Genetic Diseases in Purebred (Breeder) Dogs

Executive summary

The enthusiasm for perfect dogs triggered dog inbreeding. As such,inbreeding allows the passage of good genes from a parent to a puppy,but in some cases, inbreeding causes the passage of bad genes. Thelimitation of a gene pool and the breeding of dogs within the sameclub limit the gene variety severely. In this regards, the risk ofhereditary defects rises with each consecutive breedingsignificantly. Some of the defects include risks of bone disorders,cancer, skin, neurological diseases, eye and heart diseases, and thediseases of the immune system among others. The main problemidentified throughout the paper in regards to the genetic disordersstems from the fact that in order to create a thoroughbred, thebreeder needs genetic factor from two genetically identical parents,which means that passing on a gene associated problems to theoffspring is foreseeable. However, the future of hereditarilyacquired illnesses in thoroughbred or purebred dogs lies withscientific study, even as people continue to use modern medicinecontinues to suppress the effects of the resultant diseases. In thisregards, the discussion will revolve around the genetic disordersseen or experienced in purebred dogs.

According to biologists, breeds are interspecies groups that haverelative unvarying, physical characteristics, which develop underhuman monitoring. Dog breeds were first developed from canidsindigenous to a ge0ographical location. The intention of creatingvarious dog breeds by man was for selecting phenotypic traits such asshape, colour, conformation and behaviour (Irion et al. 24). Afterthe original breeds, later ones were developed based on thesuccessful phenotypes of the earlier experiments. While practicingintense phenotypic selection to create dogs with desired traits,there was a loss of some genetic information in the process. Some dogbreeds have been observed to lose more than others, owing tohistories of the breeding selections and practices. This selectivebreeding has created several hundreds of modern dog breeds, resultingin purebred dogs being at risk of inheriting a number of diseases,which affect both their bodies and behaviour. This paper looks at howthe occurrence of genetic diseases in purebred dogs of differentracial and breeders differ by making special reference to a number ofgenetic diseases.

Background contexts

In the past, people thought that purebred dogs were certainly ingood health than mixed breeds. However, research and relationshipwith the purebred dogs show that they frequently suffer from theimpacts of inbreeding. In fact, in spite of the covet they receivefor their beauty, the face various problems related to their purelineage. In this regards, the genetic problems that develop inpurebred animals stems from the notion that to develop a purebredpuppy one needs two dogs from the exact identical DNA segment pool.The DNA pool is already constrained and subsequent inbreeding meansthat genetic disorders exist in the parents develop into puppies. Alatest research in&nbspThe American Naturalist&nbspparalleledthe multiplicity in the dog to that transversely the whole ordercarnivora. The study found more variance between the craniums of aPekingese and a Border collie than amongst those of a coati, a SouthAmerican member of the raccoon clan and a walrus. To safeguardspecific characteristics, though, breed supporters have for anextensive period protected a highly meticulous process, adaptinghereditary lines and generating registries that specify which dogscan be brought up to yield more of the same breed thus, the problemof genetic disorder. The more restricted the sum of mates, the biggerthe coincidental that a dog will be reproduced with a family memberwho bonds related inheritable factor. In this regards, recessive DNAscause genetic illnesses, so a decent genetic factor from one parentwill undermine a bad genetic factor from the other. However, theexistence of bad genetic factors in the same parent, for example, theone that inclines them to blindness or hip dysplasia, the possibilityof a sickened puppy rises.

Skin problems

Congenital skin disorders

Martinez-Reguira describes aplasia cutis as “missing or absent skinin purebred dogs” (529). Despite the fact that the disease is rarein purebred dogs, a good number of dogs have been born with ulcers orareas that lack skin covering, which is the main symptom of thedisease. In many dog breeds, patches or hairlessness manifests nevus,which is a congenital skin disorder. The equal of this in RhodesianRidgebacks is dermoid cysts. In the Rhodesian Ridgebacks, dermoidcysts are often inherited. A number of other breeds such as theHavanese suffer from a similar disease. Dermoid cysts are skinpockets into which hair or old debris accumulates. They are mostlyfound in the skin above the backbone however, there is littleassociation with spinal cord defects. While nevus can be treated byremoval through laser treatment or cryotherapy, dermoid cysts aresurgically removed.

Hereditary hair loss

It is normal for purebred dogs to be born with or without hair. Overthe dog’s lifetime, it can develop more hair or less, as comparedto the average hair development. Caliboli says that in most cases,hereditary hair loss in pure breed dogs, also known as Alopeica, isassociated with other conditions such as abnormal teeth growth,skeletal and a number of other developmental defects (594). Alopeciamainly affects pure breeds such as Chinese Crested and AmericanHairless terrier. These dogs have defects of the teeth and limbs too.In other breeds, the genetic condition mainly affects the male dogs.Many of these affected dogs exhibit conditions of patchy skins anddental problems. All breeds with alopecia are prone to other diseasessuch as follicle infections and foreign body inflations.

Genetic disorders of the hair follicles affect a number of breederdogs. A genetic syndrome commonly known as colour dilution alopeciais due to a gene that turns the dog’s hair to blue or beige. Thissyndrome is mainly observed in Doberman Pinchers. Other breeds thathave this syndrome include Yorkshire Terriers and Greyhounds (Cadieu152). Italian Greyhounds mainly develop this syndrome before they areone year old, and through their life, they suffer follicleinflammation and continued hair loss. In Pappillons and BeardedCollies, Black hair follicle dysplasia comes with to total hair loss.Spitz-type breed often develops woolly syndromes that arecharacterized by discontinuous hair loss.

Abnormal skin growth syndrome

These are often known as hyperplastic and seborrheic syndromes(Ackerman 89). They are characterized by abnormal growth of the skincells, which leads to scaling and thickening of parts of the skin.These syndromes are associated with other inherited conditions, whichare due to sex linkages of the purebreds. While some of the abnormalskin growth syndromes are observed in localized portions of the skin,others are observed in entire regions of the skin such as under thebelly or all over the back. There are three major variations ofhyperplastic and seborrehic syndromes.

The first one, familiar footpad hyperkeratosis, is observed mainlyin Irish Terries and Dogous de Bordeaux (Field and Jackson 27). Thissyndrome is characterized by a thickened outer skin layer anddevelops in early stages of the dog’s life. In spite of the datumthat the illness is not usually congenital, it is mostly associatedwith the Irish Terries and Dogous de Bordeaux. It causes severe andsecondary infections in the dogs, and may lead to lameness however,the disease rarely comes with other skin abnormalities.

Canine ichtyosiform dermatoses are common in a number of breederdogs such as Irish Settlers, English Springer Spaniels, and LabradorRetrievers. It is also observed in other breeds such as the DobermanPinschers and Cavalier King Charles Spaniels (Frank 56). This diseaseis characterized by abnormal coverage of large scales all over thedog’s body. The nose and paws are also observed to be abnormallythickened, and this causes some discomfort to the dogs. Unlike theother hyperplastic and seborrheic syndromes, treatment of canineichthyosiform dermatoses is difficult. It can, however, be relievedby chemical treatment. Additionally, veterinaries can subscribeshampoos, which can be used to relieve the disease.

The third variety of hyperplastic and seborrheic syndromes isgranulomatous sebaceous adenitis. This variety destroys that oilglands and is associated with severe hair loss. It mainly affectsAkitas, and sometimes Standard Poodles. Like familiar footpadhyperkeratosis, it occurs in early stages of the dog’s life. Aftermonths of continuously thickening skin, progressive hair loss andpatchiness ensues. However, Akitas suffer more than the Poodles, asthey become oilier and less hairy. There is no consistent treatmentof the disease, as an array of medicated shampoos is used to treatthe disease. Should there be secondary infections aggravated byexcessive hair loss, it is recommended that the breed be examined bya trained veterinary.

Hereditary congenitl follical parakeratosis

Ross did research on this rather new syndrome, which was observed tobe affecting Labrador Retrivers, female Rottwilers and SiberianHuskies (34). This skin condition is rather strongly severe, leadingto the formation of keratins on parts of the skin. The geneticdisease is also closely related to a number of other structuraldefects on parts of the skin. In spite of the fact that little isacknowledged about this genetic disorder, Siberian Huskies quitecommonly exhibit its symptoms. The equivalent of this geneticdisorder in English Springer Spaniels is psariasiform-lichenoiddermatosis. Its symptoms are red symmetric abnormalities and smalllumps of skin, which form around the ears and some areas of thegroin. These become thick and harder as the dog grows older. Unlikein the Siberian Huskies and Rottwillers, the English SpringerSpaniels exhibit severe symptoms if left untreated. However,antibiotics and other medications that provide relief may treat thelatter. However, response to the treatment for psoriasiform-lichenoidhereditary disease is quite uncommon.

Pigmentary abnormalities

Some purebreds have hereditary skin colour abnormalities. Theseabnormalities in skin and coat colour are sometimes related. Thefirst pigmentary abnormality is albinism, which is common in Dobermanpinscher dogs. It is a quite different form of white spotting and isoften associated with pink and pale irises. Most of the affectedbreeds are at high risk of acquiring skin cancer, which is due toextreme sun radiation. The cancer is most likely to begin in areasthat have little skin and hair cover. Some species, such as Poodles,have extreme piebaldism, which is commonly associated with neurologicanomalies.

Pure breeds such as Miniature Schnauzers suffer from daurotrichiafrom a variety of hereditary pigmentary abnormality (Rolling et al.,498). The hair along the spinal cord of these dogs changes fromnormal black to golden as they age. The first colour changes arenoticed when they dogs are reaching their young adulthood. Quiteoften, the change is associated with a reduction of the hair coat onthe back. However, some purebreds with this variety of pigmentaryabnormality do not exhibit any kind of change to the skin.

Vitiligo is a hereditary pigmentary abnormality, which, however,cannot be easily recognized when the dog is still young (Clark 56).It mainly affects Belgian Tervurens and Rottweilers. The pure breedsexhibit symptoms of bleached patches of the skin, which mainlyaffects the hair on their back and claws. However, most of thesepatches in Belgian Tervvurens is mainly concentrated in the eyes andmay come and disappear in different stages of the dog’s life. Theseverity of the colour loss depends on the parent’s genes, and itcomes and goes at different rates. In spite of the datum that thereis no treatment for vitiligo, it causes no other associated healthproblems.

Defects in structural integrity

Some genetic disorders of purebreds affect the integrity andcontinuity of the skin. The first variety of this is cutaneousasthenia, which is a condition of the skin that bars the productionof enough collagen by the skin (Earley and Rawlinson 274). Thisdisease mainly affects the Rottweiles. The affected dogs have a looseand fragile skin, which can be seen right from the moment they areborn. The wounds that result heal very slowly and are easilyaggravated even by minor scratches. Should the dogs be bruised, theywill have loos skin tags hanging from the body. Such conditions makeit easy for the dogs to acquire fatal infectious diseases. Thecondition also affects the joints and eyes, which may lead to thedevelopment of loosely hanging skin in older animals. According toBreen, this condition may be treated with some vitamins, whichsupplement the skin’s ability to produce collagen for a strongerskin (54).

In Chinese Shar-Peis purebreds, cutaneous mucinosis is a structuralintegrity defect which affects the skin. This breed has excessivemucin to the extent that the skin has distinct folding and blistersall over the body (Akey 1162). Either skin biopsy or blister prickingdiagnoses this condition. However, this variety of structuralintegrity defect is not as severe as the other two, as it becomesless severe as the dog matures. The major concern with it is that ifleft unattended, the dog may suffer from allergic skin disease, whichis quite common with the Chinese Shar-Pies.

Golden Retrievers, Akitas, Toy Poodles and German ShorthairedPointers are some of the purebreds that have a group of hereditarycongenital defects, which mainly affect the attachments between theskin layers. This form of the structural integrity defect is known asepidermolysis bullosa syndrome. As a result of its effects, there aresome minor skin traumas that may be observed. The dogs have severalugly sports on their skins due to the rupturing of blisters that formon the skin (Ackerman 145). There may also be some flat ulcersdeveloping due to the problem. The worst blisters form on the mouthand genital areas. This variety of the inherited structural integritydefect is the deadliest of the three.

Inherited multisystem disorders that affect the skin

There are four major varieties of inherited multisystem disordersthat affect the skin. The first one, familiar dermatomyositis,affects young Collies and Sheland Sheepdogs (Hyun and In-Chul Park257). This skin affects the breeds’ skin and muscles. In earlystages of their lives (about 6 months old), the breeds developproblems with blood vessels and the skin. This later develops intoatrophy. The disease affects individual breeds to a different levelof severity. The conditions are worsened by wounds and exposure tothe sun, and may lead to hair loss and crusting. Response to drugsand treatment differs with the level of severity and breed.

For German Shepherds and Jack Russell Terriers breeds, familialvasculopathy is the variety of hereditary disorders that affectstheir skins. These breeds develop skin ulcers soon after they havebeen vaccinated, further vaccination worsens the condition. The mainsymptoms are swellings on the footpads and gradual loss of colour,which may lead to the development of ulcers. Practically, all thefootpads are affected to some level. Research by Zabka et al.described a more severe form of neutrophilic vasculities (510-522).This was mainly observed in Chinese Shar-Peis. However, as the dogmatures, the disease may disappear. This does however not rule outthe development of euthanasia, which is guaranteed with severe padulcers. High usage of steroids may reduce the severity, despite thefact that no treatment is uniformly effective.

Hereditary zinc deficiency syndromes affect breeds such as BullTerriers, Huskies, Malamutes and German shorthaired pointes. In theTerriers, there is retarded skin growth and pustules around mucousmembranes. These symptoms are observed at a very early age, and deathoccurs almost at about two years. The lives of the affected dogs canonly be prolonged by zinc treatment. In German shorthaired Pointersand Malamutes, symptoms develop in advanced age. There are alsocommon secondary infections, and they respond well to zinc treatment.

Lupoid dermatosis affects mainly German Shorthaired Pointers and isdiagnosed at a very young age (Ackerman 87). The initial symptoms arescaling and crusting on the head, as well as the limbs. The symptomsquickly spread to other parts of the skin, on the way causing rednessdue to the congestion of blood capillaries in the affected skinareas. The affected breeds experience pain and itchiness in theaffected areas, and often develop fevers. This hereditary skincondition worsens as the dog ages and is often fatal. Up to date,there is no known treatment for this hereditary disease.

Hearing problems

Congenital deafness in dogs is inherited in a variety of purebreddogs. According to Rak et al., inherited deafness is caused by a genedefect that is autosomal dominant, and may involve a number of othergenes (189). Should there be a lack of a clear observed problem in acertain breed, it becomes quite difficult for the owners and theveterinaries to identify the deafness at earlier stages of the dog’slife. Presently, congenital deafness has been reported forapproximately 25 pure breeds (Strain 23). The list is growing at asteady rate. Despite the fact that the genetic disease canpotentially occur in any breed, it is more common in those with whitepigmentation. Pigmentation patterns are indicators of the deafness inthe purebreds while the presence of white hair in the hair coats is agenetic indicator of high chances of deafness. The merle gene is apigmentation gene that is responsible for hereditary deafness inDappled Dachshund, Harlewquin Great Dane, and Shetland sheepdog. Onthe other hand, the piebald gene is responsible for hereditarydeafness in Bulldog Beagle, Pyrenees, English Seeter and SealuhamTerrier. However, Strain asserts that not all the purebreds withthese genes have been reported to be affected (25).

Additionally, according to research by Gauly et al., the prevalenceof congenital deafness in different breeds is rarely known (766).Some purebreds are bilaterally deaf while a number of others areunilaterally deaf. Breeds such as the English Cocker Spaniel and theBull Terrier are not usually affected by total deafness. Unilateraland bilateral deafness is seen in three quarters of all whiteNorwegian Dunker hounds. Other breeds, which have a high incidencerate for deafness, are Catahoula and the Australian shepherd. Anothermajor issue in research in purebred inherited deafness is the methodof genetic transmission (Gabriel et al. 146). For the Rottweiler andthe Pointer, the disorder has been found to have an autosomalrecessive mechanism. A high inbred research population for thepointers has been used to obscure the mode of inheritance. As forother breeds, it has been established that autosomal is dominant.However, some studies have refuted these claims. As for the Dalmatianinbreeds, deafness does not appear to be autosomal dominant. This isbecause it has been established that deaf puppies may result fromnon-deaf parents. Researchers to explain the multi-gene cause, whichis the presence of two different autosomal recessive deafness genes,have used these findings.

Chondrodysplaysia (Dwarfism)

Dwarfism if the most recognized form of chondrodysplaysia in purebreddogs (Young and Bannasch 48). Most people mistook that all smallbreeds are dwarfs. Despite the fact that some toy breeds are indeeddwarfs, most of them naturally do, or have been miniaturized. Onething to note is that all miniaturized dogs maintain the same bodyproportions as their larger counterparts, and they have bee simplybred into their small postures. On the other hand, dwarf breedsstructure has been genetically altered to produce small-shortenedlimbs while the rest of the body remains unaffected. This results ina dog with a large body but disproportionately short limbs. Overtime, chondrodysplaysia has become a gene variation for man hasmanipulated breeds that have been, which have effectively beenselected for short legs. However, the genetic condition is thecorrect build for some inbreeds. These include the Dachshund andBasset. Parker et al. say that chondrodysplysia is a structuralanomaly in these breeds (996). Other breeds such as Havanese haveskeletal conditions, which are signs of mild or moderate dwarfism.These breeds have premature and uneven growth plates, and while somemay have straight limbs, others may have all bent limbs or a mixtureof straight and bent limbs.

Organ problems

Heart disease

Cardiomyopathy is a genetic disease of purebred dogs, which affectsthe heart muscles and makes them less efficient for supplying bloodto other organs (Oyama, Sisson and Solter 44). This leads to generalweakening of the heart, resulting in congestive heart failure anddeath. Despite the fact that the disease may start at an early age,about 2 to 5 years, the signs may not be visible up to about a decadeold. By this time, the dog is at high risk of heart failure. Hevanesepurebreds are one of the breeds most affected by this disease. Inthis breed, symptoms are unexplained lethargy, coughing, andexcessive fatigue. In Pyrenees purebred dogs, the disease may benoticed in early ages. This breed responds well to medications,which, however, are not curative, but help to compensate for theincreasing heart failures.

Another form of heart disease, which is common in Havanesepurebreds, is heart murmurs (Gough and Thomas 234). These are silentturbulent sounds, which are created from the blood flowing throughfaulty valves. The congenital heart murmurs can be identified whenthe puppies are being born. In this purebred, non-congenital murmursare likely due to an insufficiency of the mitral valve, which maydevelop at any time of the dog’s life. In other breeds, such as theRhodesian Ridgebacks, murmurs develop in later stages of their life,for instance, when they are about 6-7 years old. The genetic heartdiseases that are discovered in the early life of the purebreds maynot necessarily mean that they will be saved, but it gives them achance to receive medication and live a better life.

Other genetic conditions

Other genetic conditions affecting pure breeds include neurologicaldisorders and allergies. The most common neurological disorder inpurebreds is epileptic seizures. Some purebreds, such as NorwegianDunker hounds and Rottweiler demonstrate repeated jerking of theentire body, followed by periods of temporary disorientation. Forothers, such as the English Cocker Spaniel and the Bull Terrier needmultiple seizures to be correctly diagnosed, as they seizures may bea result of medical diseases such as diabetes and liver disease.Bellumori et al. say that all pure breed dogs are more susceptible toallergies than cross breeds (1550). The American Staffordshire andthe bulldog have severe allergies that can result in death, whileothers such as the American Blue Lacy and Cavalier King have geneticallergies that are not as severe.

Conclusion

Dog enthusiasm was the trigger for dog inbreeding. However, this cameat a genetic cost these dogs suffered genetic hereditary geneticdiseases. The purebred dogs have continued to suffer from the effectsof inbreeding. The main problem identified in the paper stems fromthe fact that in order to create a purebred, the breeder needs genesfrom two genetically identical parents. This means that passing on agene related problems to the offspring is inevitable. As many dogclubs require that the dogs are bred within their club, this severelylimits gene pool variety. This significantly increases the risk ofgenetic defects, leading to diseases that have been discussed above.The future of genetically acquired diseases in purebred dogs lieswith scientific research, even as contemporary medicine continues tobe used to suppress the effects of the resultant diseases.

Works Cited

Ackerman, Lowell J.&nbspThegenetic connection: a guide to health problems in purebred dogs.American Animal Hosp Assoc, 2011. Print.

Akey, Joshua M., et al. &quotTrackingfootprints of artificial selection in the dog genome.&quot&nbspProceedingsof the National Academy of Sciences&nbsp107.3(2010): 1160-1165. Print.

Bellumori, Thomas P., et al.&quotPrevalence of inherited disorders among mixed-breed andpurebred dogs: 27,254 cases (1995–2010).&quot&nbspJournalof the American Veterinary Medical Association&nbsp242.11(2013): 1549-1555. Print.

Breen, Matthew. &quotCaninecytogenetics-from band to basepair.&quot&nbspCytogeneticand genome research&nbsp120.1-2(2008): 50. Print.

Cadieu, Edouard, et al. &quotCoatvariation in the domestic dog is governed by variants in threegenes.&quot&nbspscience&nbsp326.5949(2009): 150-153. Print.

Calboli, Federico CF, et al.&quotPopulation structure and inbreeding from pedigree analysis ofpurebred dogs.&quot&nbspGenetics&nbsp179.1(2008): 593-601. Print.

Clark, Ross D.&nbspMedical,Genetic &amp Behavioral Risk Factors of Old English Sheepdogs.Xlibris Corporation, 2014. Print.

Earley, Edward, and Jennifer T.Rawlinson. &quotA new understanding of oral and dental disorders ofthe equine incisor and canine teeth.&quot&nbspVeterinaryClinics of North America: Equine Practice&nbsp29.2(2013): 273-300. Print.

Field, Garrett, and Todd A.Jackson.&nbspThelaboratory canine. CRCPress, 2006. Print.

Frank, Linda A. &quotComparativedermatology—canine endocrine dermatoses.&quotClinicsin dermatology&nbsp24.4(2006): 317-325. Print.

Gabriel, Alexandra, et al.&quotLaryngeal paralysis‐polyneuropathycomplex in young related Pyrenean mountain dogs.&quot&nbspJournalof small animal practice&nbsp47.3(2006): 144-149. Print.

Gauly, Matthias, et al. &quotBrainstemAuditory‐EvokedPotential Assessment of Auditory Function and Congenital Deafness inLlamas (Lama glama) and Alpacas (L pacos).&quot&nbspJournalof veterinary internal medicine&nbsp19.5(2005): 756-760. Print.

Gough, Alex, and AlisonThomas.&nbspBreedpredispositions to disease in dogs and cats.John Wiley &amp Sons, 2011. Print.

Hyun, Changbaig, and In-Chul Park.&quotCongenital heart diseases in small animals: Part II. Potentialgenetic aetiologies based on human genetic studies.&quotTheveterinary journal&nbsp171.2(2006): 256-262. Print.

Irion, D.N, Schaffer, A.L., Famula, T.R., Eggleston, M.L, Hughes,S.S. and Pedersen, N.C. “Analysis of Genetic Variations in 28 DogBreed Populations with 100 Microsatellite Markers”. Journal ofHeredity. 94(1): 81-87. Print.

Martinez‐Regueira,Soledad, et al. &quotAplasia cutis congenita in a defined populationfrom northwest Spain.&quot&nbspPediatricdermatology&nbsp23.6(2006): 528-532. Print.

Oyama, Mark A., D. David Sisson,and Phil F. Solter. &quotProspective screening for occultcardiomyopathy in dogs by measurement of plasma atrial natriureticpeptide, B-type natriuretic peptide, and cardiac troponin-Iconcentrations.&quotAmericanjournal of veterinary research&nbsp68.1(2007): 42-47. Print.

Rak, Simone G., and Ottmar Distl.&quotCongenital sensorineural deafness in dogs: a molecular geneticapproach toward unravelling the responsible genes.&quot&nbspTheVeterinary Journal&nbsp169.2(2005): 188-196. Print.

Rolling, F., et al. &quotGenetherapeutic prospects in early onset of severe retinal dystrophy:restoration of vision in RPE65 Briard dogs using an AAV serotype 4vector that specifically targets the retinal pigmentedepithelium.&quot&nbspBulletinet mémoires de l`Académie Royale de Médecine de Belgique&nbsp161.10-12(2005): 497-508. Print.

Strain, George M.&nbspDeafnessin dogs and cats. Cabi,2011. Print.

Young, Amy, and Danika Bannasch. &quot4Morphological Variation in the Dog.&quotColdSpring Harbor Monograph Archive&nbsp44(2006): 47-65. Print.

Zabka, T. S., F. E. Campbell, andD. W. Wilson. &quotPulmonary arteriopathy and idiopathic pulmonaryarterial hypertension in six dogs.&quot&nbspVeterinaryPathology Online&nbsp43.4(2006): 510-522. Print.