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Huntington s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington s disease chromosomes buy 20 gr benzac amex. Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues cheap benzac line. Polyglutamine expansion as a pathological epitope in Huntington s disease and four dominant cerebellar ataxias purchase benzac from india. Aggregation of huntingtin in neuronal intranuclear inclu- sions and dystrophic neurites in brain benzac 20gr mastercard. Neurodegenerative Disease in the Fruit Fly 373 16 Modeling Neurodegenerative Diseases in the Fruit Fly George R. Given that a fundamental understanding of disease mechanisms is crucial to the rational design of therapeutic strategies, the myriad genetic techniques available in Drosophila for the study of biological phenomena might prove a useful addition to our current armamentarium of transgenic mice, in vitro and unicellular techniques, and biochemical studies. Classical genetic screens in Drosophila have uncovered numerous mutations giving rise to both ectopic developmental cell death and late-onset neuro- degeneration. Similarly, genetic study of fly homologs of human disease genes has provided important information about their function and patho- logical dysfunction. A more recent approach has utilized the targeted expression of mutant human disease genes in Drosophila to recapitulate cer- tain aspects of human disease. Identification of such modifier genes might identify new therapeutic targets for otherwise incurable disorders. The disease is associated with expansion of an unstable trinucleotide repeat within exon 1 of the gene- encoding huntingtin (Huntington s Disease Collaborative Research Group, 1993). Although this gene is, to some extent, conserved in evolution from Drosophila to man (Baxendale et al. Although a number of proteins, both novel and previously identified, have been observed to interact physically with huntingtin using techniques such as the yeast two-hybrid screen (Boutell et al. Thus, any technique that would add to our understanding of huntingtin-interacting genes might find a well-deserved place among more traditional experimental approaches to the disease. Larger repeat expansions within the gene encoding huntingtin correlate with an earlier onset of disease. Nonetheless, for any given repeat length, age of onset may vary by more than a decade (Gusella and MacDonald, 1995). Although genetic factors have been suggested to modify age of onset, only one such factor, a polymorphism in the GluR6 kainate receptor gene, has been clearly established (MacDonald et al. If other such factors could be identified and their expression modified, substantial relief from disease burden could occur even in the absence of a cure. Four published studies suggest that certain fundamental aspects of polyglutamine pathogenesis are widely conserved through evolution (Jack- son et al. Undoubtedly, despite the similarities observed in fly models of polyglutamine diseases in man, it is naive to anticipate that such models will faithfully recapitulate human pathophysiology. In many respects, though, simple invertebrate systems supply an ideal system with which to study the pathophysiologic basis of neurodegenerative diseases. Although prokary- otes and yeast lack nervous tissue, the roundworm Caenorhabditis elegans Neurodegenerative Disease in the Fruit Fly 375 and the fruit fly Drosophila melanogaster possess well-characterized nervous systems. Identification of cell death genes in the worm has been instrumental in understanding their myriad homologs in vertebrates. Although cell death pathways to date have been less well characterized in Drosophila, a few crucial players have been identified that are homologs to those identified in man. In addition, a number of interesting proapoptotic genes have been iden- tified in flies that appear to have no close mammalian homologs; nonethe- less, despite the apparent absence of related genes, a number of these genes appear to be functional in mammalian systems. Perhaps the most important aspect of invertebrate approaches is the availability of a number of genetic manipulations that are impossible or impractical to carry out in mammals. Large numbers of flies and worms can be mutagenized and screened in a short period of time, thus permitting the identification of even rare muta- tions. Given the considerable success that fly genetic approaches have had in delineating processes such as cell cycle control, signal transduction, and pattern formation, it is reasonable to anticipate that similar approaches to the study of polyglutaminopathy may yield powerful insights into disease mechanisms. This chapter will review briefly the current state of knowledge about mechanisms of cell death in Drosophila. I will then review mutations known to regulate developmental cell death in flies, as well as those associated with late-onset (here defined as post-eclosion) neurodegeneration. I will then discuss what is known about Drosophila homologs of human neuro- degenerative disease-associated genes, as well as work done to date on loss- of-function mutations in such genes and how they may shed light on human pathology. In particular, recent study of Drosophila homologs of genes impli- cated in the pathogenesis of Alzheimer s disease has been insightful. Finally, I will discuss in some detail the established models of glutamine repeat diseases in flies, with attention toward practical aspects of further develop- ing and interpreting such models. An accumu- lating body of evidence suggests that inappropriate activation of intrinsic cell death programs may underlie neurodegeneration. The deficiency line H99 provided one of the first insights into the regula- tion of cell death in Drosophila (White et al. In homozygous H99 embryos, acridine orange staining reveals an absence of developmental cell death. However, such homozygous embryos are still susceptible to apoptosis induced by ionizing radiation. Genetic analysis of this deficiency identified three pro-apoptotic genes: reaper (rpr), head involution defective (hid), and grim (White et al. Although there are sequence similarities between rpr and the death domain of tumor necrosis factor receptor-1 family members, including the low-affinity neurotrophin receptor p75, mutational analysis does not support the functional similarity suggested by this sequence (Chen et al. Apart from a short, interrupted polyglutamine tract in grim, none of these gene products shows other motifs with known homology to vertebrate proteins. Nonetheless, cell death induced by expression of rpr and hid in mammalian cell culture systems suggests that certain aspects of cell death pathways utilized by these proteins are more widely conserved, despite the apparent absence of homologs (Claveria et al. Directed expression of each of these genes in the eye results in massive cell death with the appearance of reduced, rough eyes (Grether et al. The viral gene P35, which is required for apoptosis of insect cells by the baculovirus Autographa californica (Clem et al. Both genes are homologous to apoptosis inhibitors found in a wide range of organisms, from viruses to C. Loss-of-function mutations in this pathway enhance hid- induced cell death, whereas gain-of-functions mutations suppress it. Thus, intriguing links between regulation of widely conserved signaling pathways and cell death exist; others are likely to be identified. The search for caspases in Drosophila homologous to those previously identified in vertebrates led to identification of the first Drosophila caspase, Dcp-1 (Song et al. Homozygous loss-of-function alleles of Dcp-1 show larval lethality and melanotic tumors. Impaired transfer of nurse cell cytoplasm to oocytes in Dcp-1 mutants demonstrates a requirement for this caspase in oogenesis (McCall and Steller, 1998). Loss of dredd function (using a deficiency line that deletes other genes, as well) serves as an enhancer of eye-specific rpr expression in vivo (Chen et al. Interestingly, the sequence surround- ing the catalytic cysteine of dredd differs from the canonical caspase sequence in that it contains a glutamate residue rather than a glycine, suggesting dredd may have novel substrate specificity. Neurodegenerative Disease in the Fruit Fly 379 Akt or protein kinase B, a downstream target of phosphatidyl inositol-3 kinase, has been implicated in regulating the survival of neurons in response to extracellular signals (Hemmings, 1997). As information becomes available about the function of these genes, it will be interesting to determine if their products interact with polyglutamine- expanded proteins in vivo and, if so, how this affects neuronal dysfunction and degeneration in the fly. Although such developmental cell death is not strictly comparable to late-onset neurodegenerative disease in humans, consider- ation of such mutants may provide valuable insight into mechanisms of neurodegenerative disease. Precise development of appropriate connections between neuronal processes and their targets is required for survival of neurons; such a target-dependent survival phenomenon also occurs in Drosophila. Photoreceptor neurons that fail to establish connections with the optic lobe degenerate. Conversely, optic ganglion neurons that fail to establish contact with photoreceptors in mutants of genes required for eye 380 Jackson specification such as sine oculis differentiate normally but subsequently degenerate (Cheyette et al. In the disconnected mutant, there is a defect in the pathfinding of the larval optic nerve, result- ing in the formation of photoreceptor neurons disconnected from the optic lobe (Steller et al. Such disconnected photoreceptors subsequently degenerate, as does the optic lobe target tissue, demonstrating a reciprocal requirement between neurons and their targets for survival.

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In addi- to prole affected and nonaffected cows should be per- tion buy benzac, when resting buy 20gr benzac fast delivery, the cow may tend to lie in lateral formed quality benzac 20gr. Diets with anionic salt supplementation and recumbency with the hind limbs extended to reduce those with added antioxidants may show some tendency body pressure on the udder cheap benzac 20gr otc. Generally reduction of milking fre- tions should be included in the nutritional evaluation. Blood clots that form may be stripped out as they Hemorrhage into a Gland form and do not ruin future potential. If this approach Etiology does not resolve the problem within several days, a deci- Hemorrhage into one or more glands is common at sion to stop milking and risk severe cisternal clots must parturition in cows with severe udder edema or pendu- be considered to save the cow. Cows with bloody milk virus, anaplasmosis, and Johne s disease should be ad- should be watched closely for mastitis because blood ministered. Approximately 4 to 6 L of blood should be provides an excellent growth medium for bacteria. Blood transfusion also may As opposed to the usually innocuous parturient hem- become necessary regardless of cause if the cow s ane- orrhage described previously, severe hemorrhage involv- mia becomes severe enough to warrant transfusion. Lymphosarcoma is the most common and will be considered below under a separate Signs heading. Relatively few dairy cows live to an old age, but The chief complaint for a cow with intramammary hem- those that do still have a very low incidence of mam- orrhage is persistent blood-stained milk from one or mary tumors. Anemia may develop if extensive bleeding mammary gland adenocarcinomas have been observed continues to occur over several milkings. Large (warts) are more common on the skin of the teats but intraluminal clots occasionally plug the papillary duct, also may appear on the skin of the udder. Diagnosis The clinical signs of intramammary hemorrhage are suf- Lymphosarcoma ciently diagnostic, but laboratory work should be per- formed to assess thrombocyte numbers. Coagulation Lymphosarcoma is the most common tumor to appear proles that may be used to incriminate specic bleed- within the gland and associated lymph nodes in dairy ing disorders are frequently unreliable in cattle. Focal and diffuse inltration of the gland with lym- causes of intramammary hemorrhage are seldom iden- phosarcoma and rarely adenocarcinoma has been ob- tied. Usually tumor masses in other target organs or Treatment lymph nodes supersede mammary involvement. Affected Decisions for appropriate therapy are difcult because glands may merely appear edematous rather than rm, of the likelihood of iatrogenic complications. Diffuse lymphocytic ently obvious solution is to stop milking the affected inltration of the udder may appear similar to the diffuse quarters thereby stopping further blood loss and al- mild edema that develops in hypoproteinemic cattle. The lowing pressure to build up in the gland to deter further mammary lymph nodes (supercial inguinal) may be bleeding. However, this approach may provoke such enlarged because of lymphosarcoma or chronic inam- severe blood clotting in the ductules, gland cistern, and mation and should routinely be palpated during physical teat cistern that future milking is impossible. Juvenile tumors of the gland cause an obvious en- largement that may be confused with mastitis in the undeveloped udder. Commercial true-cut biopsy needles work very well for mammary gland bi- opsies, and the procedure is safe. Treatment Juvenile tumors of the gland may be excised, but progno- sis for production in the affected gland must be guarded. Rebhun and in the two reported teat skin bromas in yearlings, long-term follow-up evaluation indicated that all glands that had undergone surgery were functional at rst calving. Cryosurgery may sufce in early stages of the disease, but udder amputation may be re- quired in advanced cases. Udder Amputation Hemimastectomy or radical mastectomy is rarely per- formed in cattle. Indi- vidual animals that undergo udder amputation must be in good general condition. Cattle with septic mastitis or in poor A, A mature Holstein affected with lymphosarcoma. The physical condition should not undergo udder amputation right supramammary lymph node is markedly enlarged until their physical condition is signicantly improved. B, A 14-year-old Holstein with mammary gland adeno- Therefore the lateral incisions must extend to the junc- carcinoma. There was diffuse neoplastic involvement of tion between the middle third and dorsal third of the the gland. Juvenile tumors found to be bromas as- rst directed toward the inguinal canal where the pu- sociated with the teat also have been recognized in two dendal arteries and then vein are ligated. Using curved Mayo scissors, the loose fascia on the proximal aspect Signs of both lateral laminae is incised starting cranially and Affected cows have a varied clinical presentation ranging extending caudally until the left and right perineal ar- from focal enlargement to diffuse and massive udder en- teries and veins are located and double ligated. The lateral laminae are then sharply transected and dissection extended on the dorsal aspect The papillary duct (teat canal) or streak canal is the of the mammary gland to complete the excision. Stab incisions The streak canal in the healthy state acts both as a are used to create portals for the drains to exit on either valvular obstruction to milk ow and as a unique deter- side of the incision and secured to the skin using a single rent to ascending infection of the gland. The skin is closed in a for- Congenital Anomalies ward interlocking pattern with a nonabsorbable material (such as polyamide), and a stent is sutured over the inci- Etiology and Signs sion to help diminish the tension on the incision. Supernumerary teats are the most common congenital abnormality, which is likely heritable in dairy cattle. The inner brous layer is a thin membrane placed caudal to the rear quarter teats or between the rear that is interposed between the mucosa and the stroma and forequarter teats. Such infections provide a chronic source of infec- case, these joined teats require special treatment and tion for other quarters in the herd. Keratinized corns or keratomas on the teats of heif- These may appear as distinct teats or only as small raised ers have been recognized. A suitable antiseptic is applied to the wound following removal, but sutures generally are not used except when a cosmetic appearance is required immedi- ately. Care must be exercised when removing supernu- merary teats, lest a true teat be removed accidentally. If confusion exists as to which teats are the true ones, the heifer should be allowed to grow for a few months and then be rechecked. Supernumerary teats cojoined to a major teat (webbed teats) need to be repaired surgically rather than just snipped off. The repair should be performed when the teat is large enough to be manipulated easily and then sutured. Aseptic technique is es- sential because infection of the future mammary gland is a major risk. Following routine preparation, a fenestrated drape is placed, and the supernumerary teat is excised by scalpel or scissors. After excision, the mucosa of the rudimentary teat should be closed with ne synthetic absorbable suture (e. The skin and stroma are sutured as a single layer using interrupted vertical mattress su- tures or alternatively closed with individual layers. Diagnosis Diagnosis of supernumerary teats, Siamese teats, and ke- ratinized corns simply requires inspection. Supernumer- ary teats cojoined to a major teat require more careful consideration and treatment, but if identied in calf- hood, the treatment is the same. Most veterinarians perform this ex- numerary teat (left) and outline of a resultant incision amination when vaccinating 4- to 8-month-old calves (right). When surgery is done at this early age, it does not matter whether the ancillary teat has a separate gland. If, however, surgery is delayed until after the rst lacta- tion, surgical repairs may become considerably more complicated because of the need to connect separate gland cisterns to the major teat. Keratin corns or keratomas may be surgically dis- sected from the teat ends, but simpler means of therapy exist. A light teat bandage held on the teat by adhesive tape may be used to moisten the keratinized material, and the keratinized material may be gently separated from the teat itself after several days of soaking. Saline, lanolin and aloe mixtures, and ichthammol ointment have all been used successfully to soften keratin corns and allow subsequent removal. A focal occlu- stroyed in these animals; nonetheless a guarded prog- sion at the distal aspect of the teat cistern is identied as nosis is justied. The rosette of Furstenberg and the streak canal (thin hyperechoic line at the tip of the teat) are normal. Injuries to the teat end with dried exudate and scabs make milkout very dif- are caused by the digit or medial dewclaw of the ipsilat- cult and predispose to mastitis.

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Oral ruminotorics-laxative-antacid pow- Treatment requires relief of the ruminal distention and ders in warm water and parenteral calcium solutions correction of the primary cause order benzac with mastercard. In instances of free-gas also should be administered to encourage rumen emp- bloat caused by hypocalcemia discount benzac online mastercard, parenteral calcium ther- tying discount benzac 20gr free shipping. Indiges- treatment of choice for progressive and severe frothy tion with tympany requires relief of the gas accumulation bloat 20gr benzac for sale. Localized perito- acute bloat of any cause is contraindicated in the dairy cow nitis with secondary ruminal tympany must be treated except in extreme cases when emergency decompression is with antibiotics, stall rest, and either a magnet, rumen- necessary. Trocharization in the dairy cow ensures perito- otomy (for hardware), or dietary changes (perforating nitis, which may be fatal or may confuse the primary diag- abomasal ulcers). If pharyngeal trauma is suspected, nosis by causing fever and signs referable to peritonitis broad-spectrum antibiotics, gentle passage of a stomach including bloat over the following days. B Chronic Bloat Etiology In calves, most cases of chronic bloat have a dietary or developmental etiology. Otherwise, these affected calves are healthy except for the free-gas bloat that develops shortly after eating. Calves that have been overtreated with oral antibiotics for systemic infec- tions or diarrhea also may develop bloat associated with abnormal rumen ora. Calves affected with diar- rhea and treated with methscopolamine or other para- sympatholytic drugs may develop a paralytic ileus and subsequent bloat that persists for 24 to 72 hours after the administration of the drug. There had been several episodes of bloat in this calf, and its general condition and hair coat are adversely affected. These calves are called ruminal drinkers because they have failure of the reticular groove reex, thus causing milk to ow directly into the rumen rather than the abomasum. Ruminal parakeratosis and hyperkeratosis result in addition to metabolic and endocrine abnormalities. The calves may have excessive intestinal production of both D and L lac- tic acid and become severely acidotic from the D-lactic acid. The bloat may occur acutely within 1 hour after feeding but may also become chronic, and in some cases there may be enough milk putrefaction to cause the calf to become quite ill. Older calves that have been weaned off milk or milk replacers also may develop chronic free-gas bloat of dietary origin if fed a low ber diet. Although this can occur on silage and grain diets, it is much more common in calves fed all-pelleted rations. Up to 10% or more of calves fed all-pelleted rations with no hay supplementa- tion will develop chronic bloat that worsens shortly after they ingest pellets and then drink large quantities of water. Many other causes of chronic bloat also exist in postweaning calves but are more difcult to diagnose and treat. Other le- Abdominal distention characteristic of vagus indigestion sions such as abdominal abscess, umbilical or urachal in a calf with abomasal impaction. These are discussed These lesions may damage the intricate vagal nerve further in the section on Vagal Indigestion. Esophageal motility disorders, illomas of the distal esophagus or cardia and lympho- although rare, should be considered as a cause of bloat sarcoma masses in the forestomach or abomasum. Thymic lymphosar- bropapillomas, a failure of eructation occurs because coma and enlarged mediastinal or pharyngeal lymph the tumor acts like a plug or one-way valve in the distal nodes resulting from the juvenile form of lymphosar- esophagus, thereby interfering with effective eructation. Generally the reticulum of eructation, or failure of motility all contribute is entrapped in the chest through the diaphragmatic to chronic rumen tympany. Observation, physical examination, and sometimes ultrasonography are extremely important in the calf because rectal examination is not possible. In adult cattle, rectal palpation coupled with other physical ndings should easily conrm rumen distention. The diagnosis of chronic bloat is conrmed by a com- bination of history and physical examination ndings. Other causes of chronic abdominal distention such as ascites, displacement of the abomasum, cecal distention, and hydrops should be ruled out. In addition to abdomi- nal auscultation and ballottement and rectal examination in cows, a stomach tube should be passed to determine whether the bloat is free gas or ingesta. Specic causes of chronic bloat should be sought through physical exami- nation, ancillary data, and surgical exploration of the ab- domen, if the value of the affected animal warrants this procedure. The reticulum was believed to volve lesions affecting the vagal nerve branches, treat- have been forced at calving through a congenital defect ment is discussed under Vagal Indigestion. Cattle also are given a great deal of chopped feed that may contain wire remnants, machinery parts, or other metallic debris. Metallic foreign bodies, such as wire and nails, are the most common agents of hardware disease. Nails of all sizes also have been recovered from cattle with hardware disease as have, on occasion, hypodermic or blood collection needles. These objects may be found rou- tinely on radiographic surveys or slaughterhouse speci- are best treated by making a temporary rumen stula mens. Although perfora- and ill thrift because of ruminal drinking of milk can be tion may occur randomly at any time in a cow harbor- weaned or fed via a bottle rather than a bucket. If they ing a sharp metallic foreign body, physical factors may become acutely ill in association with feeding milk and contribute to perforation and subsequent clinical signs. During the last trimester, the combined Chronic free-gas bloat in tetanus patients may be re- weight and size of the gravid uterus may allow the organ lieved by gentle passage of a stomach tube or preferably to act like a pendulum as a cow gets up and down; this with a surgically prepared rumen stula that provides can apply physical pressure to the rumen and reticulum, continuous escape of gas and a portal through which to contributing to perforation by an existing sharp metallic provide feed and water to the patient. Clinical incidence of hardware disease in cattle therapeutic stula is an important aid to the successful in the last trimester of pregnancy is high enough to war- treatment of tetanus cases because affected animals are rant inclusion of this disease in a differential diagnosis typically unable to eructate or swallow, and repeated for any acute illness in heavily pregnant or dry cows. These patients usually improve spontaneously 48 crimination during prehension or absence of exposure to 72 hours after the last administration of the offend- to certain high-risk feedstuffs protects the animal during ing drug. Cows with ruminal bloat caused by abomasal out- In light of the likely exposure of most dairy cattle to ow abnormalities causing reux of abomasal content metallic foreign bodies in feedstuffs, perhaps the greatest into the rumen generally have a poor prognosis. This Traumatic Reticuloperitonitis should be considered a mandatory component of pre- (Hardware Disease) ventative herd health. Etiology Traumatic reticuloperitonitis after ingestion of metallic Signs foreign bodies is one of the oldest diseases recognized in Once a metallic foreign body perforates the reticular cattle but still occurs with alarming frequency under wall, clinical signs develop. This represents a neurogenic tion, associated abdominal or thoracic viscera injury or pressure-related triggering of the regurgitation reex by the perforating object, physical features of the caus- from reticular irritation. In these less obvious cases, care- ative object, and the affected cow s stage of gestation ful physical examination and attention to detail when or lactation. This statement is in direct conict with textbook 12 hours and prompt the owner to seek veterinary atten- descriptions of the disease and seems difcult to ex- tion for the cow. When examined within of the disease in these referral patients, or they may 24 hours of onset, classic cases as described are relatively have had an initial fever spike after the acute perfora- easy to diagnose. In some cases, ease should not be ruled out by nding a normal rectal vague signs of partial anorexia, decreased milk produc- temperature. The grunt or groan is most apparent when the animal arises, lies down, or is made to move about. Abdominal pain can be difcult to detect in these patients because the diffuse severe pain overwhelms any localized attempt to elicit pain by deep abdominal pres- sure. The animal will be reluctant to rise or move about and in most instances will progress to a shocklike state within 12 to 48 hours. As the animal s condition deterio- rates, the body temperature also may plummet from the early fever to normal or subnormal. The cow has an anxious expression, sal perforation is the principle differential diagnosis for arched stance, and appears gaunt. Some patients with hard- Radiography of the reticulum has been a useful ancil- ware disease with acute localized peritonitis and most lary procedure in teaching hospitals and referral centers to patients with acute diffuse peritonitis will show a degen- aid in detecting reticular foreign bodies and abscesses of erative left shift in the leukogram. The procedure is very helpful in than 10 days) hardware disease, serum globulin is often confusing cases of abdominal disease or in conrmation elevated ( 5. Experi- have hypoproteinemia as a result of uid and protein ence with such radiographic studies and the subsequent loss into the peritoneal cavity, but this does not occur as surgical ndings allow clinicians to diagnose, determine commonly as with abomasal perforation. Because of the need or approach for surgery, and prognosticate more forestomach and abomasal hypomotility or stasis, pa- specically than possible without this ancillary aid. A tients with hardware disease have a hypochloremic, hy- portable unit has reportedly been used to take radio- pokalemic, metabolic alkalosis that varies in severity in graphs of the reticulum in cattle restrained in dorsal re- direct proportion to the degree of stasis. However, it is difcult to keep cows in that with subacute or chronic hardware disease that has position and the forced positioning of the cow could caused complete rumen stasis may have a profound worsen the peritonitis. It is debatable whether alkalosis of Diagnosis this magnitude totally results from the disease present or The diagnosis of traumatic reticuloperitonitis is based is accentuated by oral administration of ruminotoric primarily on physical examination and is aided by labo- laxative medications before blood collection. In cattle with obvious of pathophysiology for alkalosis of this magnitude, the signs of peritonitis, perforating abomasal ulcers are the prognosis is not hopeless. Perforating abomasal are abdominal ultrasonography and reticular radio- ulcers tend to cause pain in the midventral abdomen on graphy.

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