On the trail of potassium in heat injury.

In both classical and exertional heatstroke and in various animal models of human heat injury, clinical manifestations have included observations of normokalemia, hyperkalemia, and hypokalemia. This review attempts to address these observations as well as the role of potassium and potassium depletion in heat injury with an emphasis on the integration of information from the level of transmembrane potassium transport mechanisms to systems physiology. Under moderate conditions of passive heat exposure or exercise in the heat, the adaptive capacity of the Na-K pump (Na+-K+ ATPase activity) and cotransport mechanisms can ordinarily accommodate the attendant increased efflux of intracellular K+ and influx of extracellular Na+ to maintain ionic equilibrium. Several factors affecting transmembrane K+ kinetics include protracted K+ deficiency, extreme hyperthermia, dehydration, and excessive exertion. These could elicit reduced membrane potentials and conductance, futile cycling of the Na-K pump with concomitant energy depletion and greatly increased metabolic heat production, reduced arteriolar vasodilation, altered neurotransmitter release, or cell swelling, each of which could contribute to the pathophysiology of heat injury. This review represents a preliminary attempt to link transmembrane K+ pathophysiology with clinical heat injury.

Splenic effects on hemodynamics induced by hypothermia and rewarming in miniature swine.

Central arterial hemodynamic changes were assessed during cooling, hypothermia, and rewarming in splenectomized (SPX, n = 4) and unsplenectomized (SP, n = 4) 8-10 month old male Yucatan miniature swine (34.0 +/- 1.4 kg). Under isoflurane anesthesia, and using circulating-water blankets, pigs were cooled to and then maintained for 2 h at a rectal temperature (Tre) of 27 +/- 1 degrees C; hypothermia was followed by rewarming to normothermia (37 +/- 1 degrees C). There were significantly (p < or = 0.05) greater changes in central arterial hematocrit and hemoglobin (delta HCT and delta HGB) from respective precooling baseline levels in the SP group during hypothermia and early rewarming (SP: delta HCTmax = 9-10%RBC, and delta HGBmax = 3.0-3.5 g/dl vs. SPX: delta HCTmax = 3-4%RBC, and delta HGBmax = 1.5-1.8 g/dl). By the end of rewarming, splenic resequestration and extravascular fluid shifts resulted in these values returning to baseline. In addition, cardiovascular instability was seen in the SPX group compared to the SP animals as evidenced by significant tachycardia and hypotension during rewarming. We have concluded from these studies that hypothermia causes significant hemoconcentration, and that splenic contraction is the major cause of this hemoconcentration during hypothermia and initial rewarming in miniature swine. A splenectomized design should be considered for swine studies that purport to pattern human pathophysiology, especially for modelling rewarming shock.

Responses to moderate and low sodium diets during exercise-heat acclimation.

This investigation examined whether low sodium (Na+) (LNA; 68 mEq Na+.d-1) or moderate Na+ (MNA; 137 mEq Na+.d-1) intake allowed humans to maintain health, exercise, and physiologic function during 10 days of prolonged exercise-heat acclimation (HA). Seventeen volunteers, ages 19 to 21, consumed either LNA (n = 8) or MNA (n = 9) during HA (41 degrees C, 21% RH; treadmill walking for 30 min.h-1, 8 h.d-1 at 5.6 km.h-1, 5% grade), which resulted in significantly reduced heart rate, rectal temperature, and urine Na+ for both groups. There were few between-diet differences in any variables measured. Mean plasma volume in LNA expanded significantly less than in MNA by Days 11 and 15, but reached the MNA level on Day 17 (+12.3 vs. +12.4%). The absence of heat illness, the presence of normal physiologic responses, and the total distance walked indicated successful and similar HA with both levels of dietary Na+.

Symptomatic hyponatremia during prolonged exercise in heat.

Although hyponatremia (HN) has been reported among endurance athletes, its etiology often remains uncertain and of great interest to clinicians and physiologists. This case report presents physiologic evidence regarding the etiology and development of HN during exercise in the heat. A 21-yr-old male volunteer (K.G.) unexpectedly experienced symptomatic HN during a research investigation that involved controlled sodium (Na+) intake (137 mEq Na+.d-1 for 7d) and exercise-heat acclimation (41 degrees C; 30 min.h-1, 8 h.d-1 for 10 d). Fluid balance, physiologic variables, and hematologic/hormone data were measured before and after the HN episode, with similar measurements recorded for nine unaffected volunteers. The results indicated: 1) HN was verified in K.G. (plasma Na+ < 130 mEq.l-1) after only 4 h of mild, intermittent exercise in heat; 2) K.G.'s heart rate, rectal temperature, blood pressure, and Na+ losses in sweat and urine were < or = control subjects at all times; 3) between hours 4-7, an inappropriately large release of vasopressin coincided with a decrease of urine volume to 0 ml.h-1. It was concluded that a large intake (10.3 l.7h-1) and retention (2.77 l.7h-1) of water and a "low normal" initial plasma Na+ (134 mEq.l-1) were primary factors in the development of HN in K.G., whereas Na+ losses in sweat and urine were normal and served only to exacerbate HN.

Physostigmine: dose-response effects on endurance and thermoregulation during exercise.

We previously reported that the administration of 200 micrograms/kg of physostigmine (PH) to rats exercising on a treadmill resulted in decrements in both endurance (decreased running time to exhaustion) and thermoregulation. However, it was necessary to determine the dose-response effects of PH administration before PH-treated exercising rats could be used as a model with which to examine the relative anticholinergic potency of drugs. In the present work saline, 50, 100, or 200 micrograms/kg of physostigmine salicylate (0%, 40%, 50%, and 60% whole blood cholinesterase inhibition) was administered to rats (N = 12/group) prior to treadmill exercise (26 degrees C, 50% rh, 11 m/min, 6 degrees incline). The saline control group ran for 67 +/- 6 min (mean +/- SE) with a rate of rise of core temperature of 0.051 +/- 0.007 degrees C/min. The run times declined (80%, 64% and 48% of control) as rate of rise of core temperature increased (116%, 180%, and 214% of control) in a dose-dependent manner (50, 100, 200 micrograms/kg PH). Cholinergic symptoms such as salivation, tremors, and defecation were also affected in a dose-dependent manner by PH administration. Since cholinergic symptoms, thermoregulatory effects, and endurance decrements all vary in a dose-dependent manner with physostigmine administration, the exercising rat represents a useful model for examining the relative potency of cholinergic therapies.

Acceptability and effect of carbohydrate-electrolyte solutions on electrolyte homeostasis during field training.

Two lemon-lime flavored 2.5% carbohydrate-electrolyte solutions (CE1 supplemented with Na+, K+, and Mg+; and CE2 supplemented with NA+) were compared to plain water (water) and lemon-lime flavored water placebo (placebo) to evaluate their acceptability and consumption during 8 days of field training in hot weather. Acceptability ratings and consumption of CE2 and the flavored water placebo were similar and greater, respectively, than those for CE1. Average Na+ and K+ intakes, and serum electrolytes levels, were not affected during the 8-day trial. If food intake is adequate, consumption of carbohydrate-electrolyte solutions is apparently unnecessary to maintain electrolyte homeostasis.

Incidence of hypohydration when consuming carbohydrate-electrolyte solutions during field training.

Carbohydrate-electrolyte solutions (CE1, CE2) were evaluated for their ability to reduce the incidence of hypohydration during field training in hot weather (max Tamb = 88 degrees-100 degrees F). Hydration status was monitored twice daily in Army reservists who consumed ad libitum CE1, or CE2, or water, or a flavored water placebo. The water group had the highest percentage incidence of urine specific gravity greater than or equal to 1.030 (22%), whereas CE2 and flavored water placebo groups had the lowest (6% and 8%, respectively). Average total fluid intake was greatest in CE2 and lowest in CE1. CE2 and flavored water placebo were more effective than CE1 and water in reducing the overall incidence of hypohydration during this field exercise.

Carbohydrate-electrolyte solutions during field training: an overview.

The rationale and methods of evaluating two carbohydrate-electrolyte solutions at a field training exercise in hot weather are presented in this overview. The carbohydrate-electrolyte solutions were formulated to produce a multipurpose replacement beverage which could satisfy diverse requirements of troops working in hot climates. Several uses of these beverages include replacement of electrolytes and fluid while in Mission Oriented Protective Posture IV, fluid replacement for mild heat casualties, and oral rehydration therapy for treatment of diarrheal losses.

Adverse effects of dietary and furosemide-induced sodium depletion on thermoregulation.

In this study, the diuretic furosemide was used in combination with dietary sodium (Na) restriction to quantify the effects of moderate to severe Na depletion on heat tolerance in a validated model of heat stress in rats. Rats were subjected to an Na depletion regimen as follows: a control group (I, n = 17) had free access to a normal diet and tap water; group II (n = 20) consumed the same normal diet and tap water, but was treated with the diuretic furosemide at a dose of 10 mg.kg-1.d-1, ip; group III (n = 18) had free access to an Na-free diet and deionized drinking water; group IV (n = 21) consumed the same Na-free diet and electrolyte-free water, but was also treated with furosemide. Both the dietary and drug manipulations affected significant (p less than 0.05) negative electrolyte and water balances. Group IV consistently exhibited the greatest decrements. Following the 4-d depletion all four groups were acutely exposed to a 42 degrees C, 25-30% rh environmental heat stress during which time core body temperature increased. The time required for rectal temperature to reach 42.6 degrees C was significantly (p less than 0.05) decreased from a time of 242 +/- 8 min in the control group to 176 +/- 14, 181 +/- 8, and 111 +/- 11 min in groups II, III and IV, respectively. We concluded that Na deprivation and diuretic treatment can elicit a 25-50% reduction in heat tolerance due to electrolyte depletion and dehydration. These data confirm that during environmental heat stress uncompensated negative Na balance may predispose an individual to heat illnesses.

Chronic vs acute carbamate administration in exercising rats.

Physostigmine (PH), alone, and pyridostigmine (PY), in combination with atropine and 2-PAM, have been shown to protect animals against organophosphate poisoning. While acute administration of either of these carbamates increased heating rates and decreased endurance of exercising rats, chronically administered PY did not induce these decrements, and we hypothesized that chronic administration of PH could also result in similar attenuation of these effects. Thus, PH was administered acutely (iv) or chronically (osmotic mini-pump) in the following 4 groups (510-530g, male, N = 10/group): C (control, saline iv), AC-200 (acute, 200 ug/kg, 58% whole blood cholinesterase (ChE) inhibition), CH-7 (chronic, 125 ug/hr, 7 days, 60% inhib.), and CH-14 (chronic, 125 ug/hr, 14 days, 56% inhib.). Rats were run (11 m/min, 26 degrees C) to exhaustion. The run times and heating rates (% of control) were: AC-200 - 47, 213%; CH-7 - 60, 157%; CH-14 - 92, 109%. Additionally, ultrastructural changes noted in diaphragms of acutely treated animals were less evident in chronically treated animals. Thus, the decremental effects of acute PH administration on endurance, thermoregulation, and ultrastructure were attenuated with chronic administration at similar levels of ChE inhibition.

Patterns of human drinking: effects of exercise, water temperature, and food consumption.

The effects of exercise, water temperature, and food consumption on patterns of ad libitum drinking were studied in 33 men during 6 consecutive cycles of 30 min walking (4.8 km.h-1, 5% grade) and 30 min rest in a climatic chamber (40 degrees C, 40% relative humidity). On two nonconsecutive days, subjects consumed 15 degrees C (cool) water during one trial and 40 degrees C (warm) water during the other. We previously reported that two groups of drinkers can be identified during work in the heat by the criterion of body weight (BW) loss during the trial. Thus, avid drinkers (D) drank sufficiently such that they lost less than 2% of their initial BW when consuming cool water and libitum, while reluctant drinkers (RD) lost more than 2% of their BW. When warm water was provided, fluid consumption was reduced by 29% and 54% in D and RD, respectively and BW deficits were comparably increased. Intake of cool water elicited cyclic drinking patterns with higher rates during walking than during rest periods in both D and RD, whereas consumption of warm water produced this cyclic pattern only after food ingestion during the third rest. Food consumption stimulated fluid intake and reduced BW losses in both trials. Compared to pre-prandial (hours 1-2.5) rates, average post-lunch drinking rates during the last 3 h increased 14% in D and 19% in RD when consuming cool water, and by 46% and 74%, respectively, with warm water. While food consumption has been encouraged to replace electrolytes lost in sweat when working in hot climates, our results indicate that food ingestion also enhances fluid consumption.

Plasma renin activity and aldosterone: correlations with moderate hypohydration.

Adult male test subjects (n = 16) were assigned to one of three clothing configurations (Army fatigues, fatigues with impermeable chemical protective garments, and fatigues with protective garments plus protective masks) prior to exercise (level treadmill, 1.11 m/s, 50 min/h, 6 h) in a moderate (wet bulb globe temperature, WBGT = 23 degrees C) environment with ad lib water consumption. When protective masks were worn, two through-mask drinking systems were evaluated: the current gravity-fed system for fluid delivery and a new system utilizing a small hydraulic pump (Fist-Flex). Antecubital blood samples were taken prior to the start of and subsequent to the completion of exercise and analyzed for fluid-electrolyte regulatory hormones. During all trials with chemical protective garments, plasma renin activity (PRA) and aldosterone levels (PA) were significantly (p less than 0.05) elevated following the exercise protocol while neither was affected during exercise in fatigues only. Individual hypohydration levels during all trials ranged from low (0.84%) to moderate (4.04%). Levels of PRA were closely correlated (r = 0.635, t = 4.35, p less than 0.001) with hypohydration as measured by percentage of body weight lost during the 6 h trial. Likewise, PA was also correlated (r = 0.47, t = 2.81, p less than 0.01) with body weight loss. We concluded from this study that PRA and PA responses were exacerbated in moderate environments by the additional heat stress, sweat rate, and dehydration caused by the impermeable garments. Further, the logistical difficulty inherent in delivering fluid through the chemical protective mask reduced voluntary consumption, increased hypohydration, and elicited the greatest elevations in PRA and PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Variability in intake and dehydration in young men during a simulated desert walk.

Voluntary dehydration was examined in young unacclimatized men walking under simulated desert conditions. Thirty-three subjects (20-33 years) walked on a treadmill (4.82 km.h-1, 5% grade) for 30 min.h-1 for 6 h in a hot environment (40 degrees C db/26 degrees C wb, 4.02 km.h-1 windspeed). Cool (15 degrees C) water was provided ad libitum in canteens. Because thirst is stimulated and drinking should occur at about 2% body weight loss as body water, we used this criterion to identify two groups of individuals. Individuals who maintained body weight (BW) loss at less than 2% (0.44-1.88%) were defined as avid drinkers (D, n = 20) and those who exceeded the 2% BW loss (2.07-3.51%) despite the continual availability of cool (15 degrees C) water were called reluctant drinkers (RD, n = 13). RD consumed 31% less water (2.05 +/- 0.14 L) than D (2.98 +/- 0.12 L), and this resulted in a significantly greater BW loss in RD (2.65 +/- 0.11%) than D (1.16 +/- 0.11%). However, the only statistically significant differences in plasma indices of dehydration were the higher final plasma Na+ and protein levels in RD. Rectal temperature was higher in the RD, whereas final heart rates were unaffected. In the current study, about 40% of the young adult male subjects were reluctant to drink, and thus voluntarily dehydrated even when given cool water ad libitum during intermittent exercise in the heat. The reduced intake of these reluctant drinkers may be critical in predisposing them to increased risk of dehydration and heat injury.

Plasma volume expansion in rats: effects on thermoregulation and exercise.

Administration of polyethylene glycol (PEG, intraperitoneal, 3 ml, 30% solution) to adult male rats (300 g) resulted in an approximately 20% increment in plasma volume (PV) 24 h after PEG injection. When these animals were exercised (9.14 m/min, level treadmill) in a warm (30 degrees C, 30-40% relative humidity) environment, their mean endurance was increased from 67.9 (saline-treated controls, CONT) to 93.6 min (P less than 0.01). Total water loss was increased from 12.2 (CONT) to 17.2 g (PEG, P less than 0.01). Atropine administration (ATR, 200 micrograms/kg, tail vein) significantly (P less than 0.05) reduced both the endurance and the salivary water loss of CONT and PEG-treated rats, whereas it increased the heating rate (P less than 0.01) of both groups. PEG treatment reduced (P less than 0.01) the hematocrit and circulating protein levels both before and subsequent to exercise in the warm environment. Clinical chemical indexes of heat/exercise injury were generally unaffected by pharmacological intervention, whereas clinical chemical responses to exercise were related to the endurance time of each group. We concluded that expansion of PV by PEG provided significant beneficial effects on performance and thermoregulation during exercise in a warm environment.

Effects of water temperature and flavoring on voluntary dehydration in men.

Effects of water temperature and flavoring on fluid consumption and body weight losses were studied in fourteen unacclimatized men (21-33 years) during 6 hr of treadmill exercise (4.8 km.hr-1, 5% grade for 30 min.hr-1) in a hot environment. Subjects consumed each of four beverages (15 degrees C water, 40 degrees C water, 15 degrees C flavored water, and 40 degrees C flavored water) on four nonconsecutive days. We identified two groups of individuals by body weight (BW) loss during the cool water trial: drinkers (D) who lost less than 2% initial BW (0.80 +/- 0.15%) and reluctant drinkers (RD) who lost more than 2% (2.53 +/- 0.12%). Although sweat losses were not different between the two groups, D consumed 31% more cool water than RD and experienced 68% less BW loss. Compared to the warm water trial, 6 hr consumption of cool water was significantly increased in both D (59%) and RD (141%) and BW loss was dramatically reduced in both groups. Flavoring significantly enhanced warm water consumption and reduced BW loss in RD only. Reduced consumption of warm water increased rectal temperature, heart rate and plasma osmolality in both groups. The results of this study indicate that either flavoring or cooling warm water will enhance fluid intake and reduce body weight deficits in men reluctant to drink.

Plasma cortisol, renin, and aldosterone during an intense heat acclimation program.

The physiologic responses to an intense heat acclimation (HA) regimen (treadmill, 41.2 degrees C, 8 days, 56 min exercise/44 min rest) and the effects on stress and fluid balance hormone responses were examined in 13 unacclimated male volunteers. Venous blood samples were collected before (PRE) and after (POST) exercise (days 1, 4, 8) and analyzed for plasma renin activity (PRA), aldosterone (ALD), cortisol (PC), plasma volume shifts (delta PV%), sodium concentration (Na+), and potassium concentration (K+). HA responses (day 1 vs day 8) indicated reduced strain (P less than 0.05): decreased heart rate, rectal temperature, skin temperature, improved defense of PV, and attenuated PC responses. While plasma Na+ demonstrated no change during daily exercise, K+ (P less than 0.01), PC, PRA, and ALD increased (P less than 0.05) more than delta PV%(day 1: -7.1%, day 8: -5.1%) accounted for. Na+ and K+ did not change as a result of HA, and there was no change in fluid balance hormones (e.g., PRA, ALD). It was concluded that this intense heat acclimation regimen reduced physiologic strain by mechanisms other than alterations in fluid balance hormones and offered few physiologic advantages which cannot be gained through conventional heat acclimation techniques (e.g., walking).

Atropine, diazepam, and physostigmine: thermoregulatory effects in the heat-stressed rat.

We have previously reported that administration of atropine (A) to unrestrained, sedentary, heat-stressed rats resulted in a dose-dependent increase in heating rate (rate of rise of core temperature, degree C/min). Additionally, we have demonstrated that the decrements in treadmill endurance and increments in heating rate of physostigmine (PH)-treated running rats can both be restored to control levels by pretreating the animals with A and diazepam (D). Our objective in the present work was to determine if the administration of D + PH to A-treated unrestrained, sedentary, heat-stressed rats (N = 16/group, 510-530 g) could improve their thermal tolerance. The following drugs were administered singly (at 10 min intervals) via lateral tail vein: vehicle-control (C), A (200 micrograms/kg), D (500 micrograms/kg), and PH (200 micrograms/kg). After drug administration, the rats were heat-stressed (Tamb = 41.5 degrees C) until a core temperature of 42.6 degrees C was attained when they were removed to a 26 degrees C chamber. The heating rates (degrees C/min) and tolerance times (min) of the respective groups were: C- 0.02, 235; A- 0.08, 58; A D- 0.06, 94; and A + D + PH- 0.04, 143. Administration of D with A significantly decreased heating rate, and D + PH more than doubled the thermal tolerance of A-treated rats. Thus, the combination of A + D + PH not only restores PH-induced performance and thermoregulatory decrements of rats exercised in a moderate environment, but also reduces A-induced heat intolerance.

Thermoregulatory responses of middle-aged and young men during dry-heat acclimation.

Thermoregulatory responses during heat acclimation were compared between nine young (mean age 21.2 yr) and nine middle-aged men (mean age 46.4 yr) who were matched (P greater than 0.05) for body weight, surface area, surface area-to-weight ratio, percent body fat, and maximal aerobic power. After evaluation in a comfortable environment (22 degrees C, 50% relative humidity), the men were heat acclimated by treadmill walking (1.56 m/s, 5% grade) for two 50-min exercise bouts separated by 10 min of rest for 10 consecutive days in a hot dry (49 degrees C ambient temperature, 20% relative humidity) environment. During the first day of heat exposure performance time was 27 min longer (P less than 0.05) for the middle-aged men, whereas final rectal and skin temperatures and heart rate were lower, and final total body sweat loss was higher (P less than 0.05) compared with the young men. These thermoregulatory advantages for the middle-aged men persisted for the first few days of exercise-heat acclimation (P less than 0.05). After acclimation no thermoregulatory or performance time differences were observed between groups (P greater than 0.05). Sweating sensitivity, esophageal temperature at sweating onset, and the sweating onset time did not differ (P greater than 0.05) between groups either pre- or postacclimatization. Plasma osmolality and sodium concentration were slightly lower for the young men both pre- and postacclimatization; however, both groups had a similar percent change in plasma volume from rest to exercise during these tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Intramuscular and intravenous atropine: comparison of effects in the heat-stressed rat.

In our rat model of human heat injury we have administered atropine intravenously (iv); for clinical use in man, administration is by either the intramuscular (im) or iv route. In order to determine potential differences due to route of administration, we compared the dose-response effects of im and iv administration in rats. Adult male rats (500 g) were heat-stressed (41.5 degrees C) while unrestrained which enabled them to thermoregulate by saliva spreading activity. We quantitated the effects of im or iv atropine (10-4000 micrograms.kg-1) on the following variables: heating rate (rate of rise of core temperature), % weight loss (saliva production), and fecal loss (intestinal motility). Further, we examined the effects of atropine on pupil dilation in restrained rats at 26 degrees C. Heating rate was identical for both routes of atropine administration at 200 micrograms.kg-1 (equivalent to the standard 2-mg dosage in man), but the range of doses over which there was a dose-response effect on heating rate with iv administration (10-1000 micrograms.kg-1) was markedly truncated with the im route (10-50 micrograms.kg-1). Both im and iv atropine had similar effects on weight loss rate and mydriasis. The iv route is preferred because that route produced the most consistent results and the most sensitive physiological response (heating rate) is affected over a wider dose range.

Autologous red blood cell reinfusion: effects on stress and fluid regulatory hormones during exercise in the heat.

This study assessed the effects of induced erythrocythemia on stress and fluid regulatory hormones during walking exercise in the heat. Six unacclimated male subjects received approximately 600 ml of a sterile saline solution containing 50% volume-to-volume of autologous erythrocytes. Three heat stress tests (HSTs) were attempted: one approximately 2 weeks prior to the reinfusion procedure, a second 48 h after the reinfusion procedure, and a third 1 week later, corresponding to 9 d subsequent to reinfusion. Each HST comprised three consecutive 45-min exercise and 15-min rest intervals (VO2 approximately 2.0 L.min-1, 1.56 m.s-1, 6% incline, 35 degrees C, 45% rh). Blood was withdrawn before the HST and 30 min into each exercise (EX) bout. In all three HST's plasma cortisol (PC) levels were significantly (p less than 0.01) reduced during the first EX bout compared to preexercise levels, and then progressively increased during the second and third EX intervals during HST 1. During HST 2 (48 h postinfusion), however, PC levels were significantly (p less than 0.05) reduced in two blood samples (EX 2, 3) compared to the same blood samples from HST-1 (preinfusion). Plasma renin activity (PRA) and aldosterone (ALD) were significantly (p less than 0.01) increased by the exercise/heat stress, but were unaffected by erythrocythemia either 48 h or 9 d subsequent to reinfusion. PRA and ALD were correlated (r = 0.84, p less than 0.001) under all conditions. We concluded from this study that acutely induced erythrocythemia reduced the stress response to consecutive exercise/heat intervals as manifested in PC responses during HST 2.(ABSTRACT TRUNCATED AT 250 WORDS)