TALK+(FINISHED)


 * Intro **
 * Calcium is an essential element involved in many physiological processes. These include neuromuscular function (muscle contraction; nerve signalling), blood clotting and hormonal secretion. It is also vital to the integrity of bone and teeth.
 * 99% of the calcium in the body of a cow is stored in the organic mineral matrix of the skeleton, which acts as a reserve of calcium ions in exchange with the lesser calcium pools: extracellular fluid and soft tissues
 * Dairy cows have been heavily selected for the ability to produce high milk yields. This requires them to ingest, store and utilise large quantities of calcium for much of the year, placing a very high importance on the ability of their homeostatic mechanisms to operate efficiently and keep the calcium balance.
 * The 'transition period' is the time at which a pregnant cow simultaneously endures parturition and the start of lactation meaning that the demand for energy and calcium very suddenly increases, all of which places a great strain on energy supply and calcium homeostasis.
 * Some cows fail to maintain calcium homeostasis, and a smaller percentage develop the metabolic disease milk fever, also called periparturient paresis, where calcium levels in circulation decline to such a point that homeostatic mechanisms may not be able to restore balance. It is an important condition as it affects productivity and longevity of cows and the profitability of dairy operations.


 * Calcium homeostasis **
 * Animals can only obtain calcium from dietary sources, and when levels in the diet are adequate cows absorb it via active transport across the brush border epithelial cells of the lumen in the small intestine. When dietary sources are abundant, calcium can be absorbed by the cow through the rumen and via passive diffusion between the epithelial cells of the small intestine.
 * Calcium is lost through urine and faeces, as well as to the foetus and milk production in pregnant or lactating animals.




 * Homeostatic control of calcium metabolism means intracellular and extracellular calcium (particularly plasma) concentrations are maintained within a narrow range. This is regulated mainly by intestinal absorption, renal reabsorption and bone turnover, where ionised calcium is exchanged between bone and the non-bone calcium pools.
 * The coordination of these mechanisms is achieved most significantly by interaction of calcitonin, parathyroid hormone, the active metabolite of vitamin D known as 1,25-dihydroxyvitamin D [1,25-(OH)₂D] or calcitriol, by levels of calcium itself and by all corresponding receptors.
 * When a decline in plasma calcium levels (a deviation from the setpoint) is detected, the parathyroid glands are stimulated to increase secretion of parathyroid hormone, causing the kidneys to increase tubular calcium reabsorption from the glomerular filtrate. The parathyroid hormone also triggers production of the renal enzyme 1α-hydroxylase by the kidney, resulting in conversion of circulating vitamin D to 1,25-dihydroxyvitamin D.
 * This active form of vitamin D is the most significant stimulator of calcium absorption from the intestine. This is achieved through increased formation of the calcium binding protein in the intestinal epithelial cells.
 * If the demand for calcium remains high, such as in lactating cows, and plasma calcium concentration is not restored and maintained by these mechanisms, circulating parathyroid hormone levels remain elevated. In coordination with active vitamin D, bone calcium resorption is stimulated. For short term needs, calcium salts are removed from bone in a process known as osteocytic osteolysis. In cases of prolonged demand for calcium by the body, osteoclastic bone resorption occurs, involving resorption of the bone matrix.
 * Once plasma calcium levels are restored to the setpoint, these mechanisms cease as the negative feedback loop decreases secretion of parathyroid hormone.
 * If plasma calcium levels increase beyond the setpoint, a reverse of these processes occur, stimulated by the hormone calcitonin, secreted by the thyroid.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Homeostatic control means plasma calcium in a healthy adult cow is ideally maintained between 8.5 and 10 mg/dL.



** Failure of homeostasis and development of hypocalcaemia **
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">The onset of lactation generates a sudden, very high demand on calcium homeostasis. There is often an imbalance between the high calcium output in the large quantities of colostrum produced and the influx of calcium to maintain the extracellular pool (plasma) from bone, kidney and intestine. Most animals are able to adapt through a parathyroid hormone response, after a period of subclinical hypocalcaemia.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Sometimes a cow will not adapt and recover calcium balance. Anywhere between 5 and 20% of cows will develop milk fever, a severe metabolic disease, each year. It normally occurs within 12 to 24 hours of parturition, but can occur several weeks before or after, as well as unfortunate occurrences of relapse weeks after the start of lactation.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Also known as parturient or periparturient paresis, milk fever is hypocalcaemia serious enough to present clinical signs, or usually when plasma calcium levels are between 8 mg/dL and 6 mg/dL. In the most severe cases where clinical signs last several hours or more, plasma calcium concentrations are less than 5.5mg/dL. The animals that develop milk fever are unable to adapt to the increased demand for calcium, meaning that there is a serious failure of homeostasis. If allowed to proceed, the course of the disorder is swift and in several increasingly worse stages. Many will die if left untreated.

<span style="font-family: 'Times New Roman',Times,serif;">**<span style="background-color: transparent; color: #000000; font-size: 16px; text-decoration: none; vertical-align: baseline;">Clinical signs and pathology of disease **
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Initially there are signs of hyper excitability, anorexia, listlessness and muscle weakness leading to an awkward gait when walking. Body temperature usually declines as condition worsens, revealing the deceptive nature of the term milk fever, as fever is not a clinical symptom.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Soon the cow is likely to lie in sternal recumbency with its head pulled around to face its side, as muscles weaken further due to the lack of calcium required for muscle contraction. Calcium must be present for calcium channels to operate and for troponin-C molecules to form in muscle tissue, allowing muscle contraction. This also commonly results in ruminal atony and constipation due to a loss of smooth muscle contractile function. Bloat therefore is a related symptom.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt; line-height: 115%;">When the cow is no longer able to stand, the <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;"> pressure exerted by the weight of the cow can cause a ‘crush syndrome’ eﬀect in as little as 4 hours, causing a restriction of blood supply to the muscles and nerves followed by necrosis of these tissues resulting in the 'downer cow' syndrome.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt; line-height: 115%;">If the cow is parturient it can be a great threat to the calf as stasis of the muscles means that the birthing process is essentially suspended.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt; line-height: 115%;">A weak pulse can be detected at this stage of the decline, along with weak heart sounds and tachycardia. Heart muscle contractile function is compromised
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt; line-height: 115%;">By the time the cow is almost losing consciousness, it is laterally recumbent with a temperature as low as 32°C (normal temp 38-38.5°C); it can appear dead at this latest stage of milk fever.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt; line-height: 115%;">Death can occur in a few to several hours, and is likely at a rate of 60-70% without treatment.
 * <span style="font-family: 'Times New Roman',Times,serif;"> Related conditions that affect cows that are suffering or have suffered milk fever are numerous and varied in cause. Complications are common. Hypocalcaemia reduces the ability of immune cells to respond to stimuli and therefore significantly increases a cows susceptibility to mastitis, retained fetal membranes, displaced abomasum, dystocia and ketosis.

<span style="font-family: 'Times New Roman',Times,serif;">**<span style="background-color: transparent; color: #000000; font-size: 16px; text-decoration: none; vertical-align: baseline;">Predisposing factors **
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Age
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Clinical hypocalcaemia is very rare in cows at first lactation, but the incidence increases considerably in cows in their third lactation and older. Studies have shown that younger animals have more efficient intestinal absorption mechanisms and can adapt more readily to low calcium diets by increasing this efficiency than older animals. This is likely explained by the studies showing that the intestinal receptors for 1,25-dihydroxyvitamin D decline in quantity with age. Older animals are also less able to mobilise calcium from bone, and have a greater milk production which has been shown to be positively correlated with risk of hypocalcaemia due to the greater demand for calcium.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Breed
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Different studies have suggested that dairy cow breeds such as Channel Island, Swedish Red and White, and Jerseys are all more susceptible to milk fever than Holsteins in particular. One study showed that intestinal receptors for 1,25-dihydroxyvitamin D are around 15% less in Jerseys than Holsteins.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Metabolic alkalosis
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">This condition is mostly caused by a diet that supplies more cations (for example potassium K, sodium Na, calcium Ca and magnesium Mg) than anions (for example chloride Cl, sulphate SO₄ and phosphate PO₄), causing a difference in electrical charge in body fluids. Hydrogen ions, having a positive charge, must be lost to restore neutrality, leading to an increase in pH of the blood.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Metabolic alkalosis has been shown to blunt the homeostatic response of dairy cows to parathyroid hormone because it is believed that it causes a change in conformation of the parathyroid hormone receptor in all target tissues. This means bone calcium is not resorbed as efficiently and renal reabsorption of calcium is not as high. Active vitamin D formation by the kidneys is also inhibited so intestinal calcium absorption cannot be so effectively enhanced. Thus the cow cannot benefit from these homeostatic mechanisms and restore plasma calcium.
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">Hypomagnesaemia
 * <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 13px; text-decoration: none; vertical-align: baseline;">This is attributed to development of hypocalcaemia as low levels of magnesium also interferes with the ability of parathyroid hormone to act on its target tissues, particularly in relation to magnesium’s action as a co-factor allowing parathyroid hormone to stimulate cyclic AMP production (necessary for operation of calcium channels).

<span style="font-family: 'Times New Roman',Times,serif;">**<span style="background-color: transparent; color: #000000; font-size: 16px; text-decoration: none; vertical-align: baseline;">Control (prevention) **


 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Prevention of hypocalcaemia, not just milk fever, should be a major goal of dairy farms


 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">The DCAD method
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">To prevent metabolic alkalosis from attributing to the development of hypocalcaemia, it is possible to <span style="font-family: 'Times New Roman',Times,serif;">induce a compensated metabolic acidosis in the cow restoring the ability of parathyroid hormone to regulate blood calcium levels
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">To do so, it is necessary to reduce dietary cations, in particular potassium and sodium, and to increase dietary anions, particularly chloride and sulfate.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">The addition of anionic salts to the diet, recommended for three weeks prior to parturtion, causes a reduction in what is known as the Dietary Cation-Anion Difference (DCAD), subsequently lowering the pH of the blood. The mild metabolic acidosis that results increases tissue responsiveness to parathyroid hormone and can significantly reduce the incidence of hypocalcaemia.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Feeding a calcium-deficient diet
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">If cows are fed a diet that supplies less than the required concentration of calcium, it can cause a slight decline in plasma calcium. This stimulates increased release of parathyroid hormone, in turn triggering homeostatic mechanisms for restoration of plasma calcium.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">If this is done days prior to parturition, these mechanisms, including osteoclastic bone resorption, are already active and the cow is able to utilise, with maximum efficiency, the calcium provided to them in a lactation ration. The demand for calcium is more easily overcome and hypocalcaemia can be avoided.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">This method is not recommended if cows are being fed a diet with negative DCAD values.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Higher dietary magnesium
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">A higher dietary magnesium concentration prior to calving ensures that passive diffusion of magnesium in the rumen can occur and levels of magnesium in the blood will be adequate.


 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">If total absorbed diet calcium is substantially less than required by the cow it is possible to stimulate the secretion of parathyroid hormone before calving which can stimulate bone Ca resorption and intestinal Ca absorption mechanisms prior to calving to prevent milk fever.



<span style="font-family: 'Times New Roman',Times,serif;">**<span style="background-color: transparent; color: #000000; font-size: 16px; text-decoration: none; vertical-align: baseline;">Treatment **
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Treatment of milk fever and hypocalcaemia should be done as early as possible, especially if recumbency is present, due to the potentially crippling effects of downer cow syndrome.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">The fastest way to restore normal plasma Ca concentration is to administer an IV injection of Ca salts (commonly Ca borogluconate).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">The most eﬀective IV Ca dose is about 2 g Ca/100 kg BW.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">A good rule of thumb is to administer the Ca at a rate of 1 g/min.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">If administered too rapidly, fatal arrhythmia of the heart and cessation during systole can occur.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Intravenous Ca treatments elevate blood Ca above normal for about 4 hours.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Calcium salts can also be injected subcutaneously, but absorption is variable since blood ﬂow to the periphery is often compromised.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">The amount of Ca that can be injected into a single subcutaneous site should be limited to 1–1.5 gCa (50–75 mL of most commercial preparations).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Ca preparations designed for intramuscular administration are also available (Ca levulinate or Ca lactate).
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Most of these preparations must be limited to 0.5–1.0 g Ca/injection site to avoid tissue necrosis.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">To get an eﬀective dose of Ca into the clinically hypocalcaemic animal might therefore require 6–10 injections into widely separated spots.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">This can greatly impact meat quality in the site of injection and have therefore fallen out of favour.
 * <span style="font-family: 'Times New Roman',Times,serif; font-size: 10pt;">Oral Ca treatments are not recommended as treatments for clinical milk fever cases, though they can be eﬀective aids in prevention of milk fever.

<span style="font-family: 'Times New Roman',Times,serif;">//Treatment (revised to shorten and focus on physiology)//
 * <span style="font-family: 'Times New Roman',Times,serif;">//Should be implemented as early as possible//
 * <span style="font-family: 'Times New Roman',Times,serif;">//The fundamental principal of treatment once milk fever has set in is to restore the plasma calcium concentration of a cow. This prevents or lessens the debilitating symptoms that inhibits the cow's ability to overcome the decline in plasma calcium, and aims to allow the cow to re-establish calcium homeostasis.//
 * //<span style="font-family: 'Times New Roman',Times,serif;">Most commonly achieved through an IV injection of calcium salts, usually calcium borogluconate, (recommended 2g Ca/100 kg bodyweight) that can also include magnesium, phosphorus and an energy source (dextrose). Must be administered slowly as it can result in cardiac arrest. //
 * <span style="font-family: 'Times New Roman',Times,serif;">//Subcutaneous administration is less common, as blood flow to the periphery is often compromised by advanced milk fever//
 * <span style="font-family: 'Times New Roman',Times,serif;">//Oral gels containing calcium salts are given before, during and around 12-24 hours after parturition, as a preventative treatment measure. They are highly concentrated sources of calcium and force passive diffusion across the rumen to obtain fastest results.//

<span style="font-family: 'Times New Roman',Times,serif; font-size: 14px; line-height: 21px;">**CONCLUSION**


 * <span style="font-family: 'Times New Roman',Times,serif;">Hypocalcaemia in dairy cows is an economically important disease, both in its subclinical form and when it shows itself in severe clinical effects.
 * <span style="font-family: 'Times New Roman',Times,serif;">It reduces the ability of a cow's immune cells to respond to stimuli, affects their productivity in the ensuing lactation, and reduces a dairy cow's productive life.
 * <span style="font-family: 'Times New Roman',Times,serif;">It costs the dairy industry not only through loss of production but also in the cost of control and treatment measures.
 * <span style="font-family: 'Times New Roman',Times,serif;">As with all health issues, prevention appears to be better than cure as the potential for complications arising from hypocalcaemia is high and difficult to prevent once milk fever sets in.
 * <span style="font-family: 'Times New Roman',Times,serif;">We think future research will involve focus on greater detailing of the regulatory mechanisms of calcium metabolism and how to control this to the cow's greatest advantage.

<span style="font-family: 'Times New Roman',Times,serif; font-size: 110%;">**REFERENCES**

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<span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · When the cow is no longer able to stand, the condition is known as ‘downer cow’. <span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · If the cow is parturient it can be a great threat to the calf as stasis of the muscles means that the birthing process is essentially suspended. <span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · A weak pulse can be detected at this stage of the decline, along with weak heart sounds and tachycardia. Heart muscle contractile function is compromised. <span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · By the time the cow is almost losing consciousness, it is laterally recumbent with a temperature as low as 32°C (normal temp 38-38.5°C); it can appear dead at this latest stage of milk fever. <span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · Death can occur in a few to several hours, and is likely at a rate of 60-70% without treatment. <span style="display: block; height: 1px; left: -10000px; overflow-x: hidden; overflow-y: hidden; position: absolute; text-indent: -18pt; top: 2180px; width: 1px;"> · Related conditions that affect cows that are suffering or have suffered milk fever are numerous and varied in cause. Complications are common.