Tsdnc proceedings 2010 - adjusted.pmd

Nutritional and Animal Welfare Implications to Lameness
Jan K. Shearer1
Department of Veterinary Diagnostic and Production Animal Medicine Abstract
metalloproteinase enzymes and peripartumhormones, such as estrogen and relaxin. The implications of this are that in addition to feeding fermentive disorders occurring secondary to the and nutrition, dairy farmers must pay particular consumption of feedstuffs that contain relatively large attention to cow comfort during the transition period.
amounts of highly fermentable carbohydrates. It The digital cushion consisting of fat and loose may be complicated by diets that offer less than connective tissue is an important support structure adequate levels of effective fiber. Lactic acid in the claw. Recent work suggests that body accumulates within the rumen, leading to rumenitis condition score mirrors size (i.e. fat content) of the and a change in the rumen flora that favors lactate digital cushion and may be very important to the production. The change in rumen flora is also integrity and health of claws. Whereas, most have associated with the release of endotoxins within the thought that lame cows become thin, their research rumen. These endotoxins, along with various other suggests that thin cows become lame. Maintenance vaso-active substances (including lactate), are of good body condition throughout the first 120 absorbed into the blood stream where they disrupt days of lactation may prove to be a very important the normal flow of blood within the tissues of the feeding objective. The welfare implications of corium. Inflammation of the corium initiates the lameness are huge. Lameness affects performance, release of potent metalloproteinase enzymes that causes pain, and disrupts the cow’s ability to express cause destruction of the suspensory apparatus of normal behavior. The underlying causes of lameness the 3rd phalanx. Sinking and rotation of the 3rd phalanx follows with compression and damage to preponderance of information on the pathogenesis the supporting tissues and structures of the corium of lameness in recent years, there is little question that precipitates the development of sole ulcers and that housing is a major contributor to the white line disease. In recent years, research from development of lameness disorders. Overcrowding, the United Kingdom suggests that damage to the stall design and stall surfaces, flooring, and specific suspensory apparatus is likely to occur by other management practices restrict resting and force mechanisms. Their work demonstrates that as cows to stand for longer periods. Smooth and animals’ progress toward calving, rigidity and manure slurry covered or wet floors are slippery strength of the collagenous connective tissue of the and may precipitate injuries due to falling. Abrasive suspensory apparatus is significantly reduced flooring conditions cause excessive wear and (Tarleton et al., 2002; Tarleton and Webster, 2002).
lameness due to thin soles. Anything that increases They propose that these changes are potentially a the incidence of lameness contributes to poor animal welfare. Treatment of lameness needs to be timelyand carefully administered.
1Contact at: 2436 Lloyd Veterinary Medical Center, Department of Veterinary Diagnostic and Production Animal Medicine,Ames, IA, 50011-1250, (515) 294-3731, FAX: (515) 294-1072, Email: [email protected] Rumen Acidosis and the Vascular Distur-
and eventually arterio-venous shunting (Vermunt and bances Contributing to Laminitis
Rumen disorders that result in acidosis are usually associated with the ingestion of large amounts inflammation, accompanied by swelling, hemorrhage, of highly fermentable carbohydrate-rich feeds, and death of corium tissues. Functional disturbances resulting in the excessive production and follow, including the activation of matrix accumulation of lactic acid in the rumen (Nocek, metalloproteinases (MMP) that degrade the
1997). In its acute form, rumen acidosis is a life collagen fiber bundles of the suspensory apparatus threatening disease characterized by severe toxemia, of the third phalanx (i.e. P3, the bone within the ataxia, incoordination, dehydration, ruminal stasis, claw capsule). These changes are exacerbated by bloat, weakness, recumbency, and ultimately death.
the activation of epidermal growth and necrosis The subclinical form of rumen acidosis (better known factors that contribute to structural alterations as SARA, for SubAcute Rumen Acidosis) occurs involving the basement membrane and capillary more commonly. Clinical manifestations would walls. Although somewhat complicated, these are include: variable feed intake, depressed fat test, the major lesions associated with laminitis at the cell poor body condition despite sufficient energy intake, and tissue level. A more comprehensive discussion mild to moderate diarrhea, and occasional cases of of these may be found in other recent publications epistaxis (nose-bleed) or hemoptysis (the (van Amstel and Shearer, 2006; Greenough, 2007).
expectoration of blood from the mouth).
Laminitis (Pododermatitis aseptica diffusa)
establish a direct link between rumen acidosis and laminitis, yet observation and clinical experience important predisposing cause of disorders affecting suggests feeding is an important underlying factor the digit in cattle. It is characterized by disrupted (Nordlund, 2002). Acidosis causes varying degrees blood flow (as described above) that results in of rumenitis which permits absorption of lactate, inflammation and the activation of potent enzymes endotoxins (from the death of gram negative (metalloproteinases) that damage tissues responsible microorganisms in the rumen), and bioactive for suspending the third phalanx (P3) within the claw
messengers, such as histamine and serotonin, from horn capsule. To understand this phenomenal the rumen wall. These combined with vasoactive suspensory system and what happens when it fails substances, such as epinephrine and norepinephrine, is fundamental to understanding the pathogenesis cytokines, prostaglandins and other substances, of claw disorders (i.e. ulcers and white line disease) have direct effects on the vascular endothelium that initiate a cascade of events, including a decrease inblood flow caused by the simultaneous dilatation of arterioles and constriction of venules. Damage towalls of blood vessels leads to the extravasation The laminar corium (sensitive lamina) of the (leaking) of blood and blood fluids into extra- claw is the primary suspensory tissue for P3. Cows vascular (into the tissues surrounding the vessels) essentially “hang in their claws” by virtue of a series tissues of the corium. This is complicated still further of laminar folds that are anchored on the abaxial, by stagnation of blood within the capillaries and other dorsal, and axial surface of P3 and extend outward small blood vessels, resulting in thrombosis (clotting), to interdigitate with the lamelle of the wall. Beneath ischemia (lack of blood flow), hypoxia (low oxygen), P3 are tissues which make up the underlying support structure for P3. This tissue is composed of loose Activation of matrix metalloproteinases by connective tissue from the solar and perioplic corium and caudally by the digital cushion. The digitalcushion is an important support structure composed of loose connective tissue and varying amounts of studied the supportive capacity of the suspensory adipose tissue. It has become the object of attention apparatus of P3 in first lactation heifers and age- by several researchers in recent years as recent matched maiden heifers during the peripartum observation suggests that the size and type of fat period (Tarleton et al., 2002; Tarleton and Webster, within the digital cushion may have important 2002). They observed increased laxity, reduced implications in the occurrence of lameness (Lischer rigidity, decreased load-bearing capacity, and a clear deterioration in the structural integrity of hooves infirst lactation heifers. Furthermore, these changes Inflammation leading to destruction of the appeared to be progressive over the period of 2 dermal-epidermal junction results in weakening of weeks prior to calving until 12 weeks post-calving.
the suspensory apparatus that predisposes to the These hoof characteristics were not observed in downward displacement and rotation of the P3. The age-matched maiden heifers. Workers suggested result is compression of the corium and supporting that these changes would permit sinking of P3 and tissues that lie between P3 and the sole which thus predispose affected animals to compression of predisposes to the development of sole ulcers (Ossent and Lischer, 1998). In some cases, rotationof the apex of P3 is severe enough to cause dysfunction of the corium in this region and observations were explored, and in the process, predispose to a toe ulcer. If, on the other hand, researchers identified a unique ~ 52kD gelatinolytic sinking of the P3 is such that the rear portion sinks enzyme they termed as “hoofase”. This enzyme the furthest, compression at the heel-sole junction was isolated from all specimens derived from calving will result in the development of a sole or heel ulcer.
heifers; however, none was found in specimens from Sole ulcers are one the most common claw lesions the maiden heifers. Researchers also sampled each in dairy cattle and constitute one of the most costly of the study groups to determine if there was a relationship between hoofase and the types andlevels of MMP isolated from the connective tissue Displacement of P3 by Alternate
samples. Interestingly, researchers observed the Mechanisms
highest levels of hoofase in pregnant heifersapproximately 2 weeks prior to calving. In addition, While most have considered rumen acidosis they found highly significant increases in the activated to be the primary cause of laminitis, lameness form of MM-2, a very important metalloproteinase researchers in recent time suggest that it is more involved in the mediation of collagen remodeling in complicated than previously believed. In fact, the normal animals (Tarleton and Webster, 2002). On claws of cows and particularly heifers are less the other hand, levels of metalloproteinase-9 (MM- resistant to compressive loading forces than 9), the enzyme most consistently associated with previously thought and especially so during the peri- inflammation as related to rumen acidosis, was not partum period. The confinement of cows on hard found in significant quantities in either the first surfaces is potentially one of the single most lactation or maiden heifers. This suggested that the important predisposing causes of lameness in dairy classical form of rumen acidosis-induced laminitis was not a cause of the changes observed. There were marginal increases in “proMM-2” (a German researchers suggest that sinking and metalloproteinase normally responsible for rotation of P3 may be associated with as of yet physiological and pathological remodeling of unexplained structural alterations occurring on the connective tissues). Researchers concluded that surface of P3 where the suspensory tissues are these results indicate that hoofase plays a very anchored (Mulling and Lischer, 2002). It is clear important role in the activation of MM-2 and that despite the preponderance of information linking weakening of the suspensory apparatus by a laminitis to feeding conditions and rumen acidosis, mechanism quite different than that related to rumen softer flooring surfaces and cow comfort cannot be acidosis. Considering the observations of this study, overlooked as requirements for animals during the indicating that peak hoofase activity occurs approximately 2 weeks prior to calving and that itcontinues well into the early postpartum period, one Ulcers of the Toe, Sole and Heel
must conclude that hoofase may have a very (Pododermatitis circumscripta, Rusterholtz
important role in the cause of claw lesions.
Ulcer/Sole Ulcer, Toe Ulcer and Heel Ulcer)
Displacement of P3 results in compression of the solar and perioplic corium between P3 and the sole. Contusion and bruising of the corium at suggested yet another mechanism for weakening of the toe, sole ,and heel causes injury and dysfunction the dermal-epidermal segment between the wall and of the corium. In cases where displacement of P3 P3. Their work suggests that weakening of the involves severe rotation of its apex, a toe ulcer may suspensory tissue may be the result of hormonal develop. If, on the other hand, sinking of P3 is changes that normally occur around the time of such that the rear portion sinks furthest, compression calving (Tarleton and Webster, 2002; Webster, of the solar and perioplic corium of the heel will 2002; Knott et al., 2006). In particular, hormones lead to development of a sole ulcer at the heel-sole such as estrogen and relaxin, responsible for junction (Raven, 1989). Toussaint Raven has relaxation of the pelvic musculature, tendons, and characterized this as the “typical site”, i.e., the site ligaments around the time of calving, are thought to most commonly associated with the development have a similar effect on the suspensory tissue of P3 as well. Whereas this is likely a natural phenomenonaround the time of calving, housing animals on soft An ulcer is defined as a full-thickness defect surfaces during the transition period (4 weeks prior or break in the epidermis that exposes the corium.
to calving through 4 to 8 weeks after calving) may One of the earliest indications of a developing sole be an important management procedure to reduce ulcer is hemorrhage in the sole, particularly when it or alleviate the potential for permanent damage to occurs at the heel-sole junction. If the animal exhibits these tissues. Researchers base this opinion on pain when pressure is applied to this area, it offers observations that fewer claw lesions occurred in good evidence that the ulcer is in the clinical stage.
heifers housed in straw yards compared with those With additional time and trauma associated with housed in free stalls during the transition period.
weight bearing, this lesion will likely progress to a Researchers concluded that first lactation animals, full-thickness horn defect or ulcer. In the pre-clinical in particular, would benefit from softer flooring or early stages of development, despite the size of surfaces during the peripartum period .
some hemorrhages, pressure as might be appliedwith a hoof tester causes little or no discomfort.
Treatment of these cases may be accomplished by lowering the heel on the affected claw so that it may the corium. Granulation tissue bleeds freely and have time with reduced weight bearing for rest and recurrence rates for ulcers with exposed granulation repair. If, on the other hand, one is able to illicit pain by putting gentle pressure over this area with a hooftester, one should not only lower the heel on the affected claw but also consider application of a foot ulcers, one must recognize their multi-factorial block to the healthy claw to insure complete relief etiology. The metabolic factors responsible for from weight bearing. When identified early, these sinking and rotation of P3 include rumen acidosis cases will usually recover quite rapidly (within 3 to and laminitis and also the effects of enzyme activity and hormonal changes that are most common duringthe transition period. The mechanical factors of greatest importance are those that contribute to lameness and even gentle pressure with a hoof tester unbalanced load bearing within and between claws.
over the ulcer site will illicit a positive pain response.
The work of Toussaint Raven (Raven, 1989) Removal of superficial layers of horn may uncover demonstrates that weight does not distribute itself an area of exposed corium that is extremely sensitive.
evenly but more so to the outer claw. This increased Assuming minimal damage of the corium, these may weight bearing leads to accelerated horn growth be treated by thinning horn around the base of the and overloading of the outer claw, the consequence ulcer and lowering this area relative to the weight of which increases weight load and pressure on the bearing surface of the healthy claw. It is also corium. The biomechanics of loading within the advisable to avoid leaving a crater or hole in the weight bearing surface are also affected by toe sole that will fill with organic matter. Instead, slope length. When the toe is long, the sole in the region the sole axially toward the interdigital space.
of the toe is always thicker. This creates a greater Recovery time for ulcers requires a minimum of 20 distribution of weight caudally toward the heel-sole to 30 days, and based on studies by European junction and is therefore believed to be a contributor workers, recovery may take as much as 50 to 60 to the development of sole and heel ulcers. The days in severe cases. The objective should be to purpose of maintenance or preventive hoof trimming provide relief from weight bearing on the affected procedures is to re-establish appropriate weight claw for at least 1 month by means of a foot block bearing within and between claws by eliminating and an additional 20 to 30 days by corrective abnormal overgrowth that leads to overloading of trimming to adjust load bearing between the two claws. It is important to remember that if there hasbeen significant damage to the corium, recovery may Finally, size and type of fat within the digital be extended. In some cows, this may require that a cushions has become a source of interest in new block be applied as soon as the first one is no understanding the pathogenesis of sole ulcers longer functional due to wear (van Amstel and (Bicahlo et al., 2009). The digital cushion lies immediately above the loose connective tissue ofthe corium and beneath P3. It consists of 3 roughly parallel cylinders (axial, central, and abaxial) inflammation has resulted in granulation tissue composed primarily of fat which serve as shock formation: 1) apply the corrective trimming absorbers in the heel. Studies by Swiss researchers procedures described above, 2) carefully remove have found that the digital cushion of heifers is smaller the granulation tissue with a sharp hoof knife. Be in size and contains more saturated fat, which careful not to damage adjacent normal tissues of reduces it cushioning value as compared with mature cows. These characteristics of the digital cushion in studies are now beginning to suggest that when the heifers may increase the vulnerability of young animals to claw diseases, particularly sole and heel compromised, the corium becomes vulnerable to ulcers. Furthermore, observation of the feet of mechanical injury. Knowing that cows mobilize fat animals suffering laminitis indicates that the sinking from multiple body locations, it is reasonable to of P3 leads to damage of the digital cushions and assume that they would likely mobilize fat from the replacement of the fat with firmer connective (even DC as well. In the study described above, cartilaginous or cartilage-like) tissue. The researchers noted a decrease in thickness of the combination of a harder less flexible digital cushion DC and also evidence of a change in the DC and compression of the corium caused by sinking composition as BCS decreased (Bicalho et al, of P3 results in greater damage to the corium in the heel and consequently, a greater risk of sole andheel ulcers.
demonstrated that the highest prevalence of sole Effects of Body Condition on Claw Disorders
ulcers occurred near peak lactation (i.e., 60 to 100days in milk); the point at which shrinking of the The impression of most people is that lame digital cushion was approaching nadir. This is not cows lose weight. This is logical since lameness unlike observations from other studies and also causes pain and reduces their interest in walking or supports an association with a thinner, less functional standing and therefore the number of trips a cow digital cushion. However, the rumen acidosis- might be willing to make to the feedbunk. However, laminitis complex, the effects of hoofase or activation a recent study suggests that rather than lame cows of metalloproteinase activity, and/or the impact of becoming thin, it may be that thin cows become peri-partum hormonal changes can all be theorized lame (Bicalho, et al, 2008). These researchers as causes of these conditions in a similar time-frame.
investigated the relationship between claw lesions Therefore, these observations neither preclude nor (ulcers and white line disease) and thickness of the reduce the significance of other causative factors as digital cushion (DC) in 501 lactating Holstein cows.
mentioned earlier in this chapter. Rather, they They found that the prevalence of sole ulcers and highlight lameness’s complicated pathogenesis and white line disease increased as thickness of the DC decreased. They also observed that digital cushionthickness decreased steadily throughout lactation, Welfare Implications of Lameness
reaching nadir (i.e., its lowest point) at 120 days
after calving. Body condition scores (BCS) of cows
were positively associated with thickness of the DC, typically include 3 basic questions: 1) is the animal whereby an increase in BCS was associated with a functioning well (in other words, is it producing well), corresponding increase in mean thickness of the DC.
2) does the animal have pain or is it distressed, and3) is the animal able to express or perform natural Results of this study add further credence behaviors (Frazer, 2008; Von Keyserlingk et al., to the idea that claw lesions bear a close relationship 2009)? When we consider lameness in the context to external factors, in particular, confinement housing of these concerns, we fail to achieve the objectives and hard flooring surfaces. Furthermore, it is of good welfare by any of these measures.
tempting, if not reasonable, to theorize that the Lameness reduces milk production and reproductive mobilization of fat in early lactation is a significant performance. It causes pain and interferes with the risk factor for lameness. The results of several animal’s ability to move about freely or confidently to interact with herd mates in behaviors such as large Holstein cow include: head end against a wall, estrus behavior or interactions to establish minimum length should be 9.5 to 10 feet; stalls oriented head to head, 8 to 8.5 feet, andrecommended stall width varies from 46 to 50 inches Housing considerations to improve welfare of (Faull et al., 1996; Anderson, 2002; Cook, 2009).
Lame cows have a particularly difficult time Poor cow comfort is not only an important rising or lying down in poorly designed stalls bedded predisposing cause of lameness, but it’s also what with mattresses. They fare much better in sand keeps cows lame. Key factors are overcrowding, stalls because the foot is able to gain much better poor stall design, inadequate bedding and grooming traction in the loose bed of sand (Cook, 2006).
of stalls, abrasive flooring surfaces, slurry covered This alone is believed to contribute significantly to or wet and slippery flooring surfaces, and the duration of lameness in individual cows. The management practices that contribute to excessive ideal housing condition for a lame cow is a soft standing and reduce time available for resting surface (as might be found on an earthen surface), (Shearer and van Amstel, 2007). In short, failure without the normal restrictions that come with a stall.
to maximize cow comfort is likely to increase the Where weather conditions are unfavorable, special prevalence, incidence, and duration of lameness, needs barns with bedded packs provide friendly while simultaneously extending time required for Leonard evaluated the effect of lying time contribute to claw horn overgrowth, which leads to on first-calf heifers in overcrowded conditions overburdening or overloading of claws and ultimately (Leonard et al., 1996). He found that heifers which contributes to the development of disorders of the spent 10 or more hours per day lying down had foot, such as ulcers and white line disease (Raven, significantly better claw health than those that spent 1989). Furthermore, the manner in which concrete 5 hours/day or less lying down. Cows will normally is finished has significant consequences for foot and lie down and rest for as much as 11 to 14 hours/ leg health. Rough finishes increase the rate of claw day. Less time resting usually means less time horn wear and has been associated with a higher ruminating or “cud-chewing”. When cud-chewing incidence of lameness (Wells et al., 1993). New time is reduced, the natural buffering of rumen concrete is particularly abrasive because of the sharp edges and protruding aggregate that naturallydevelop as it is cures. These may be removed by dragging heavy concrete blocks or a steel scraperover the flooring surface. They may also be Design features of stalls that appear to be removed mechanically by grinding or polishing of most important are: 1) the provision of sufficient space for movement associated with lying and rising,2) adequate resting space within the stall, and 3) a well-cushioned bed. Placement of the neck rail contributes to claw horn overgrowth that may appears to affect perching and time spent standing require more frequent trimming of claws. Smooth in stalls. Generally speaking, stall dimensions for a surfaces are also slippery and predispose to injury, usually of the upper leg and hip from falling.
Observation of cow behavior indicates that cows Grooving the surface of smooth concrete floors prefer the softer surface offered by the rubber increases traction and reduces injuries from falling.
belting. In fact, in barn conditions where the stall is Most recommend grooving a parallel or diamond poorly designed or inadequately bedded or pattern in the floor to maximize traction. Grooves groomed, cows often find the rubber flooring more should be 3/8 to 1/2 inch wide and 1/2 inch deep.
comfortable than the adjoining stall. When this When grooves are wider than 1/2 inch, the floor is happens, cows may block access to the feed less comfortable because support at the weight manger. Properly textured rubber surfaces generally bearing surface is less uniform. For the same reason, it is advised that the floor area between the grooves compressibility (Rushen and Passille, 2006). It can be kept flat and uniform as well. Grooves in also be slippery when walking surfaces are slurry walkways that run in a parallel pattern should be 2 covered or wet. Grooving the belts (only belts to 3 inches apart, whereas grooves on a diamond without reinforcing wires) helps reduce slipping pattern may be slightly wider at 4 to 6 inches on center. The diamond pattern is considered to beparticularly useful in high traffic areas. As much as possible, avoid orienting grooves at right angles to related to manure handling and securing it to the the direction of the manure scraper travel (Shearer underlying floor. For example, in flush barns where rubber may not be properly secured, manure andother debris may become entrapped beneath the rubber making for a very uneven surface. In barns continually exposed to manure slurry and moisture.
that scrape manure, depending upon how the rubber Since claw horn absorbs moisture readily, feet of is secured to the floor, scraping may result in cows in free stall housing systems are softer. In frequent displacement of the rubber. Rubber flooring housing systems where floors are abrasive, wetter must be secured in such a way as to make it resistant and thus softer, claws wear more rapidly, to displacement by either the twisting or turning predisposing to thin sole problems. But, in addition action of the wheels or the scraper itself. Despite to effects on horn hardness, at least one study these drawbacks, rubber belting is a flooring indicates that the exposure of claws to manure slurry modification that appears to improve cow and foot has very detrimental effects on the intercellular matrix comfort, but research has yet to establish its value claw horn (Kempson et al., 1998). In other words, in reducing the incidence of common claw lesions the health and integrity of claw horn is reduced for such as sole ulcers (Vanegas et al., 2006), with one cows with near constant exposure to manure slurry.
exception. That exception is excessive wear from Possibly, the best example is heel horn erosion, a aggressive concrete. When rubber is strategically common disorder in confinement housed animals.
used in areas such as parlor holding areas and exit It is believed that manure slurry not only increases and travel lanes, it can reduce some of problems the susceptibility of heel horn to erosion but also with rapid wear rates (Shearer and van Amstel, provides the ideal environment required to support 2007). But, it is not a substitute for a poorly the growth of organisms that actually breakdown designed stall or management errors that contribute incorporated rubber belting along feed mangers andin alleys or walkways to and from the milking parlor.
Treatment of Lameness Conditions
tissues causes excruciating pain and also delaysrecovery, both of which are welfare negatives.
Trimmers should approach corrective trimming tasks ulcer or white line disease, generally require with compassion and sensitivity to the fact that these corrective trimming procedures and in most cases are already painful conditions, and with careful application of a foot block to relieve weight bearing techniques, they can provide prompt relief. Careless on diseased or damaged claws. All loose and/or disregard for the pain a cow may experience during undermined horn should be removed without causing and following treatment of these conditions amounts damage to the underlying nerve-rich corium. A sharp hoof knife is the fundamental requirement forconducting these procedures since careful dissection Pain Management
of claw lesions to distinguish healthy from diseasedtissue is the primary objective of corrective trimming techniques. Severe lesions may require extensive are limited by the lack of drugs or information on work and thus corrective trimming procedures may analgesics in cattle, for economic reasons, and be very uncomfortable for the animal. When pain concerns relative to food safety. Flunixin meglamine is severe, it may be necessary to stop and apply local anesthesia via ring block or intravenous regional Whitehouse Station, NJ) is frequently used for pain anesthesia techniques. Anesthesia reduces in cattle, but its value as an analgesic is probably discomfort for the animal and permits the removal overestimated by most people who use it for that of necrotic tissue with less risk of inadvertent damage purpose. Its primary use is as a non-steroidal anti- to surrounding normal tissues (Shearer, 2008).
inflammatory agent. Aspirin is another option, butmost consider it to be of doubtful value in cattle.
Pain management, beyond local anesthesia, remains impression that the proper treatment of claw lesions a major weakness in livestock disease therapy.
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Source: http://www.vetinst.narod.ru/article/Shearer.pdf

Microsoft word - announcement _closure of register_ _e_ 120229

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DRAFT: Please cite as a draft paper. The Evidentiary Burden for Overturning Government’s Choice of Regulatory Instrument: The Case of Direct-to-Consumer Advertising of Prescription Drugs Canada Research Chair, Scientific Director of the CIHR Institute of Health Services & Policy Research, Associate Professor, Faculty of Law, Department of Health Policy, Management & Evaluati

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