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The role of parity before and after N-methyl-N-nitrosourea (MNU) treatment in protection against mammary carcinogenesis was investigated. The effect of lactation on reduction in the incidence of mammary carcinoma was also examined. Parous rats were compared with respective age-matched virgins (AMVs). Pregnancy and lactation prior to MNU exposure significantly reduced both the incidence of mammary carcinoma (22 versus 72%) and the average number of mammary carcinomas per rat (0.22 versus 0.86) and significantly prolonged the latency of the carcinomas (247 versus 215 days). Pregnancy and lactation following MNU exposure also significantly reduced both the incidence of mammary carcinoma (25 versus 94%) and the average number of mammary carcinomas per rat (0.25 versus 1.50) and significantly prolonged the latency (240 versus 155 days). Lactation showed an additive effect on the reduction in mammary cancer. Pregnancy suppressed the number of estrogen receptor (ER)- and progesterone receptor (PgR)-positive cells and lowered the cell proliferation rate in the non-tumoral mammary glands. Since the majority (>76%) of the mammary carcinomas was hormone dependent in both the parous and AMV rats, pregnancy and lactation appear to decrease the ER- and/or PgR-positive cells presumed to be the progenitors of hormone-dependent carcinomas and they lowered the cell turnover necessary for tumor promotion in parous rats, resulting in a lower mammary carcinoma yield.
The muscle contents of high-energy phosphates and their derivatives [ATP, ADP, AMP, creatine phosphate (CrP), and creatine], glycogen, some glycolytic intermediates, pyruvate, and lactate were compared in 11 dogs performing prolonged heavy exercise until exhaustion (at ambient temperature 20.0 +/- 1.0 degrees C) without and with trunk cooling using ice packs. Without cooling, dogs were able to run for 57 +/- 8 min, and their rectal (Tre) and muscle (Tm) temperatures increased to 41.8 +/- 0.2 and 43.0 +/- 0.2 degrees C, respectively. Compared with noncooling, duration of exercise with cooling was longer by approximately 45% while Tre and Tm at the time corresponding to the end of exercise without cooling were lower by 1.1 +/- 0.2 and 1.2 +/- 0.2 degrees C, respectively. The muscle contents of high-energy phosphates (ATP + CrP) decreased less, the rate of glycogen depletion was lower, and the increases in the contents of AMP, pyruvate, and lactate as well as in the muscle-to-blood lactate ratio were smaller. The muscle content of lactate was positively correlated with Tm. The data indicate that with higher body temperature equilibrium between high-energy phosphate breakdown and resynthesis was shifted to the lower values of ATP and CrP and glycolysis was accelerated. The results suggest that hyperthermia developing during prolonged muscular work exerts an adverse effect on muscle metabolism that may be relevant to limitation of endurance.
In order to provide reference data, adenine nucleotide, creatine phosphate, glycogen, glycolytic intermediates and lactate muscle contents were measured in 49 dogs under resting conditions and during prolonged physical exercise of moderate intensity performed until exhaustion. Both the resting and exercise values of the measured variables were remarkably similar to those described in human subjects, except muscle lactate content which achieved higher values during submaximal exercise in dogs than in men.
It has been suggested that the histological and histochemical features of human muscle are important in determining performance capacity. The relationship between muscle fibre types (Type I, slow twitch fibres; Type II, fast twitch fibres) and performance on standardized tests has been studied in subjects accustomed to physical exercise, and related to their patterns of lactate metabolism, expressed as the onset of blood lactate accumulation (OBLA). This variable was found to be the best predictor of endurance capacity of the variables studied. It is suggested that in healthy male subjects muscle lactate is crucial in short, intense forms of exercise (the higher the lactate formation, the better the performance) and also in prolonged, "endurance' forms of exercise (the later the onset of lactate formation, the higher the sustainable exercise intensity). In subjects with a high proportion of fast twitch fibres, more lactate will be formed at the same exercise intensity. This is advantageous for short intense exercise but impairs endurance performance. The deleterious effects induced by glycogen depletion were studied and found to be most pronounced in subjects rich in fast twitch (glycogen-dependent) fibres. Indications were also obtained that muscular performance is regulated in different ways in males and females. In women an inverse relationship was found between fast twitch fibres and muscle power, and between fatigue and lactate concentration, whereas direct relations were found in men.
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Anoxic turtles accumulate high levels of lactate in blood. To avoid fatal acidosis, turtles exploit buffer reserves in their large mineralized shell. The shell acts by releasing calcium and magnesium carbonates and by storing and buffering lactic acid. Together with profound metabolic depression, shell buffering permits survival without oxygen for several months at 3 degrees C.
The changes of hepatic energy metabolism during normothermic and hypothermic ischemia were investigated using rats with portajugular shunt. In addition, some blood parameters were estimated as to whether they could reflect the changes in hepatic energy level (represented by energy charge, EC). In this study, [pyruvate]/[lactate] x 1/K(K = 1.11 x 10(-4)) and [2-oxoglutarate] x [ammonia]/[glutamate] x 1/K(K = 3.87 x 10(-3) mmole) were used as indexes of cytosolic and mitochondrial redox state, respectively. The following results were obtained. 1) Though hepatic EC recovered after 30 minutes of ischemia, it didn't recover after 60 minutes of normothermic ischemia. 2) The recovery of the hepatic EC even after 60 minutes of ischemia was observed in hypothermic condition. 3) Mitochondrial redox state changed like hepatic EC, however, some dissociations were observed between cytosolic redox state and hepatic EC in hypothermic ischemia. 4) The changes of mitochondrial and cytosolic redox state were reflected in those of arterial ammonia and lactate level, respectively. As a result, hypothermia can prolong the safe ischemic period due to its stabilizing effect on mitochondrial redox state. In addition, the changes of the hepatic EC are reflected in those of arterial ammonia and lactate level. In hypothermic condition, however, ammonia seemed a better parameter than lactate in assessing hepatic EC.
When isolated hepatocytes from fasted rats were incubated with 10 mM lactate, the [lactate]/[pyruvate] ratio measured at the beginning of the incubation was raised above 70:1 but declined to a steady level of about 8:1 within 40 min. The rate of gluconeogenesis from lactate was initially slow but gradually increased over the incubation period becoming maximal by 30 min. The simultaneous addition of lactate and ethanol resulted in an initial [lactate]/[pyruvate] ratio above 250:1 which by 60 min had declined to a new steady-state level of approx. 60:1. The lactate, ethanol combination also brought about a prolongation of the lag phase before glucose synthesis became maximal; however, by 40 min the rate of gluconeogenesis was independent of the presence of ethanol. Thus the inhibitory effect of ethanol on glucose synthesis was manifest only over the early portion of the incubation period. When asparagine, a precursor of malate/aspartate components, was added to the incubation mixture, the lag before maximal rates of glucose formation from lactate in the absence or presence of ethanol was almost abolished. The presence of asparagine also rapidly lowered the [lactate]/[pyruvate] ratio of hepatocytes incubated with lactate plus ethanol establishing a steady-state level of 15:1 within 10-15 min. Asparagine enhanced the rate of lactate-stimulated ethanol oxidation, particularly during the early part of the incubation. In endeavouring to elucidate which of the products of asparagine catabolism (i.e. ammonia and aspartate) were responsible for these effects, we found that a small and constant level of ammonia, formed by the degradation of urea by urease, almost reproduced the effects of asparagine on the [lactate]/[pyruvate] ratio, glucose synthesis and ethanol oxidation. A bolus addition of 10 mM aspartate or 4 mM ammonia to cells metabolising lactate and ethanol were less effective than a steady-state low ammonia concentration, generated from urea/urease. Our studies suggest that asparagine or a low concentration of ammonia, by providing components of the malate/aspartate shuttle, can ameliorate some of the metabolic effects of ethanol on the liver.
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PURPOSE: Investigation of the clinical, imaging, and in vivo MR spectroscopy (MRS) characteristics of disorders of mitochondrial function. METHODS: Clinical, imaging (five CT and 20 MR examinations), and MRS (six studies in five patients) findings in 19 patients with mitochondrial disorders were retrospectively reviewed. Results were critically analyzed and, when applicable, compared with results in the literature. RESULTS: Patients included four with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), two with myoclonus, epilepsy, and ragged red fibers (MERRF), two with Kearns-Sayre syndrome, seven with Leigh syndrome, one with progressive cerebral poliodystrophy (Alpers syndrome), and three with trichopoliodystrophy (Menkes disease). MELAS, MERRF, and Kearns-Sayre tended to occur in older children and adults, whereas Leigh syndrome, Alpers syndrome, and Menkes disease occurred in infants and young children. All diseases involved gray matter early in their course, manifest primarily as T2 prolongation, with the deep cerebral nuclei being involved more often than the cerebral cortex. When T2 prolongation was seen in the white matter (MELAS, MERRF, Kearns-Sayre, Leigh), the peripheral and retrotrigonal white matter showed early involvement. Patients with Menkes disease showed rapidly progressive atrophy accompanied by large subdural hematomas. Proton MRS showed an elevated lactate level in involved regions of the brain; the lactate peak disappeared in old areas of T2 prolongation. CONCLUSIONS: Mitochondrial disorders have a wide range of both clinical and imaging findings. Although no one set of findings is diagnostic of these disorders, the combination of deep gray matter involvement and peripheral white matter involvement in young adults or children should suggest the diagnosis, especially when associated with an elevated lactate level on proton MRS.
The actions of intravenous glucagon and amylin, a newly discovered hyperglycemic pancreatic islet hormone, have been compared in 20-h fasted and fed, lightly anesthetized rats, and in rats made hypoglycemic with an insulin infusion. In fasted animals, amylin (75 nmol/kg) was more effective than glucagon (90 nmol/kg) in increasing plasma glucose (glucose increment 4.55 vs. 1.71 mM, P < 0.001). Amylin elicited a marked increase in plasma lactate, as previously reported, whereas glucagon did not alter plasma lactate. In fed animals, glucagon elicited twice as much increase in plasma glucose as did amylin; amylin again elicited a marked lactate increase that was greater (increment 1.45 vs. 0.97 mM, P < 0.05) and more prolonged than in the fasted state, whereas glucagon was without effect on lactate levels. These findings are consistent with glucagon's known action to promote hyperglycemia from hepatic glycogenolysis and amylin's demonstrated action to promote muscle glycogenolysis and increase lactate supply to the liver. Infusions of sodium lactate that produced plasma lactate increments similar to those evoked by 75 nmol/kg amylin evoked patterns of glucose response in fasted and fed rats similar to those evoked by amylin. Thus increased lactate supply to the liver may account for amylin's hyperglycemic effects. Amylin and glucagon could each restore plasma glucose to control levels in fasted animals made hypoglycemic by insulin infusion (plasma glucose reduced to 3.3 mM). A bolus of 75 nmol/kg amylin was more effective than 180 nmol/kg glucagon, restoring basal glucose levels for > 3 h, whereas glucagon restored it for < 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)
The ontogenetic development of the immune system is a well-defined, almost stereotyped event. The anlagen of the human thymus can be distinguished in the third and fourth branchial arches in the sixth week of gestation. Several distinct responses have been observed in the first trimester of fetal development. In addition to genetic factors, environmental influences such as nutrition play an important role in influencing the developing human immune system. Adverse factors that impair fetal growth hinder immunological maturation as well. These include maternal malnutrition, smoking, alcohol and other substance abuse, placental insufficiency and infection. The immunocompetence of low birth weight infants is compromised; those who are small for gestation show persistent immunological impairment for several months, even years. Prolonged effects on immune responses can be seen in animal models of fetal malnutrition. A second area where interactions occur between dietary factors and the immune system is the IgE-mediated allergic response. Those with a family history of atopy are at high risk of developing allergic disease in late childhood and adult life. The enormous costs of atopic disease in terms of health management and physical and emotional isolation have led to attempts at prevention. These strategies include restriction of the mother's diet during pregnancy and lactation to exclude common allergenic foods and prolonged exclusive breast feeding. Casein or whey hydrolysate formulas are advisable in those not breast fed.
We hypothesized that reliance on lactate as a means of energy distribution is higher after a prolonged period of acclimatization (9 wk) than it is at sea level due to a higher lactate Ra and disposal from active skeletal muscle. To evaluate this hypothesis, six Danish lowlanders (25 +/- 2 yr) were studied at rest and during 20 min of bicycle exercise at 146 W at sea level (SL) and after 9 wk of acclimatization to 5,260 m (Alt). Whole body glucose Ra was similar at SL and Alt at rest and during exercise. Lactate Ra was also similar for the two conditions at rest; however, during exercise, lactate Ra was substantially lower at SL (65 micro mol. min(-1). kg body wt(-1)) than it was at Alt (150 micro mol. min(-1). kg body wt(-1)) at the same exercise intensity. During exercise, net lactate release was approximately 6-fold at Alt compared with SL, and related to this, tracer-calculated leg lactate uptake and release were both 3- or 4-fold higher at Alt compared with SL. The contribution of the two legs to glucose disposal was similar at SL and Alt; however, the contribution of the two legs to lactate Ra was significantly lower at rest and during exercise at SL (27 and 81%) than it was at Alt (45 and 123%). In conclusion, at rest and during exercise at the same absolute workload, CHO and blood glucose utilization were similar at SL and at Alt. Leg net lactate release was severalfold higher, and the contribution of leg lactate release to whole body lactate Ra was higher at Alt compared with SL. During exercise, the relative contribution of lactate oxidation to whole body CHO oxidation was substantially higher at Alt compared with SL as a result of increased uptake and subsequent oxidation of lactate by the active skeletal muscles.
The objective of the work was to assess the blood lactate levels in type 2 diabetics selected at random, treated for prolonged periods with buformin. 77% of the investigated group of diabetics (N = 70) had elevated blood lactate levels and 16% of them had hyperlactataemia (more than 5.0 mmol/l). In 33% patients with an originally elevated lactataemia after 12 weeks of discontinued buformin treatment the lactic acid blood levels reached normal values. The lactate levels declined significantly (by more than 25% of the original value) after 6 weeks without buformin treatment in another 45% of the diabetic patients. In 18% of the investigated patients, who had high lactate levels even after discontinuation of treatment, in two-thirds neither impaired function of the kidneys and liver nor cardiac disease or alcoholism were detected.
The aim of the present study was to investigate the relationships between lactate exchange and removal abilities and the capacity to prolong exercise, as assessed by the time to exhaustion (Tlim) at a work rate corresponding to VO(2)max (Pa max ). The individual blood lactate recovery curves obtained for 13 untrained subjects after 5 min 90 % Pa max exercise were fitted to the biexponential time function: La(t) = La(0) + A(1) (1-e (-gamma(1) x t) + A(2) (1-e (-gamma(2) x t), where t is time into the recovery, La(0) is the arterialized lactate concentration measured at the end of the exercise, gamma(1) and gamma(2) are velocity constants denoting the lactate exchange and removal abilities, respectively. Tlim was positively related to gamma(1) and gamma(2) (r = 0.60, p < 0.05 and r = 0.56, p < 0.05, respectively) but was negatively related to La(0) (r = 0.75, p < 0.01). gamma()1 was positively related to the capillary density (r = 0.69, p < 0.01) and to the number of capillaries per type I fiber area (r = 0.62, p < 0.05). It was concluded that 1) high lactate exchange and removal abilities would allow continuing a high-intensity exercise for a longer duration, and 2) a high capillary density may explain the associated high lactate exchange ability.
We examined the hypoxic tolerance phenomenon in vitro. Brief exposure to hypoxia induced the production of basic fibroblast growth factor (bFGF) mRNA and protein in rat cortical neurons and protected them from hypoxic injury. Cortical neurons were cultured from 18th-day rat embryos in a serum-free medium and subjected to brief (4 h) and/or prolonged (24 h) hypoxia. Neuronal damage was assessed by quantifying lactate dehydrogenase (LDH) activity in the medium. After brief hypoxia, LDH release was identical to that of the controls, whereas prolonged hypoxia caused a significant increase in LDH release, indicating neuronal death. However, if brief hypoxia was applied 2 days prior to the prolonged hypoxia, no increase in LDH release was observed. The bFGF mRNA expression was assessed with Northern blot and protein immunoreactivity with Western blot analysis. The brief period of hypoxia caused a 2.5-fold increase in bFGF mRNA and considerable bFGF protein expression 1 day later, but prolonged hypoxia caused increase in the expression of bFGF mRNA at 2 days and no protein expression until 3 days after the start of the hypoxia. When cells were subjected to prolonged hypoxia 2 days after brief hypoxia, however, no increase in bFGF mRNA was observed, while bFGF protein was expressed continuously. We also observed that exogenously applied bFGF reduced neuronal injury produced by prolonged hypoxia. The results obtained with this model suggest that brief hypoxia induces bFGF protein and thus tolerance to subsequent lethal hypoxia. Basic FGF might play a role as a tolerance-associated factor in this process. Thus, an in vitro model is useful for assessing the response of cortical neurons to hypoxic stress and for researching new factors related to ischemic tolerance.