Robinson, M. M.\ Hadlow, W. J.\ Knowles, D. P.\ Huff, T. P.\ Lacy, P. A.\ Marsh, R. F.\ Gorham, J. R. Journal of Comparative Pathology 1995 113 3 241-251
USDA-ARS Animal Disease Research Uni
Cattle are susceptible to experimental infection with the Stetsonville isolate of the transmissible mink encephalopathy (TME) agent. Susceptibility to other TME isolates was investigated in 2 groups of calves inoculated intracerebrally with the homogenate of mink brain containing the Hayward or the Blackfoot isolates. A third group was inoculated with a brain homogenate from a steer infected with the Stetsonville isolate in its primary cattle passage and a fourth group was inoculated with a pool of brain homogenate from the 3 cattle experimentally infected with a sheep and goat scrapie agent in its primary cattle passage.
Clinical signs of neurological disease appeared in each steer of every group between 15 and 25 months after inoculation. An encephalopathy characterized by severe spongiform change and pronounced astrocytosis occurred in the 3 groups inoculated with the TME agent. The neurohistological changes in the steers inoculated with the cattle-passaged scrapie agent were slight and subtle. Analysis of the octapeptide repeat region of the bovine protease-resistant protein (PrP) gene showed that variations in incubation period, clinical signs, and neurohistological changes were unrelated to the homozygous or heterozygous condition of 6 or 6/5 octapeptide repeats.
"Most believe that [BSE] is of recent origin initiated by feeding rendered animal protein from scrapie-infected sheep to cattle. . . . This paper explores an alternative hypothesis that BSE existed in cattle populations in an unrecognized form for a much longer time until amplified by changes in the rendering process that allowed cattle to cattle transmission to occur. This viewpoint is supported by observations that transmissible mink encephalopathy, a disease that first occurred 45 years ago, is likely caused by feeding downer cows to mink."
"There are two incidents of [transmissible mink encephalopathy] which occurred in Ontario in 1963 and Stetsonville (Wisconsin) in 1985, where the mink rancher stated with a high degree of certainty that sheep had not been fed. The Stetsonville incident is especially interesting because this rancher was a 'dead stock' feeder who used mostly dairy cows which he collected daily within a 50-mile radius of his mink ranch. ... If TME results from feeding infected cattle tissues to mink, there must be an unrecognized BSE-like infection in American cattle and in other countries where TME has been reported. This hypothetical agent need not have biological properties identical to those of the BSE agent because it is likely that cattle could be infected with several 'strains' as are sheep."
"I went to the meeting of the U.S. Livestock Association (in late 1985) and reported that there is strong circumstantial evidence that mink encephalopathy is caused by feeding infected dairy cows to the mink. I tried to put them on the alert to look for such a disease in dairy cows. To try to experimentally back this up, we inoculated two Holstein steers with the mink brain in the summer of '85. Within 18 months, both of these cows came down with the brain lesions seen with spongiform encephalopathy. ... The reason I feel so strongly is that we have a unique perspective here in this laboratory because we work on mink encephalopathy. I believe mink encephalopathy is caused by feeding downer cows to mink. I think our evidence is very sound, and I think our experimental studies on inoculation of cattle are sound."
What Marsh found, however, was a TSE that caused different symptoms: infected animals simply fall over, like downer cows. "Downer Cow Disease" is a syndrome involving a far larger number of animals than rabies, and no procedure for routine diagnosis. Accordingly, Marsh concludes that:
"The only way to absolutely prevent cattle-to-cattle transmission ... is to ban the feeding of ruminant animal protein to other ruminants. ... It is unlikely that surveillance programs will provide adequate warning since it will be almost impossible to detect the disease in the first few animals affected, and an incubation period of 3-8 years may allow a decade of exposure before the disease is recognized." (Source: "BSE: A New Disease in Cattle?")
Marsh sees mink outbreaks, like zoo or wildlife outbreaks, as naturally limiting in terms of contagion, but massive outbreaks of contained animals, where there is ample opportunity for contagion, as limited by genetic variation, age, gender and normative compensatory processes.
But maybe the limits are off in multiparous, old age animals, especially when receiving hormones and turning over massive amounts of calcium.
"In the months since Gajdusek's arrest and weeks since Saitoh's murder, as no other explanations have come forward, I have wondered what could have been the motivation, what the intimidation could be about. Certainly the murder of Saitoh and his daughter could have been a mistake. Gajdusek could simply have gone too far in his cultural relativism.
But there are some big money issues in the mix, such as transgenic mice, growth hormone, drug development, and chemical toxin liability. I have become intrigued by Saitoh's interest in the shift in the glutamate - calcium intracellular flux and the resulting shift to amyloid accumulation intracellularly as opposed to an intercellular messenger path.
The University of Kentucky Brown-Sanders Center for Aging has an Alzheimer's Ezine with a summary by Saitoh and a Eulogy in the same issue."
If it is this excitotoxic process which accelerates the neurodegeneration in Alzheimer's Disease, and also in other neurodegenerative diseases, then I could see a link to BSE. That's the long way around to what Saitoh would have to do with intimidation about BSE. Not the cause, but the mechanisms by which a neurodegenerative process picks up speed, is what I think could be the link. Gajdusek seemed to hope he had the key, from the Papua New Guinea population, for resisting the neurodegeneration of HTLV-1.
Field advisories paint a picture for Downer Cow Syndrome of mostly neurological symptoms for mostly Milk Fever, in mostly aged cows, around parturition, with a largely confused and extreme set of suggestions for more, or less calcium, and additional hormones. With plenty of glutamate in the diet as well, a neural excitotoxic episode at parturition could put a cow's brain down as quickly as indicated in the reports.
The similarity in pattern I was referring to is the increased calcium turnover, increased endocrine disruption, and perhaps increased pesticide use, which, in comparison to earlier decades, could accelerate an age related, stress related, genetically predisposed disorder to an epidemic, even without the addition of an infectious vehicle in feed supplements. That is the pattern that I see as similar on U.S. and European dairy farms.
Milk fever, or parturient paresis, is a metabolic disease of dairy cows which usually afflicts animals just preceding or immediately following freshening. While the exact cause of this disease is not completely understood, it is associated with the onset of lactation and failure of the animal to maintain an adequate supply of calcium from both feed intake and mobilization from the bone. In milk fever animals, the blood serum calcium levels will drop from a normal g to 12 milligrams (mg)/100 milliliter (ml) to 3 to 7 mg/100 ml, and blood phosphorus levels will drop from a normal of 6 to 8 mg/100 ml to below 5 mg/100 ml.
Several factors are known to affect the incidence of milk fever in dairy cattle. Older animals are more susceptible than are young cows. Milk fever occurs more frequently in Jerseys than in the other dairy breeds. High producing animals are more prone to milk fever than are low producers. Cows with a previous history tend to have repeat cases of milk fever.
SYMPTOMS OF MILK FEVER
Symptoms commonly observed in animals with milk fever include: 1. Dull eyes and action 2. Subnormal body temperature 3. Cold and drooping ears 4. Staggering gait and incoordination 5. Weakness and partial paralysis of rear legs 6. Muscle spasms 7. Inability to rise 8. Lying on the sternum with head tucked into flankIn advanced cases, the cow may lie completely outstretched on her side. If left untreated complete paralysis and coma, followed by death, will result. Death can occur within a few hours from the onset of milk fever. Therefore, immediate attention is necessary. Usually, animals will respond quickly to a slow intravenous infusion of a calcium gluconate solution. This solution must be administered slowly; it can stop the heart if given too quickly. Cows which do not respond to the intravenous injection may be suffering from a complication of the condition called the "downer cow" syndrome. Therefore, it is advisable to contact your veterinarian for diagnosis before starting treatment.
FEEDING TO PREVENT MILK FEVER
Providing a ration with adequate levels of calcium and phosphorus during the dry period is the most practical method of reducing the incidence of milk fever. The feeding program should be adjusted so the calcium: phosphorus ratio of the total ration is between 1.5:1 and 2.5:1. Ratios not in this range increase the risk of milk fever.
The actual amounts of calcium and phosphorus in the diet are also important. Minimum percentages needed in the total diet for dry cows are 0.40 percent calcium and 0.26 percent phosphorus (dry basis). Intakes of more than 0.2 pounds of calcium per dry cow per day should be avoided.
The dairy cow's parathyroid gland secretes a hormone which draws calcium from the cow's bones to help meet the increased demand for calcium when milk flow begins at freshening. High levels of calcium in the dry cow diet cause the parathyroid gland to become less active. When this mechanism of bone calcium mobilization is not activated, the cow is forced to rely mainly on calcium absorption from the gut which is often inadequate for high levels of milk production. Feeding rations low in calcium for two weeks prior to calving has been helpful in stimulating parathyroid activity and reducing the incidence of milk fever. This practice should be used only in problem herds. It is important that adequate levels of calcium be fed both before and after the two week treatment period.
Probable Causes: 1. Decreased mass of the calcium pool prior to parturition and failure of calcium absorption to increase fast enough after the onset of lactation. 2. Excessive bone formation due to elevated levels of gonadal hormones. Probable Factors Involved: 1. Low calcium intake especially for dry cows 2. Low phosphorus intake 3. Excessive calcium intake (High legume intake by dry cows; Over supplementation with calcium.) . . . 10. Toxemia 11. Nerve or muscle damage (Injury at calving, damage from going down, or lying on limbs for a prolonged period.) Problem Situations: 1. When over 10-15% of the cows are afflicted on an annual basis, the higher value applies to a herd with a lot of previous cases which may make the cows more susceptible. 2. When a high proportion of cows in a sizeable group of freshenings is afflicted. (ex. 5 out of 8 cows). Forms:1. Typical milk fever - Acute form affecting cows usually within a few days after parturition, but sometimes in late lactation or dry period. Responds well to treatment.
2. Refractory or atypical milk fever - Acute form with little or no response to treatment. Cow may remain alert, eat and milk but cannot regain its feet, may become a "creeping" downer cow with flexed pasterns and posterior paralysis. Rupture of the large muscle or group of muscles in one or both hind legs may complicate the picture. Similar fracture or dislocation of a high joint may have occurred when the cow went down initially or in struggling to rise. In addition to usual treatment, administer intramuscularly 50 mg of selenium and 680 units vitamin E. As a last resort, do not milk for 24-48 hours or inflate udder with air, and administer 2 lbs of Epsom salts in one gallon of water to remove possible toxins and provide ample magnesium.
3. Tremors or sub-acute - Cows easily excited, twitching, tremors. Usually a number of cows involved, many of which are in late lactation, dry or recently fresh. Often there is magnesium involvement.
Control Suggestions: 1. Make certain that standard plus mineral tests on forages are available. 2. Submit feed program request with notation of high incidence in proper place on form. 3. Submit blood samples for metabolic profiling at the Large Animal Diagnostic Lab, Penn State or other laboratories. . . . 5. Use plain calcium borogluconate for the initial treatment to keep refractory cases at a minimum. 6. Last resort - use one of the following: a. Feed mixed with the grain or other quickly eaten feed, 100 grams (3.5 oz) of ammonium chloride per head daily beginning not less than 2 days before and continuing at least 2 days after freshening..\ . . . d. Administer high calcium boluses (about 75 grams of calcium carbonate as soon as possible after calving and within 8 hours of freshening.
Nonambulatory (downer) cattle are . . . Less than 1% of the cattle handled and transported are downers, . . . Dairy cattle are 75% of the downers (McNaughton,1993). . . . In New Zealand, downed cattle that arrive at the slaughter plant at night are often euthanized and sent to rendering.l. . . . The emphasis needs to be on preventing downer animals. I estimate that 75% of all downed cattle are preventable by good management. It is likely that 10% of the bad dairies areresponsible for 90% of the downers.
Observations by the author indicate that cattle with broken limbs are a small percentage of downers, and many downed cattle are weak and emaciated. McNaughton, M.T.(1993). Not for sale, mobile slaughterers: the meat industry's grey trade. Meat and Poultry, September,28-44
1) Last case in U.S. of TME in mink was in 1985, over ten years ago. 2) Non-ambulatory cattle still fed (raw) to U.S. mink. 3) Since 1985 outbreak, the U.S. Mink industry has realized that sheep materials should be avoided due to scrapie. [Actually, scrapie was considered the likely cause of TME for quite some time PRIOR to the 1985 outbreak, which is significant primarily because it contraindicates sheep as the source of infection.] 4) Setsonville Mink Rancher does not support the comment that only 'downed' cows were fed prior to 1985 outbreak. States that other "uncharacterized" animal materials were fed. [If by "uncharacterized" you mean "not exclusively downer cows," this is correct. However, the rancher was emphatic that sheep were NOT fed.] 5) USDA concluded 1993 report with "Given the potentially large number of nonambulatory cows fed to mink and the historically sporatic occurrence of spongiform encepalopathy in mink, it was concluded that if a TSE exists in U.S. cattle, then it is very rare or the conditions for its transmission to mink must be highly specific." (BSE: Implications for the U.S., 12/93, USDA:APHIS:VS).
[This is correct and in line with Marsh's conclusions. Marsh speculates that if a strain of BSE is responsible for TMEs, it may be occurring through spontaneous mutations similar to the mutations which have been theorized as the cause for incidence of "spontaneous CJD" in the human population at a rate of one case per million people per year. This is, of course, theory and conjecture.]
Marsh, R.F., 1993: Bovine spongiform encephalopathy: a new disease of cattle? Arch. Virol. Suppl.7, 255-259. R.F. Marsh and W.J. Hadlow, "Transmissible encephalopathy," Rev. sci. tech. Off. int. Epiz., 1992, 11 (2), 539-550. Joel McNair, "BSE: A Ticking Time Bomb in Downer Cows?" in Agri-View (a weekly farm newspaper), Iola, WI, June 17, 1993. R.F. Marsh, "Transmissible Mink Encephalopathy, Scrapie and Downer Cow Disease: Potential Links," Proceedings of the Third International Workshop on Bovine Spongiform Encephalopathy, Bethesda, MD, December 9-10, 1992. R.F. Marsh, Richard A. Bessen, Scott Lehmann and G.R. Hartsough, "Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy," Journal of General Virology (1991), 72, 589-794. Jeremy Cherfas, "Mad Cow Disease: Uncertainty Rules," Science, Sept. 28, 1990, pp. 1492-1493. Marsh, Richard and Wustenberg, William, "Is it safe to feed meat and bone meal?" Hoard's Dairyman. (Sorry, I don't have the date of publication.) R.F. Marsh and R.A. Bessen, "Epidemiological and Experimental Studies on Transmissible Mink Encephalopathy," in Transmissible Spongiform Encephalopathies: Impact on Animal and Human Health, Karger-Verlag, Developments in Biological Standardization (Fred Brown, ed.), Heidelberg, June 23-24, 1992. Marsh, R.F., "Transmissible Mink Encephalopathy," in Prion Disease of Humans and Animals (S.B. Prusiner, ed.), Ellis Horwood, Chichester, England, pp. 299-306.