Influence of cognitive impairment on the freezing of gait in non demented people with Parkinson's disease. / Influencia del deterioro cognitivo en la congelacion de la marcha en pacientes con enfermedad de Parkinson sin demencia.

INTRODUCTION: Freezing of gait (FOG) is a motor disturbance usually appearing in advanced Parkinson's disease (PD). Cognitive and executive function seems to play an important role in this phenomenon. AIM: To investigate if cognitive and kinematic parameters correlate with FOG in PD patients without dementia. PATIENTS AND METHODS: We conducted an observational cross-sectional study. Participants were classified in two groups: freezers and non-freezers. Clinical information was obtained by Hoehn and Yahr scale, Unified Parkinson's Disease Rating Scale and balance test of Short Physical Performance Battery. Cognitive function was evaluated using Minimental Examination and the Fuld Object Memory Evaluation; executive function was assessed with the Frontal Assessment Battery test. Battery kinematic parameters were assessed by means of gait speed, cadence, stride length and stride time. RESULTS: Twenty-five participants with PD without dementia completed the evaluation. Statistical significant differences between freezers and non-freezers were found in global cognition (p = 0,02), memory (p = 0,04), executive function (p = 0,04), cadence (p = 0,02), stride length (p = 0,04) and stride time (p = 0,01). CONCLUSION: Cognitive parameters may have an important contribution to the manifestation of freezing of gait in PD. These results may have important clinical implications for developing future non-pharmacological and cognitive interventions strategies targeted to PD patients with FOG.

TITLE: Influencia del deterioro cognitivo en la congelacion de la marcha en pacientes con enfermedad de Parkinson sin demencia.Introduccion. La congelacion de la marcha (CDM) es una alteracion motora que suele aparecer en estadios avanzados de la enfermedad de Parkinson (EP). Las funciones cognitivas y ejecutivas parecen tener un papel importante en la aparicion de este fenomeno. Objetivo. Investigar si los parametros cognitivos y cinematicos se correlacionan con la CDM en pacientes con EP sin demencia. Pacientes y metodos. Estudio observacional y transversal. Los participantes se clasificaron en dos grupos: con y sin CDM. La informacion clinica se obtuvo mediante la escala de Hoehn y Yahr, la Unified Parkinson's Disease Rating Scale y la prueba de equilibrio de la Short Physical Performance Battery. La funcion cognitiva se valoro con el miniexamen cognitivo y la Fuld Object Memory Evaluation, y la funcion ejecutiva, con la Frontal Assessment Battery. Los parametros cinematicos se valoraron mediante la velocidad de la marcha, la cadencia, la longitud del paso y el tiempo del paso. Resultados. Veinticinco participantes con EP sin demencia completaron el programa. Se encontraron diferencias estadisticamente significativas entre individuos con y sin CDM en cognicion global (p = 0,02), memoria (p = 0,04), funcion ejecutiva (p = 0,04), cadencia (p = 0,02), longitud del paso (p = 0,04) y tiempo del paso (p = 0,01). Conclusion. Diversos parametros cognitivos pueden contribuir de forma importante en la aparicion de la CDM en la EP. Estos resultados pueden tener implicaciones clinicas relevantes para el desarrollo de estrategias e intervenciones no farmacologicas y cognitivas dirigidas a pacientes con EP y con CDM.

The influence of winter and summer seasons on physical fitness in aged population.

Epidemiological studies have described the association between physical fitness and health. Few have reported the impact of seasonal variation on fitness determinants, in elderly. We investigated the effects of summer and winter environmental conditions on physical fitness, in both exercise and non-exercise elders. 371 non-institutionalized older adults (74.1% female; 78.4 ±â€¯5.3 years) randomly recruited from a total sample of 1338 subjects from north of Portugal, were prospectively followed during 1 year and 3 assessments were performed - April (baseline), October (summer season) and April (winter season). Four groups were defined, according to reported habits of exercising: Exercise (EG); Winter Exercise (WG); and Summer Exercise (SG); non-Exercise (nEG). Muscle strength was assessed with handgrip and isometric knee extension test, and aerobic capacity with the 6 min walking test. Repeated measures ANOVA with two between-subjects factors were run for independent variables, considering a three Time points. Significance set at p < .05. Findings show that: (1) men were fitter than women; (2) EG showed better results than nEG (p = .000), but not different than WG or SG, (3) nEG physical fitness was not significantly different from WG and SG; (4) SG and WG showed similar results; (5) there was significant group-by-time interaction for all variables in study. Among elderly, the regular physical exercise determined better cardiorespiratory fitness and levels of strength compared to individuals that were not exercising, however, no season impact was observed. Independently of exercising mode, regular, seasonal or not exercising, the pattern of changes in physical fitness throughout the year was similar.

Lack of GSK3ß activation and modulation of synaptic plasticity by dopamine in 5-HT1A-receptor KO mice.

Psychiatric disorders are associated with excitation-inhibition (E-I) balance impairment in the prefrontal cortex. However, how the E-I balance is regulated is poorly known. The E-I balance of neuronal networks is linked to the action of numerous neuromodulators such as dopamine and 5-HT. We investigated the role of D2-receptors in tuning the E-I balance in a mouse model of anxiety, the 5-HT1A-receptor KO mice. We focused on synaptic plasticity of excitation and inhibition on layer 5 pyramidal neurons. We show that D2-receptor activation decreases the excitation and favors HFS-induced LTD of excitatory synapses via the activation of GSK3ß. This effect is absent in 5-HT1A-receptor KO mice. Our data show that the fine control of excitatory transmission by GSK3ß requires recruitment of D2-receptors and depends on the presence of 5-HT1A-receptors. In psychiatric disorders in which the number of 5-HT1A-receptors decreased, therapies should reconsider how serotonin and dopamine receptors interact and control neuronal network activity.

Influence of cognitive impairment on fall risk among elderly nursing home residents.

BACKGROUND: Information relating the severity of cognitive decline to the fall risk in institutionalized older adults is still scarce. This study aims to identify potential fall risk factors (medications, behavior, motor function, and neuropsychological disturbances) depending on the severity of cognitive impairment in nursing home residents. METHODS: A total of 1,167 nursing home residents (mean age 81.44 ± 8.26 years; 66.4% women) participated in the study. According to the MEC, (the Spanish version of the Mini-Mental State Examination) three levels of cognitive impairment were established: mild (20-24) "MCI", moderate (14-19) "MOCI", and severe (≤14) "SCI". Scores above 24 points indicated the absence cognitive impairment (NCI). Information regarding fall history and fall risk during the previous year was collected using standardized questionnaires and tests. RESULTS: Sixty falls (34%) were registered among NCI participants and 417 (43%) among people with cognitive impairment (MCI: 35%; MOCI: 40%; SCI: 50%). A different fall risk model was observed for MCI, MOCI, SCI, and NCI patients. The results imply that the higher the level of cognitive impairment, the greater the number of falls (F1,481 = 113.852; Sig = 0.015), although the level of significance was not maintained when MOCI and SCI participants were compared. Depression, neuropsychiatric disturbances, autonomy constraints in daily life activity performance, and low functional mobility were factors closely associated with fall risk. CONCLUSION: This study provides evidence indicating that fall risk factors do not hold a direct correlation with the level of cognitive impairment among elderly nursing home care residents.

Effects of two different exercise programs on gait parameters in individuals with Parkinson's disease: a pilot study.

To date, little attempt has been made to compare or evaluate the effects of different physical exercise programs on gait disorders in people with Parkinson's disease (PD). This pilot study is aimed at obtaining preliminary data of the effects of two different exercise programs on gait parameters in people with PD by means of a biomechanical three-dimensional motion analysis. Twenty-five individuals with idiopathic PD participated either in a land-based (LB) or in a LB plus water-based (LWB) exercise program for 16 weeks. The efficacy of both exercise programs was quantified by means of a biomechanical gait analysis from which spatiotemporal and sagittal plane kinetic (gait speed, stride length, cadence, stride time, simple support time, double support time) and kinematic (angles of the hip, knee, and ankle joints) variables were recorded. Once the intervention ended, significant changes were observed in stride length and single/double support time variables in all the patients. The intergroup analysis revealed the existence of significant differences only in the gait Speed and hip Angle parameters. Few significant improvements in the amplitude of lower limb joints were found. These results suggest that land-based and land-plus-water-based exercise programs can be considered as a useful physical rehabilitation alternative, both equally capable of improving gait impairment on Parkinson's disease.

Influence of the cognitive impairment level on the performance of the Timed "Up & Go" Test (TUG) in elderly institutionalized people.

The purpose of this study was to determine clinical variables influence (comorbid medical condition, functional independence, depressive and neuropsychiatric symptoms) on the performance of the TUG, taking into account the level of cognitive impairment in elderly institutionalized people. A cross-sectional analysis of 405 sedentary older adults living in rural home care facilities was carried out. All the participants performed the TUG and the Mini Mental State Examination (MMSE). Those who were screened positive for cognitive impairment carried out a battery of specific test aimed to assess their functional independence (Katz Index (KI)), memory function (Fuld Object Memory Evaluation (FOME)), depressive symptoms (Cornell Scale) and neuropsychiatric disturbances (Neuropsychiatric Inventory (NPI)). Applying multiple linear regression, TUG was associated with age (ß=0.161, p<0.001), MMSE (ß=-0.013, p<0.001) and KI (ß=0.621, p<0.001). According to the defined regression model, it was noticed that the higher the level of cognitive impairment, the lower the adjustment of the model (R(2)=0.593; R(2)=0.493; R(2)=0.478). In conclusion, it seems that the performance of the TUG in institutionalized elderly people who screened positive for dementia, is mainly influenced by their functional independence and their age. Comorbid medical condition, depressive and neuropsychiatric symptoms do not seem to show any association, regardless of the level of cognitive impairment.

The Senior Fitness Test as a functional measure in Parkinson's disease: a pilot study.

OBJECTIVE: This pilot study aimed to determine if the Senior Fitness Test (SFT) battery can be applied to subjects with Parkinson's disease (PD) and whether its results can be reliable indicators of disease severity. METHODS: Thirty people with mild to moderate PD performed the SFT and completed the Parkinson's Disease Questionnaire (PDQ-39) and the Unified Parkinson's Disease Rating Scale (UPDRS). To compare the metric properties of the SFT battery with the UPDRS and the PDQ-39, a SFT sum-score was created. RESULTS: The tests that compose the SFT were successfully completed by the patients, except for the "Two-Minute Step Test" (2MST), which had to be shortened. We observed a strong correlation among the SFT's sum-score and the total scores of the PDQ-39 and the UPDRS. Some correlation was also found among the SFT's sum-score and the analyzed subscales, except for those assessing mental and cognitive levels. CONCLUSION: The SFT appears to be a useful tool to assess functional fitness in people with PD: it can be carried out in the clinical setting albeit with some minor modifications. However, its validity as an indicator of disease severity remains to be confirmed.

Nucleoplasmic reticulum is not essential in nuclear calcium signalling mediated by cyclic ADPribose in primary neurons.

Nuclear calcium regulation is essential for controlling nuclear processes such as gene expression. Recent studies, mostly performed on immortalized or transformed cell lines, reported the presence of a nucleoplasmic reticulum (NR). It has been suggested that NR acts as a storage organelle having an important role in nuclear Ca2+ signalling. However, whether NR is present and necessary in primary neurons for generation of nuclear Ca2+ signalling has never been investigated. Here, we show, by confocal microscopy and by electronic microscopy, that nuclei in intact neurons or isolated nuclei are not endowed with NR. Finally, our experiments performed on isolated nuclei from Aplysia giant neurons show that the nuclear envelope acts as a functional Ca2+ store which can be mobilized by the second messenger cyclic ADPribose to elicit a nucleoplasmic Ca2+ elevation. Our study provides evidence that nuclear Ca2+ signals can be independent of the presence of NR in neurons.

Specific Ca2+ signaling evoked by cholecystokinin and acetylcholine: the roles of NAADP, cADPR, and IP3.

In order to control cell functions, hormones and neurotransmitters generate an amazing diversity of Ca2+ signals such as local and global Ca2+ elevations and also Ca2+ oscillations. In pancreatic acinar cells, cholecystokinin (CCK) stimulates secretion of digestive enzyme and promotes cell growth, whereas acetylcholine (ACh) essentially triggers enzyme secretion. Pancreatic acinar cells are a classic model for the study of CCK- and ACh-evoked specific Ca2+ signals. In addition to inositol 1,4,5 trisphosphate (IP3), recent studies have shown that cyclic ADPribose (cADPr) and nicotinic acid adenine dinucleotide phosphate (NAADP) release Ca2+ in pancreatic acinar cells. Moreover, it has also been shown that both ACh and CCK trigger Ca2+ spikes by co-activation of IP3 and ryanodine receptors but by different means. ACh uses IP3 and Ca2+, whereas CCK uses cADPr and NAADP. In addition, CCK activates phospholipase A2 and D. The concept emerging from these studies is that agonist-specific Ca2+ signals in a single target cell are generated by combination of different intracellular messengers.

Bombesin-induced cytosolic Ca2+ spiking in pancreatic acinar cells depends on cyclic ADP-ribose and ryanodine receptors.

Different hormones and neurotransmitters, using Ca2+ as their intracellular messenger, can generate specific cytosolic Ca2+ signals in different parts of a cell. In mouse pancreatic acinar cells, cytosolic Ca2+ oscillations are triggered by activation of acetylcholine (ACh), cholecystokinin (CCK) and bombesin receptors. Low concentrations of these three agonists all induce local Ca(2+)spikes, but in the case of bombesin and CCK these spikes can also trigger global Ca2+ signals. Here we monitor cytosolic Ca2+ oscillations induced by low (2-5 pM) concentrations of bombesin and show that, like ACh- and CCK-induced oscillations, the bombesin-elicited responses are inhibited by ryanodine(50 microM). We then demonstrate that, like CCK- but unlike ACh-induced oscillations, the responses to bombesin are abolished by intracellular infusion of the cyclic ADP ribose (cADPr) antagonist 8-NH2-cADPr (20 microM). We conclude that in mouse pancreatic acinar cells, bombesin, CCK and ACh all produce local Ca2+ spikes by recruiting common oscillator units composed of ryanodine and inositol trisphosphate receptors. However, bombesin and CCK also recruit cADPr receptors, which may account for the global Ca2+ signals that can be evoked by these two agonists. Our new results indicate that each Ca2+ -mobilizing agonist, acting on mouse pancreatic acinar cells, recruits a unique combination of intracellular Ca2+ channels.

Two different but converging messenger pathways to intracellular Ca(2+) release: the roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate.

Hormones and neurotransmitters mobilize Ca(2+) from the endoplasmic reticulum via inositol trisphosphate (IP(3)) receptors, but how a single target cell encodes different extracellular signals to generate specific cytosolic Ca(2+) responses is unknown. In pancreatic acinar cells, acetylcholine evokes local Ca(2+) spiking in the apical granular pole, whereas cholecystokinin elicits a mixture of local and global cytosolic Ca(2+) signals. We show that IP(3), cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) evoke cytosolic Ca(2+) spiking by activating common oscillator units composed of IP(3) and ryanodine receptors. Acetylcholine activation of these common oscillator units is triggered via IP(3) receptors, whereas cholecystokinin responses are triggered via a different but converging pathway with NAADP and cyclic ADP-ribose receptors. Cholecystokinin potentiates the response to acetylcholine, making it global rather than local, an effect mediated specifically by cyclic ADP-ribose receptors. In the apical pole there is a common early activation site for Ca(2+) release, indicating that the three types of Ca(2+) release channels are clustered together and that the appropriate receptors are selected at the earliest step of signal generation.

Attraction or repulsion by local Ca(2+) signals.

Recent studies have shown that cytosolic Ca(2+) signals, generated on one side of a nerve growth cone, can induce turning either towards or away from the side of the Ca(2+) signal, depending on the global Ca(2+) level. The results indicate that local Ca(2+) signals may provide important directional cues for axon guidance.

New Ca2+-releasing messengers: are they important in the nervous system?

In the nervous system, Ca2+ signalling is determined primarily by voltage-gated Ca2+-selective channels in the plasma membrane, but there is increasing evidence for involvement of intracellular Ca2+ stores in such signalling. It is generally assumed that neurotransmitter-elicited release of Ca2+ from internal stores is primarily mediated by Ins(1,4,5)P3, as originally discovered in pancreatic acinar cells. The more-recently discovered Ca2+-releasing messenger, cyclic ADP-ribose (cADPR), which activates ryanodine receptors, has so far only been implicated in a few cases, and the possible importance of another Ca2+-releasing molecule, nicotinic acid adenine dinucleotide phosphate (NAADP), has been ignored. Recent investigations of the action of the brain-gut peptide cholecystokinin on pancreatic acinar cells have indicated that NAADP and cADPR receptors are essential for Ca2+ release. Tools are available for testing the possible involvement of NAADP and cADPR in neurotransmitter-elicited intracellular Ca2+ release, and such studies could reveal complex mechanisms that control this release in the nervous system.

Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca(2+) signals.

Agonist-evoked cytosolic Ca(2+) spikes in mouse pancreatic acinar cells are specifically initiated in the apical secretory pole and are mostly confined to this region. The role played by mitochondria in this process has been investigated. Using the mitochondria-specific fluorescent dyes MitoTracker Green and Rhodamine 123, these organelles appeared as a bright belt concentrated mainly around the secretory granule area. We tested the effects of two different types of mitochondrial inhibitor on the cytosolic Ca(2+) concentration using simultaneous imaging of Ca(2+)-sensitive fluorescence (Fura 2) and electrophysiology. When carbonyl cyanide m-chlorophenylhydrazone (CCCP) was applied in the presence of the Ca(2+)-releasing messenger inositol 1,4, 5-trisphosphate (IP(3)), the local repetitive Ca(2+) responses in the granule area were transformed into a global rise in the cellular Ca(2+) concentration. In the absence of IP(3), CCCP had no effect on the cytosolic Ca(2+) levels. Antimycin and antimycin + oligomycin had the same effect as CCCP. Active mitochondria, strategically placed around the secretory pole, block Ca(2+) diffusion from the primary Ca(2+) release sites in the granule-rich area in the apical pole to the basal part of the cell containing the nucleus. When mitochondrial function is inhibited, this barrier disappears and the Ca(2+) signals spread all over the cytosol.

Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells.

Many hormones and neurotransmitters evoke Ca2+ release from intracellular stores, often triggering agonist-specific signatures of intracellular Ca2+ concentration. Inositol trisphosphate (InsP3) and cyclic adenosine 5'-diphosphate-ribose (cADPR) are established Ca2+-mobilizing messengers that activate Ca2+ release through intracellular InsP3 and ryanodine receptors, respectively. However, in pancreatic acinar cells, neither messenger can explain the complex pattern of Ca2+ signals triggered by the secretory hormone cholecystokinin (CCK). We show here that the Ca2+-mobilizing molecule nicotinic acid adenine dinucleotide phosphate (NAADP), an endogenous metabolite of beta-NADP, triggers a Ca2+ response that varies from short-lasting Ca2+ spikes to a complex mixture of short-lasting (1-2s) and long-lasting (0.2-1 min) Ca2+ spikes. Cells were significantly more sensitive to NAADP than to either cADPR or InsP3, whereas higher concentrations of NAADP selectively inactivated CCK-evoked Ca2+ signals in pancreatic acinar cells, indicating that NAADP may function as an intracellular messenger in mammalian cells.

Intracellular glucose switches between cyclic ADP-ribose and inositol trisphosphate triggering of cytosolic Ca2+ spiking.

Cyclic ADP-ribose (cADPR) is a potentially important intracellular Ca2+ releasing messenger [1-5]. In pancreatic acinar cells where intracellular infusion of both inositol trisphosphate (IP3) and cADPR evoke repetitive Ca2+ spiking [6], the cADPR antagonist 8-NH2-cADPR [7], which blocks cADPR-evoked but not IP3-evoked Ca2+ spiking, can abolish Ca2+ spiking induced by physiological levels of the peptide hormone cholecystokinin (CCK) [8]. We have tested the effect of intracellular glucose on the ability of IP3, cADPR and CCK to induce cytosolic Ca2+ spikes in pancreatic acinar cells. In order to gain access to the intracellular cytosol, we used the whole-cell configuration of the patch-clamp technique [9] and monitored cytosolic Ca2+ concentration changes by measuring the Ca(2+)-dependent ionic current [10-13]. Glucose (300 microM to 10 mM) in the patch pipette/intracellular solution prevented cADPR from evoking Ca2+ spiking. The same effect was observed with 2-deoxy-glucose, but not L-glucose. In contrast, glucose potentiated IP3-evoked Ca2+ spiking. CCK evoked Ca2+ spiking irrespective of the presence or absence of intracellular glucose, but the cADPR antagonist 8-NH2-cADPR blocked CCK-evoked Ca2+ spiking only in the absence of intracellular glucose. This suggests that the hormone can evoke Ca2+ spiking via either the IP3 or the cADPR pathway. The intracellular glucose level may control a switch between these two pathways.

The cyclic ADP ribose antagonist 8-NH2-cADP-ribose blocks cholecystokinin-evoked cytosolic Ca2+ spiking in pancreatic acinar cells.

In order to investigate the possible involvement of cyclic ADP ribose as an intracellular messenger for hormone-evoked cytosolic Ca2+ signalling, we performed experiments on intracellularly perfused mouse pancreatic acinar cells. Both a stable inositol 1,4,5 trisphosphate analogue (IP3) and cyclic ADP ribose (cADPR) evoked regular spikes of Ca2+ dependent ion current, reflecting cytosolic Ca2+ spiking. The effect of cADPR, but not IP3, was abolished by the presence intracellularly of the cADPR antagonist 8-NH2-cADPR. External application of cholecystokinin (CCK) in a physiological concentration (2.5-5 pM) evoked a mixture of short-lasting and longer-lasting spikes of Ca2+-dependent ion current. These effects were abolished by the presence intracellularly of 8-NH2-cADPR (18 muM). Increasing the CCK concentration to 15 pM could overcome the inhibition by 18 muM of the antagonist. These experiments provide fresh evidence for the involvement of cADPR receptors in the hormone-evoked cytosolic Ca2+ signalling process in pancreatic acinar cells.

Involvement of cAMP in the regulation of high affinity choline uptake by rat brain synaptosomes.

The role of cAMP in the regulation of the high affinity choline uptake (HACU) was investigated in resting and KCl-stimulated rat brain synaptosomes. The data indicate that the permeable cAMP analogue, monobutyryl-8-bromo cAMP, increased dose-dependently the HACU in resting synaptosomes. Treatments of resting synaptosomes by oxotremorine, quinacrine, and promethazine resulted in a reduced cAMP formation with a concomitant decrease of HACU. The reduction of HACU could be completely counteracted by the monobutyryl-8-bromo cAMP following oxotremorine treatment and was only partially inhibited in quinacrine and promethazine treated resting synaptosomes. KCl stimulation resulted in a significant increase in cAMP formation and HACU by the synaptosomes. The different profile of data obtained following the previous pharmacological treatments in KCl-stimulated synaptosomes suggests that both cAMP and phospholipase A2 pathways may act synergistically to coordinate the neuronal choline incorporation.

Acidosis-induced modifications of high-affinity choline uptake by synaptosomes: effects of pH readjustment.

Acidosis (pH 6.0) led to significant decrease in high-affinity choline uptake by rat brain synaptosomes. The effects persisted following pH readjustment (7.4) of the incubation medium, consisting of decrease in both Km and Vmax of the affinity system. pH readjustment coincided with synaptosomal leakage of lactate dehydrogenase (LDH) and with instability of the synaptosomal suspension as evidenced from turbidity modifications of the preparation. LDH leakage occurred when acidosis was performed with lactic acid, whereas it was not seen following H3PO4 acidosis, probably because of the rapid diffusion of the protonated from of lactic acid across membranes. Turbidity modifications of the suspension were prevented by EDTA. The present results indicate that acidosis to pH level comparable to what is observed in brain ischemia is deleterious for cholinergic mechanisms. They also suggest that alkaline pH shifts that occur after blood reperfusion of ischemic brain tissue might be critical for the survival of cells.

Effects of iron-induced lipid peroxidation and of acidosis on choline uptake by synaptosomes.

The effects of iron-induced lipid peroxidation and of lactic acidosis on [3H]choline uptake were investigated on crude synaptosomes prepared from rat cerebral cortices. Fe(2+)-induced lipid peroxidation as evidenced from the production of thiobarbituric acid reactives substances (TBARS) was correlated with a decrease in high-affinity choline uptake (HACU). Trolox C, a free radical scavenger, prevented both Fe(2+)-induced TBARS production and decrease in HACU. Lactic acidosis (pH 6.0 for 30 or 60 min) increased the TBARS production with concomitant decrease in HACU (-48%, -78%, respectively). The acidosis dependent decrease was not reversible following pH 7.4 readjustment after 60 min acidosis. It was not prevented by trolox C, although trolox C inhibited the acidosis-induced production of TBARS. The results suggest that the contribution of acidosis to peroxidative damages is probably of less importance in comparison to other cytotoxic mechanisms.