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|Blood'''Sweat Rate'''|'''Sweat Rate'''|140'''Sweat Concentration'''|[[Sodium Loss]]|3.2[[Sodium Loss]]|'''Sweat Concentration'''|1.5[[Sodium Loss]]||3.9[[Sodium Loss]]
|-
|Sweat of un-acclimated, unfit'''(l/hr)'''|'''(mg/cm2/min)'''|80'''(mmol/l)'''|'''(mg/hr)'''|1.8'''(tsp/hr)'''|'''(mmol/l)'''|0.9'''(mg/hr)'''||2.2'''(tsp/hr)'''
|-
|Sweat of un-acclimated, fit'''0.5'''|'''0.49'''|6022|249|0.1.4| 31|355|0.7||1.72
|-
|Sweat of acclimated, fit'''1'''|'''0.98'''|4032|732|0.93| 46|1044|0.4|-| '''1.5'''| '''1.47'''| 43| 1450| 0.6| 61| 2066| 0.9|-|'''2'''|'''1.96'''| 53| 2402| 1| 75| 3423| 1.5|-| '''2.5'''| '''2.45'''| 63| 3589| 1.5| 90| 5113| 2.2
|}
This table is based on the research quoted below showing a linear relationship between sweat rate and sweat sodium concentration. ==Sodium Loss and Sweat Rate==The concentration of sodium in sweat depends on the sweat rate. This is believed to be because the sweat is released with a high sodium concentration, then the sodium is reabsorbed before it reaches the surface. The faster the sweating, the less chance for reabsorption. [[File:Sweat Rate Sodium Concentration - adjusted.jpg|none|thumb|400px|Sweat rate and sodium concentration<ref name="Buono-2008"/>, adjusted using the formula for regional patch collection<ref name="Baker-2009"/>.]]===Converting per-area sweat rates to whole body sweat rates===We can convert from per-area sweat rates to whole body sweat rates by using a [http://www.halls.md/body-surface-area/bsa.htm Body Surface Area Calculator]. For example, a 135 pound, 70 inch high person has a skin surface area of 1.74 m<sup>2</sup>, which is 17,400 cm<sup>2</sup>. Therefore 1 mg/cm<sup>2</sup>/min is 17,400 mg/min, or 17.4 g/min or 1,044 g/hour, or 1 liter/hour. ==Sodium Loss and Fitness==While some sources suggest that increased fitness reduces the sodium concentration in sweat research<ref name="Hamouti-2011"/> shows this is not the case. For both trained and untrained individuals sodium concentration depends mainly on sweat rate. In fact, for a given relative intensity (% of [[VO2max|V̇O<sub>2</sub>max]]) trained individuals will be performing a greater absolute work rate and therefore have a greater sweat rate and sodium concentration.[[File:Sodium Source Tablein sweat trained and untrained.jpg|none|thumb|400px|Sweat sodium concentration against sweating rate, showing for three different work intensities and for trained and untrained individuals. Note that this data is not adjusted for regional patch collection, so the rates are too high and should be scaled by 0.67.]]==Sodium Loss and Heat Acclimation==A study<ref name="Buono-2007"/> shows that the sodium concentration of sweat is reduced by [[Heat Acclimation Training]]. The study used three bouts of 30 min. of exercise in environmental chamber with 10 min. of rest between each bout.[[File:Sweat Rate Sodium Concentration for heat adaptation - adjusted.jpg|none|thumb|400px|Sweat sodium concentration against sweating rate, before and after 10 days of heat acclimation training, adjusted using the formula for regional patch collection<ref name="Baker-2009"/>.]]==Sodium Loss and Skin Temperature==A study<ref name="Shamsuddin-2005"/> of sweating great sodium concentration for different temperatures has shown that sodium reabsorption is greater at high temperatures. Unfortunately the units used in this study are not comparable with other studies. The mechanism behind this is unclear, but the implication is that the sodium concentration of sweat in cooler weather may be higher than expected from the above studies. [[File:Sweat Rate Sodium Concentration for skin temperatures.jpg|none|thumb|400px|Sweat sodium concentration against sweating great, shown for two different skin temperatures.]]=Sodium Retention=The human body has mechanisms to try to maintaining its sodium balance. Greater sodium intake results in the excess being excreted in the sweat and urine. Conversly, restricted sodium intake will result in a reduction of the sodium concentration of the sweat<ref name="CONN-1946"/>. This reduction in the sodium concentration occurs at all sweating rates, but the relationship between sodium concentration and sweat rate remains a straight line<ref name="Sigal-1968"/>. So at any given sweat rate, a restricted sodium intake will result in less sodium in the sweat. However, even on a restricted sodium intake, the more you sweat, the greater the sodium concentration. Comparing the maximum sodium concentration of sweat between a salt intake of 500mg/day and 20,000mg/day, the low salt intake reduced the sodium concentration by 30-48%<ref name="Sigal-1968"/>. [[File:SodiumIntakeSweatConcentration.jpg|none|thumb|500px|The effect of high (20,000mg/day NaCL) and low (500mg/day NaCL) on the sodium concentration of sweat at various sweat rates<ref name="Sigal-1968"/>. Three subjects were put on the diet for a week, then tested for five days while remaining on that diet. The two tests were separated by a month.]]=Sodium Intake=
Below are some sample sources of Sodium, with the concentrations defined.
{| {{table}} | alignclass="centerwikitable" style="background:#f0f0f0;"|'''! Source'''| align="center" style="background:#f0f0f0;"|'''! Sodium - mmol per liter'''| align="center" style="background:#f0f0f0;"|'''! Sodium - grams per liter'''| align="center" style="background:#f0f0f0;"|'''! Sodium - grams per pint'''| align="center" style="background:#f0f0f0;"|'''! Salt - grams per pint'''
|-
|Gatorade||18||0.4||0.2||0.5
|-
|Water + 1/4 Teaspoon salt per quart||27||0.6||0.3||0.75
|-
|Gatorade+ 1/4 Teaspoon salt per quart||45||1.0||0.5||1.2
|-
|S-Caps + 8oz water*||65||1.4||0.7||1.7
|-
|Salt Stick + 8oz Water||38||0.84||0.4||0.98
|-
|Salt Stick + 16oz Water||19||0.42||0.2||0.49
|}
Note: S-Caps does not specify the amount of fluid to take with each capsule, but does mention 'at least one cup', so this ratio is used. The per-pint and per-liter equivalents assumes assume a constant ratio of one capsule per 8oz of water. See also [[Comparison of Gels]]. ===Examples=Example Sodium Losses==
Here are some hypothetical examples
* Adam, a fit, heat acclimatized runner, weighs himself before and after his four hour run and the difference is 8 pounds, which is roughly equivalent to 8 pints /4 liters of sweat. We Based on 1 liter/hour of sweating we estimate that Adam has lost 0.4 grams of sodium per pint, for a total of 3.2 grams of sodium, which is 8 grams of salt or about 1.3 2 teaspoons. * Bob, a fit, but is not heat acclimatized runner, weighs himself before and after his run and the difference is 10 losses 9 pounds, which is roughly equivalent to 10 in three hours (9 pints of /4.5 liters). From the sweat. We rate we estimate that Bob has lost 0.7 grams of sodium per pint, for a total of 7 grams of sodium, which is 17 grams of salt or about 3 teaspoons.* Charlie, a fit, but not heat acclimatized runner, weighs himself before and after his run and the difference is 8 pounds, which is roughly equivalent to 8 pints of sweat. Charlie had also consumed 80 ounces of Gatorade on the run. This gives an estimate of 8+5=13 pints of sweat. At 0.7 grams of sodium per pint, that’s a total of 9 grams of sodium, which is 23 grams of salt or about 4 teaspoons3. The Gatorade provided approximately 1 gram of sodium, or a 1/2 teaspoon. * For the next run, Charlie changes his drink to add 1/4 teaspoon of extra salt to his Gatorade. He sweats and drinks the same amounts as the previous run. This time, his drink provides him with 4.7 grams of salt, or 3/4 teaspoon of saltteaspoons. ===Sodium Loss Sweat Rates While Running===
Sweat rates in male runners have been measured in the range from 0.75-2.23 in winter to 0.99-2.55 in the summer (Liters per hour)<ref name="acsm"/>. At the low end, we can imagine a fit runner finishing a 3-hour marathon in winter and sweating only 2.25 Liters. Assuming they are also heat acclimated, they would only lose 2 grams of sodium, which is 5 grams of salt, less than a teaspoon. On the other end of the scale, a fit, but unacclimatized runner completing a 5 hour marathon in summer would sweat out nearly 13 Liters, 18 grams of sodium, which is 45 grams of salt or more than 7 teaspoons.
There is a table showing a range of values at [[Sodium Loss]].
The evidence for hydration and electrolyte status causing [[Cramps]] is somewhat ambiguous, but supplementing your electrolyte intake may help.
* Intracellular fluid (ICF) which is 40% of body weight
* Extracellular fluid (ECF) which is the other 20% of body weight
** plasma Plasma is 25% of ECF/5% body weight** interstitial Interstitial fluid which is 75% of ECF/15% of body weight, typically 11 Liters/22 pints. The volume of extracellular fluid is typically 15 liters in a 70 kg human, and the 50 grams of sodium it contains is about 90% of the body's total sodium content.==Symptoms of Dehydration=These symptoms are for the general public<ref name="CLINC"/>==These symptoms are for the general public, and there is evidence<ref name="SYMPT"/> that they may not apply to athletes suffering from mild dehydration.{| {{table}}| alignclass="centerwikitable" style="background:#f0f0f0;"|'''! symptom'''| align="center" style="background:#f0f0f0;"|'''! mild dehdration dehydration (3-5% body weight)'''| align="center" style="background:#f0f0f0;"|'''! Moderate dehdration dehydration (6-9% body weight)'''| align="center" style="background:#f0f0f0;"|'''! Severe dehdration dehydration (>10% body weight)'''
|-
| Level of consciousness||Alert ||Lethargic ||Obtunded
|-
| Capillary Refill||2 seconds||2-4 seconds||>4 seconds
|-
| Blood Pressure||Normal||Normal supine, lower standing||lower
|-
| Skin Turgor||Normal||Slow||Tenting
|-
| Eyes||Normal||Sunken||Very Sunken
|}
<references>
<ref name="RosnerKirven2006">M. H. Rosner, J. Kirven, Exercise-Associated Hyponatremia, Clinical Journal of the American Society of Nephrology, volume 2, issue 1, 2006, pages 151–161, ISSN [http://www.worldcat.org/issn/1555-9041 1555-9041], doi [http://dx.doi.org/10.2215/CJN.02730806 10.2215/CJN.02730806]</ref>
<ref name="CLINC">Clinical Studies in Fluid and Electrolyte Balance</ref>
<ref name="SYMPT">J. McGarvey, J. Thompson, C. Hanna, T. D. Noakes, J. Stewart, D. Speedy, Sensitivity and specificity of clinical signs for assessment of dehydration in endurance athleteshttp://bjsm.bmj.com/content/early/2010/04/22/bjsm., British Journal of Sports Medicine, volume 44, issue 10, 2008.053249.abstract</ref> <ref name="ref5">Caffeine dehydration : Caffeine and alcohol - just how dehydrating are they?, pages 716–719, ISSN [http://www.pponlineworldcat.co.ukorg/encycissn/caffeine0306-dehydration.htm http://www.pponline.co.uk/encyc/caffeine3674 0306-dehydration.htm3674]</ref> <ref name="ref6">Muscle Cramps : No link between hydration and cramps, doi [http://wwwdx.pponlinedoi.co.ukorg/encyc/muscle-cramps10.htm http:1136//wwwbjsm.pponline2008.co053249 10.uk1136/encyc/muscle-crampsbjsm.2008.htm053249]</ref> <ref name="ref7Nilsson-1973">Hydration - fluid intake advice and tips[http://wwwLH.pponlineNilsson, Liver glycogen content in man in the postabsorptive state.co.uk/encyc/hydration, Scand J Clin Lab Invest, volume 32, issue 4, pages 317-fluid-intake-advice-and-tips-40789 http://www.pponline.co.uk/encyc/hydration-fluid-intake-advice-and-tips-40789]</ref> <ref name="ref8">The Relation Of Glycogen To Water Storage In The Liver23, Dec 1973, PMID [http://www.jbcncbi.org/cgi/reprint/96/2/367nlm.pdf http://wwwnih.jbc.orggov/cgipubmed/reprint/96/2/367.pdf4771101 4771101]</ref> <ref name="ref9González-Alonso-1995">Cracking the Code on Hydration[http://wwwJ.active.com/cycling/Articles/CrackingGonzález-the-Code-on-Hydration.htm http://wwwAlonso, R.active.com/cycling/Articles/CrackingMora-the-Code-on-HydrationRodríguez, PR.htm]</ref> <ref name="ref10">Hyponatremia[http://enBelow, EF.wikipedia.org/wiki/Hyponatremia http://en.wikipedia.org/wiki/Hyponatremia]</ref> <ref name="ref11">Coyle, Dehydration reduces cardiac output and increases systemic and cutaneous vascular resistance during exercise[http://www.edb.utexas.edu/coyle/pdf%20library/%286329%20Dehydration%20reduces%20cardiac%20output%20&%20increases%20systemic%20&%20cutaneous%20vascular%20resistance%20during%20exercise,%20J%20Appl%20Physiol%2079J Appl Physiol (1985), volume 79, issue 5,%201487pages 1487-96,%201995.pdf Nov 1995, PMID [http://www.edbncbi.utexasnlm.edunih.gov/coylepubmed/pdf%20library/%2863%29%20Dehydration%20reduces%20cardiac%20output%20&%20increases%20systemic%20&%20cutaneous%20vascular%20resistance%20during%20exercise,%20J%20Appl%20Physiol%2079,%201487-96,%201995.pdf8594004 8594004]</ref> <ref name="ref14Graham-1998">TE. Graham, E. Hibbert, P. Sathasivam, Metabolic and exercise endurance effects of coffee and caffeine ingestion[http://jap.physiology.org/cgi/content/full/, J Appl Physiol (1985), volume 85/, issue 3/, pages 883 -9, Sep 1998, PMID [http://japwww.physiologyncbi.orgnlm.nih.gov/cgi/contentpubmed/full/85/3/8839729561 9729561]</ref> <ref name="ref15Falk-1990">B. Falk, R. Burstein, J. Rosenblum, Y. Shapiro, E. Zylber-Katz, N. Bashan, Effects of caffeine ingestion on body fluid balance and thermoregulation during exercise., Can J Physiol Pharmacol, volume 68, issue 7, pages 889-92, Jul 1990, PMID [http://www.ncbi.nlm.nih.gov/pubmed/2383801 http://www.ncbi.nlm.nih.gov/pubmed/2383801]</ref> <ref name="ref16Maughan-2003">RJ. Maughan, J. Griffin, Caffeine ingestion and fluid balance: a review., J Hum Nutr Diet, volume 16, issue 6, pages 411-20, Dec 2003, PMID [http://ptwww.wkhealthncbi.com/pt/re/jhnd/abstractnlm.00009862-200312000-00004nih.htm;jsessionid=KNhWhGQSZnXhY11p2f7qnnmn1Q7z376shvhsK7hTWDLVGQhWpGGJ%21811725889%21181195628%218091%21-1 http:gov/pubmed/pt.wkhealth.com/pt/re/jhnd/abstract.00009862-200312000-00004.htm;jsessionid=KNhWhGQSZnXhY11p2f7qnnmn1Q7z376shvhsK7hTWDLVGQhWpGGJ!811725889!181195628!8091!-119774754 19774754]</ref> <ref name="ref17Kratz-2005">A. Kratz, AJ. Siegel, JG. Verbalis, MM. Adner, T. Shirey, E. Lee-Lewandrowski, KB. Lewandrowski, Sodium Status status of Collapsed Marathon Runnerscollapsed marathon runners., Arch Pathol Lab Med, volume 129, issue 2, pages 227-30, Feb 2005, doi [http://arpadx.allenpressdoi.comorg/arpaonline/?request=get-document&doi=10.1043%2F1543/1543-2165%282005%29129%3C227(2005)129<227:SSOCMR%3E2>2.0.CO%3B2 http://arpa.allenpress.com/arpaonline/?request=get-document&doi=;2 10.1043%2F1543/1543-2165%282005%29129%3C227(2005)129<227:SSOCMR%3E2>2.0.CO%3B2;2], PMID [http://www.ncbi.nlm.nih.gov/pubmed/15679427 15679427]</ref>
<ref name="acsm">http://journals.lww.com/acsm-msse/_layouts/oaks.journals/ImageView.aspx?k=acsm-msse:2007:02000:00022&i=TT2
</ref>
<ref name="ref4">Micronutrient Information Center - Sodium
</ref>
<ref name="Stolarz-Skrzypek-2011">K. Stolarz-Skrzypek, T. Kuznetsova, L. Thijs, V. Tikhonoff, J. Seidlerová, T. Richart, Y. Jin, A. Olszanecka, S. Malyutina, Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion., JAMA, volume 305, issue 17, pages 1777-85, May 2011, doi [http://dx.doi.org/10.1001/jama.2011.574 10.1001/jama.2011.574], PMID [http://www.ncbi.nlm.nih.gov/pubmed/21540421 21540421]</ref><ref name="Buono-2008">MJ. Buono, R. Claros, T. Deboer, J. Wong, Na+ secretion rate increases proportionally more than the Na+ reabsorption rate with increases in sweat rate., J Appl Physiol (1985), volume 105, issue 4, pages 1044-8, Oct 2008, doi [http://dx.doi.org/10.1152/japplphysiol.90503.2008 10.1152/japplphysiol.90503.2008], PMID [http://www.ncbi.nlm.nih.gov/pubmed/18653750 18653750]</ref><ref name="Hamouti-2011">N. Hamouti, J. Del Coso, JF. Ortega, R. Mora-Rodriguez, Sweat sodium concentration during exercise in the heat in aerobically trained and untrained humans., Eur J Appl Physiol, volume 111, issue 11, pages 2873-81, Nov 2011, doi [http://dx.doi.org/10.1007/s00421-011-1911-6 10.1007/s00421-011-1911-6], PMID [http://www.ncbi.nlm.nih.gov/pubmed/21431880 21431880]</ref><ref name="CONN-1946">JW. CONN, MW. JOHNSTON, LH. LOUIS, Relationship between salt intake and sweat salt concentration under conditions of hard work in humid heat., Fed Proc, volume 5, issue 1 Pt 2, pages 230, 1946, PMID [http://www.ncbi.nlm.nih.gov/pubmed/20984571 20984571]</ref><ref name="Shamsuddin-2005">AK. Shamsuddin, T. Kuwahara, A. Oue, C. Nomura, S. Koga, Y. Inoue, N. Kondo, Effect of skin temperature on the ion reabsorption capacity of sweat glands during exercise in humans., Eur J Appl Physiol, volume 94, issue 4, pages 442-7, Jul 2005, doi [http://dx.doi.org/10.1007/s00421-005-1354-z 10.1007/s00421-005-1354-z], PMID [http://www.ncbi.nlm.nih.gov/pubmed/15843956 15843956]</ref><ref name="Buono-2007">MJ. Buono, KD. Ball, FW. Kolkhorst, Sodium ion concentration vs. sweat rate relationship in humans., J Appl Physiol (1985), volume 103, issue 3, pages 990-4, Sep 2007, doi [http://dx.doi.org/10.1152/japplphysiol.00015.2007 10.1152/japplphysiol.00015.2007], PMID [http://www.ncbi.nlm.nih.gov/pubmed/17600161 17600161]</ref><ref name="Baker-2009">LB. Baker, JR. Stofan, AA. Hamilton, CA. Horswill, Comparison of regional patch collection vs. whole body washdown for measuring sweat sodium and potassium loss during exercise., J Appl Physiol (1985), volume 107, issue 3, pages 887-95, Sep 2009, doi [http://dx.doi.org/10.1152/japplphysiol.00197.2009 10.1152/japplphysiol.00197.2009], PMID [http://www.ncbi.nlm.nih.gov/pubmed/19541738 19541738]</ref><ref name="Fitzpatrick">Fitzpatrick's Dermatology in General Medicine, Chapter 81. Biology of Eccrine, Apocrine, and Apoeccrine Sweat Glands</ref><ref name="Sigal-1968">CB. Sigal, RL. Dobson, The effect of salt intake on sweat gland function., J Invest Dermatol, volume 50, issue 6, pages 451-5, Jun 1968, PMID [http://www.ncbi.nlm.nih.gov/pubmed/5652824 5652824]</ref><ref name="Goulet2012">E. D. B. Goulet, Effect of exercise-induced dehydration on endurance performance: evaluating the impact of exercise protocols on outcomes using a meta-analytic procedure, British Journal of Sports Medicine, volume 47, issue 11, 2012, pages 679–686, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsports-2012-090958 10.1136/bjsports-2012-090958]</ref><ref name="Goulet2011">E. D. B. Goulet, Effect of exercise-induced dehydration on time-trial exercise performance: a meta-analysis, British Journal of Sports Medicine, volume 45, issue 14, 2011, pages 1149–1156, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsm.2010.077966 10.1136/bjsm.2010.077966]</ref><ref name="Convertino-1996">VA. Convertino, LE. Armstrong, EF. Coyle, GW. Mack, MN. Sawka, LC. Senay, WM. Sherman, American College of Sports Medicine position stand. Exercise and fluid replacement., Med Sci Sports Exerc, volume 28, issue 1, pages i-vii, Jan 1996, PMID [http://www.ncbi.nlm.nih.gov/pubmed/9303999 9303999]</ref><ref name="WallWatson2013">B. A. Wall, G. Watson, J. J. Peiffer, C. R. Abbiss, R. Siegel, P. B. Laursen, Current hydration guidelines are erroneous: dehydration does not impair exercise performance in the heat, British Journal of Sports Medicine, 2013, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsports-2013-092417 10.1136/bjsports-2013-092417]</ref><ref name="beverageWWW">How to Calculate Your Sweat Rate - Beverage Institute for Health and Wellness, http://www.beverageinstitute.org/article/how-to-calculate-your-sweat-rate/, Accessed on 25 June 2015</ref><ref name="Shirreffs-1997">SM. Shirreffs, RJ. Maughan, Restoration of fluid balance after exercise-induced dehydration: effects of alcohol consumption., J Appl Physiol (1985), volume 83, issue 4, pages 1152-8, Oct 1997, PMID [http://www.ncbi.nlm.nih.gov/pubmed/9338423 9338423]</ref><ref name="ROBERTS-1963">KE. ROBERTS, mechanism of dehydration following alcohol ingestion., Arch Intern Med, volume 112, pages 154-7, Aug 1963, PMID [http://www.ncbi.nlm.nih.gov/pubmed/14044808 14044808]</ref><ref name="RubiniKleeman1955">Milton E. Rubini, Charles R. Kleeman, Ezra Lamdin, Studies on alcohol diuresis. I. The effect of ethyl alcohol ingestion on water, electrolyte and acid-base metabolism 12, Journal of Clinical Investigation, volume 34, issue 3, 1955, pages 439–447, ISSN [http://www.worldcat.org/issn/0021-9738 0021-9738], doi [http://dx.doi.org/10.1172/JCI103092 10.1172/JCI103092]</ref><ref name="Eggleton-1942">MG. Eggleton, The diuretic action of alcohol in man., J Physiol, volume 101, issue 2, pages 172-91, Aug 1942, PMID [http://www.ncbi.nlm.nih.gov/pubmed/16991552 16991552]</ref><ref name="Shirreffs-1996">SM. Shirreffs, AJ. Taylor, JB. Leiper, RJ. Maughan, Post-exercise rehydration in man: effects of volume consumed and drink sodium content., Med Sci Sports Exerc, volume 28, issue 10, pages 1260-71, Oct 1996, PMID [http://www.ncbi.nlm.nih.gov/pubmed/8897383 8897383]</ref><ref name="Maughan-1995">RJ. Maughan, JB. Leiper, Sodium intake and post-exercise rehydration in man., Eur J Appl Physiol Occup Physiol, volume 71, issue 4, pages 311-9, 1995, PMID [http://www.ncbi.nlm.nih.gov/pubmed/8549573 8549573]</ref><ref name="Nose-1988">H. Nose, GW. Mack, XR. Shi, ER. Nadel, Role of osmolality and plasma volume during rehydration in humans., J Appl Physiol (1985), volume 65, issue 1, pages 325-31, Jul 1988, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3403476 3403476]</ref>
</references>