D. As he tracked his patient s progressively severe dementia, Alzheimer once asked Auguste D to write her name. The number of Alzheimer s disease patients has grown from the first diagnosed case in 1906 to an estimated 25 million world- wide (3). Tangles occur in living neurons but also are found as extracellular remains following nerve cell death. The most salient are senile plaques that show degenerating neurites in proximity to large extracellular amyloid deposits. Amyloid cores are made of polymerized amyloid beta (A`) peptide and contain a small variety of inflammatory From: Contemporary Clinical Neuroscience: Molecular Mechanisms of Neurodegenerative Diseases Edited by: M. As yet, however, no consen- sus exists regarding the primary pathogenic molecules. In this chapter, evidence is reviewed that strongly implicates a role for neurotoxins derived from A` peptides (for earlier reviews, see refs. Nonetheless, central roles also can be argued for inflammatory processes (23) and for cytoskeletal dysfunction linked to aberrant tau phosphorylation (24 26). Whichever molecular abnormality proves primary, the pathogenic phenomena are closely interrelated. Reciprocally, tau phosphorylation and microtubule A` Fibrils and Oligomers 3 dysfunction alter A` metabolism (30,31), and inflammatory glial proteins influence the nature of A`-derived toxic aggregates (refs. Emerging data show that toxic A`-derived fibrils and oligomers exert a selective impact on signal transduction molecules that are coupled physiologically to mechanisms of apoptosis and synaptic plasticity. The A` cascade is supported strongly by human pathology, transgenic modeling, and experimental nerve cell biology (see Milestones in Fig. Core Component of Alzheimer s Amyloid Is A` The first molecular milestone en route to the A` cascade hypothesis was reached in 1984 by Glenner and Wong (37). Their purification and analysis of the core component of Alzheimer s amyloid showed it to be a 4-kDa peptide, designated now as amyloid beta (A`). Although A`1 40 and A`1 42 are the predominant monomeric forms, peptides isolated from Alzheimer-afflicted brain tissue show length variations at both ends (46). The unusual tandem hydrophobic/hydrophilic domains of A` strongly influence its structure in solution and its biological properties (see Fibril Hypothesis, below). Several mutations in and around the A` sequence now are known to be pathogenic (50 56). Consistent with the A` cascade hypothesis, however, the established factors all contribute to anomalous accumulation of A` peptide. This is a salient feature because the more hydro- phobic A`1 42 has a particularly strong tendency to self-associate into neurotoxic multimers (see Fibril Hypothesis, below). Elevated A` accumulation is recapitulated in cell culture models that carry disease-associated transgenes (67 70). This, however, is not the case, as shown in the capstone discovery by Yankner et al.

By T. Mitch. William Carey University.