A Single Residue within the MCR-1 Protein Confers Anticipatory Resilience.

The envelope stress response (ESR) of Gram-negative enteric bacteria senses fluctuations in nutrient availability and environmental changes to avert damage and promote survival. It has a protective role toward antimicrobials, but direct interactions between ESR components and antibiotic resistance genes have not been demonstrated. Here, we report interactions between a central regulator of ESR viz., the two-component signal transduction system CpxRA (conjugative pilus expression), and the recently described mobile colistin resistance protein (MCR-1). Purified MCR-1 is specifically cleaved within its highly conserved periplasmic bridge element, which links its N-terminal transmembrane domain with the C-terminal active-site periplasmic domain, by the CpxRA-regulated serine endoprotease DegP. Recombinant strains harboring cleavage site mutations in MCR-1 are either protease resistant or degradation susceptible, with widely differing consequences for colistin resistance. Transfer of the gene encoding a degradation-susceptible mutant to strains that lack either DegP or its regulator CpxRA restores expression and colistin resistance. MCR-1 production in Escherichia coli imposes growth restriction in strains lacking either DegP or CpxRA, effects that are reversed by transactive expression of DegP. Excipient allosteric activation of the DegP protease specifically inhibits growth of isolates carrying mcr-1 plasmids. As CpxRA directly senses acidification, growth of strains at moderately low pH dramatically increases both MCR-1-dependent phosphoethanolamine (PEA) modification of lipid A and colistin resistance levels. Strains expressing MCR-1 are also more resistant to antimicrobial peptides and bile acids. Thus, a single residue external to its active site induces ESR activity to confer resilience in MCR-1-expressing strains to commonly encountered environmental stimuli, such as changes in acidity and antimicrobial peptides. Targeted activation of the nonessential protease DegP can lead to the elimination of transferable colistin resistance in Gram-negative bacteria. IMPORTANCE The global presence of transferable mcr genes in a wide range of Gram-negative bacteria from clinical, veterinary, food, and aquaculture environments is disconcerting. Its success as a transmissible resistance factor remains enigmatic, because its expression imposes fitness costs and imparts only moderate levels of colistin resistance. Here, we show that MCR-1 triggers regulatory components of the envelope stress response, a system that senses fluctuations in nutrient availability and environmental changes, to promote bacterial survival in low pH environments. We identify a single residue within a highly conserved structural element of mcr-1 distal to its catalytic site that modulates resistance activity and triggers the ESR. Using mutational analysis, quantitative lipid A profiling and biochemical assays, we determined that growth in low pH environments dramatically increases colistin resistance levels and promotes resistance to bile acids and antimicrobial peptides. We exploited these findings to develop a targeted approach that eliminates mcr-1 and its plasmid carriers.

Carry-Over Quality of Pre-acclimatization to Altitude Elicited by Intermittent Hypoxia: A Participant-Blinded, Randomized Controlled Trial on Antedated Acclimatization to Altitude.

Intermittent normobaric hypoxia (IH) is increasingly used to pre-acclimatize for a sojourn to high altitude. There is a number of hypoxia - protocols observing the hypoxic ventilatory response (HVR), but little is known about the carry - over quality of the Lake Louise Score (LLS). We thus studied a week - long, 1 h per day poikilocapnic hypoxia protocol on whether acclimatization could be carried over for one week. Rationale for this was that it usually takes one week to get from Europe, Britain or the United States to the base camp of a major mountain. Forty-nine healthy volunteers of both sexes were exposed to daily bouts of 1 h at an inspiratory fraction of oxygen (FiO2) of 0.11 or 0.21 (control) for 7 consecutive days. Seven days after cessation of IH or sham exposures participants were again subjected to hypoxia (FiO2 = 0.11) for 6 h and measurements of isocapnic HVR and blood gases out of the arterialized earlobe were taken and LLS was assessed. In those with IH exposures LLS was reduced which was not the case in those with sham exposure (87 vs. 50%). Changes in HVR or the arterial hemoglobin saturation were not observed. Gender neither affected LLS nor HVR nor blood gases or carry -over quality. We found that our week - long, hypoxia protocol grants a reduction in LLS that can be carried over the time span of one week. In this way, antedated acclimatization may improve safety and comfort on the mountain.

Systemic Blood Pressure Variation During a 12-Hour Exposure to Normobaric Hypoxia (4500 m).

This study was aimed at evaluating a potential association between blood pressure variation and acute mountain sickness (AMS) during acute exposure to normobaric hypoxia. A total of 77 healthy subjects (43 males, 34 females) were exposed to a simulated altitude of 4500 m for 12 hours. Peripheral oxygen saturation, heart rate, systemic blood pressure, and Lake Louise AMS scores were recorded before and during (30 minutes, 3, 6, 9, and 12 hours) hypoxic exposure. Blood pressure dips were observed at 3-hour mark. However, systolic blood pressure fell more pronounced from baseline during the initial 30 minutes in normobaric hypoxia (-17.5 vs. -11.0 mmHg, p = 0.01) in subjects suffering from AMS (AMS+; n = 56) than in those remaining unaffected from AMS (AMS-; n = 21); values did not differ between groups over the subsequent time course. Our data may suggest a transient autonomic dysfunction resulting in a more pronounced blood pressure drop during initial hypoxic exposure in AMS+ compared with AMS- subjects.

Is decision making in hypoxia affected by pre-acclimatisation? A randomized controlled trial.

INTRODUCTION: Decision making is impaired in hypoxic environments, which may have serious or even lethal consequences for mountaineers. An acclimatisation period prior to high altitude exposures may help to overcome adverse effects of hypoxia. Thus, we investigated possible effects of short-term pre-acclimatisation on decision making in hypoxia. METHODS: In a randomized controlled study design, 52 healthy participants were allocated to a hypoxia group (HG: short-term pre-acclimatisation by the use of intermittent hypoxia 7×1h at FiO2=12.6%, equivalent to 4500m) or a control group (CG: sham pre-acclimatisation 7×1h at FiO2=20.9%, equivalent to 600m). The number of risky decisions was assessed using the Game of Dice Task at four time points during a 12-hours stay in hypoxia (FiO2=12.6%). RESULTS: 42 (HG: 27, CG: 25) participants completed the study. The number of risky decisions was significantly (p=0.048 as determined by 4×2 ANCOVA) reduced in the hypoxia group compared to the control group, partial η2=0.11, when the age-effect on decision making was controlled. Self-reported positive affective valence prior to decision making was negatively related to the number of risky decisions, r<-0.38. CONCLUSION: Short-term pre-acclimatisation might influence decision making in hypoxia in a positive way and might be considered as a risk-reducing preparation method prior to exposures to hypoxic environments. Positive affective states seem to have a medium-sized protective effect against risky decision making.

Is acute mountain sickness related to trait anxiety? A normobaric chamber study.

INTRODUCTION: Some mountaineers are more prone to the occurrence of acute mountain sickness (AMS) than others. State anxiety during altitude exposure might be associated with AMS development. We hypothesized that trait anxiety might be higher in AMS cases compared to non-AMS cases. The aim of the present study was to study the relationship between AMS development and trait anxiety. METHODS: In an observational study design, AMS incidence during a 12-hour exposure to normobaric hypoxia (FiO2=12.6%, equivalent to 4500m) was determined by the Lake Louise Scoring System. Trait anxiety (State Trait Anxiety Inventory) and confounding variables were assessed in a follow-up questionnaire (37months after hypoxic exposure). RESULTS: Twenty nine participants returned the follow-up questionnaire. AMS incidence was 38%. Both unadjusted and adjusted logistic regression analyses did not reveal trait anxiety as a significant variable in relation to AMS. DISCUSSION: Based on the findings of this preliminary study, there is no evidence that AMS development under normobaric conditions is related to trait anxiety. Differences to previous studies might be explained by the type of hypoxia, by different sample characteristics and by considering sleep disturbances in the calculation of the AMS score. However, future studies with larger sample sizes may help to clear the relationship between AMS development and the personality factor anxiety.

Hypoxia triggers high-altitude headache with migraine features: A prospective trial.

BACKGROUND: Given the high prevalence and clinical impact of high-altitude headache (HAH), a better understanding of risk factors and headache characteristics may give new insights into the understanding of hypoxia being a trigger for HAH or even migraine attacks. METHODS: In this prospective trial, we simulated high altitude (4500 m) by controlled normobaric hypoxia (FiO2 = 12.6%) to investigate acute mountain sickness (AMS) and headache characteristics. Clinical symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after six and 12 hours in hypoxia. O2 saturation was measured using pulse oximetry at the respective time points. History of primary headache, especially episodic or chronic migraine, was a strict exclusion criterion. FINDINGS: In total 77 volunteers (43 (55.8%) males, 34 (44.2%) females) were enrolled in this study. Sixty-three (81.18%) and 40 (71.4%) participants developed headache at six or 12 hours, respectively, with height and SpO2 being significantly different between headache groups at six hours (p < 0.05). Binary logistic regression model revealed a significant association of SpO2 and headache development (p < 0.05, OR 1.123, 95% CI 1.001-1.259). In a subgroup of participants, with history of migraine being a strict exclusion criterion, hypoxia triggered migraine-like headache according to the International Classification of Headache Disorders (ICHD-3 beta) in n = 5 (8%) or n = 6 (15%), at six and 12 hours, respectively. INTERPRETATION: Normobaric hypoxia is a trigger for HAH and migraine-like headache attacks even in healthy volunteers without any history of migraine. Our study confirms the pivotal role of hypoxia in the development of AMS and beyond that suggests hypoxia may be involved in migraine pathophysiology.

Influence of Acute Normobaric Hypoxia on Hemostasis in Volunteers with and without Acute Mountain Sickness.

INTRODUCTION: The aim of the present study was to investigate whether a 12-hour exposure in a normobaric hypoxic chamber would induce changes in the hemostatic system and a procoagulant state in volunteers suffering from acute mountain sickness (AMS) and healthy controls. MATERIALS AND METHODS: 37 healthy participants were passively exposed to 12.6% FiO2 (simulated altitude hypoxia of 4,500 m). AMS development was investigated by the Lake Louise Score (LLS). Prothrombin time, activated partial thromboplastin time, fibrinogen, and platelet count were measured and specific methods (i.e., thromboelastometry and a thrombin generation test) were used. RESULTS: AMS prevalence was 62.2% (LLS cut off of 3). For the whole group, paired sample t-tests showed significant increase in the maximal concentration of generated thrombin. ROTEM measurements revealed a significant shortening of coagulation time and an increase of maximal clot firmness (InTEM test). A significant increase in maximum clot firmness could be shown (FibTEM test). CONCLUSIONS: All significant changes in coagulation parameters after exposure remained within normal reference ranges. No differences with regard to measured parameters of the hemostatic system between AMS-positive and -negative subjects were observed. Therefore, the hypothesis of the acute activation of coagulation by hypoxia can be rejected.

Symptom progression in acute mountain sickness during a 12-hour exposure to normobaric hypoxia equivalent to 4500 m.

The diagnosis and quantification of severity of acute mountain sickness (AMS) continue to be problematic. What symptoms should be included in a score and how to weigh any given symptom in the total score remain matter of debate. Seventy seven healthy male (n=43) and female (n=34) volunteers, aged between 18 and 42 years, were exposed to normobaric hypoxia (Fio2=12.6%≙4500 m) for 12 hours. Symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after 30 min, 3, 6, 9, and 12 hours in hypoxia. AMS scores continued to increase steeply during the entire hypoxia exposure in subjects suffering from AMS (LLS>2). Headache was the predominant symptom and the severity of nausea progressed faster in subjects who left the hypoxia room prematurely (severely affected by AMS) compared to those moderately affected (LLS>2 but completing the 12-h hypoxia exposure). Whereas headache scores up to 6 hours in hypoxia were not correlated with other AMS symptoms, nausea was correlated with dizziness and fatigue (r=0.45 and 0.56, p<0.01). Cluster analysis identified three different distributions of symptom severity compatible with being very likely free of AMS (cluster 1), compatible with very likely suffering from AMS (cluster 3), and compatible with ambiguous allocation (cluster 2). In conclusion, our findings confirm that headache plus one or more of the symptoms nausea, dizziness, and fatigue of at least mild to moderate severity are required for diagnosis of AMS. The inter-relationship between nausea, dizziness, and fatigue, however, raises the question whether each of these symptoms should be given equal diagnostic weighting. The time course of symptom progression within the first hours at altitude may provide clinically important information on the severity of subsequent AMS development and will support the decision to start therapeutic intervention.

Resting arterial oxygen saturation and breathing frequency as predictors for acute mountain sickness development: a prospective cohort study.

INTRODUCTION: The study evaluated the predictive value of arterial oxygen saturation (SaO2) after 30-min hypoxic exposure on subsequent development of acute mountain sickness (AMS) and tested if additional resting cardio-respiratory measurements improve AMS prognosis. METHODS: Fifty-five persons were exposed to a simulated altitude of 4,500 m (normobaric hypoxia, FiO2 = 12.5%). Cardio-respiratory parameters, SaO2, blood lactate, and blood pressure were measured after 30 min of exposure. AMS symptoms were recorded after 3, 6, 9, and 12 h (Lake-Louise Score). Three models, based on previously published regression equations for altitude-dependent SaO2 values of AMS-susceptible (SaO2-suscept = 98.34 - 2.72 ∗ alt - 0.35 ∗ alt(2)) and AMS-resistant (SaO2-resist = 96.51 + 0.68 ∗ alt - 0.80 ∗ alt(2)) persons, were applied to predict AMS. Additionally, multivariate logistic regression analyses were conducted to test if additional resting measurements improve AMS prediction. RESULTS: The three models correctly predicted AMS development in 62%, 67%, and 69% of the cases. No model showed combined sensitivity and specificity >80%. Sequential logistic regression revealed that the inclusion of tidal volume or breathing frequency in addition to SaO2 improved overall AMS prediction, resulting in 78% and 80% correct AMS prediction, respectively. CONCLUSION: Non-invasive measurements of SaO2 after 30-min hypoxic exposure are easy to perform and have the potential to detect AMS-susceptible individuals with a sufficient sensitivity. The additional determination of breathing frequency can improve success in AMS prediction.

Association between body water status and acute mountain sickness.

PURPOSE: The present study determined the association between body fluid variation and the development of acute mountain sickness (AMS) in adults. METHODS: Forty-three healthy participants (26 males and 17 females, age: 26 ± 6 yr, height: 174 ± 9 cm, weight: 68 ± 12 kg) were passively exposed at a FiO2 of 12.6% (simulated altitude hypoxia of 4500 m, PiO2 = 83.9 mmHg) for 12-h. AMS severity was assessed using the Lake Louise Score (LLS). Food and drink intakes were consumed ad libitum and measured; all urine was collected. Before and after the 12-h exposure, body weight and plasma osmolality were measured and whole-body bioimpedance analysis was performed. RESULTS: The overall AMS incidence was 43% (38% males, 50% females). Participants who developed AMS showed lower fluid losses (3.0 ± 0.9 vs. 4.5 ± 2.0 ml/kg/h, p = 0.002), a higher fluid retention (1.9 ± 1.5 vs. 0.6 ± 0.8 ml/kg/h, p = 0.022), greater plasma osmolality decreases (-7 ± 7 vs. -2 ± 5 mOsm/kg, p = 0.028) and a larger plasma volume expansion (11 ± 10 vs. 1 ± 15%, p = 0.041) compared to participants not developing AMS. Net water balance (fluid intake--fluid loss) and the amount of fluid loss were strong predictors whether getting sick or not (Nagelkerkes r(2) = 0.532). The LLS score was related to net water balance (r = 0.358, p = 0.018), changes in plasma osmolality (r = -0.325, p = 0.033) and sodium concentration (r = -0.305, p = 0.047). Changes in the impedance vector length were related to weight changes (r = -0.550, p<0.001), fluid intake (r = -0.533, p<0.001) and net water balance (r = -0.590, p<0.001). CONCLUSIONS: Participants developing AMS within 12 hours showed a positive net water balance due to low fluid loss. Thus measures to avoid excess fluid retention are likely to reduce AMS symptoms.

Race performance and exercise intensity of male amateur mountain runners during a multistage mountain marathon competition are not dependent on muscle strength loss or cardiorespiratory fitness.

The aims of this study were to quantify the cardiorespiratory fitness level of amateur mountain runners and to characterize the related cardiorespiratory and muscular strain during a multistage competition. Therefore, 16 male amateur participants performed an incremental treadmill test before the Transalpine-Run 2010. Besides race time, heart rate (HR) was monitored using portable HR monitors during all stages, and countermovement jump ability was assessed after each stage. Overall race time and race times of the single stages were not related to any of the cardiorespiratory fitness parameters assessed during the incremental treadmill test (e.g., V[Combining Dot Above]O2max, ventilatory threshold). Average HR during the first stage was 81 ± 7% of the maximal HR and decreased to 73 ± 6% during the following stages. Creatine kinase activity as an indirect marker of muscle damage and strain amounted to 1,100 ± 619 U·L-1 after the third stage and was related to the decrease in the mean HR between stage 1 and stage 2 (r = -0.616, p < 0.05). Jump ability decreased continuously in the course of the race but was not related to exercise intensity. In conclusion, this study showed that race performance during a multistage mountain marathon does not depend on cardiorespiratory fitness parameters determined in the laboratory. Furthermore, the mean HR decreased after the first stage and remained constant during the following stages independent of the decreased muscle strength. We interpret these data to mean that performance differences were a result of insufficient recovery after the first day of multistage mountain running and the different individual pacing strategies. It is worth mentioning that also other factors, not determined in this investigation, could be responsible for the present outcomes (e.g., nutrition, genetics, psychological and environmental factors, or different training programs).

MRI evidence: acute mountain sickness is not associated with cerebral edema formation during simulated high altitude.

Acute mountain sickness (AMS) is a common condition among non-acclimatized individuals ascending to high altitude. However, the underlying mechanisms causing the symptoms of AMS are still unknown. It has been suggested that AMS is a mild form of high-altitude cerebral edema both sharing a common pathophysiological mechanism. We hypothesized that brain swelling and consequently AMS development is more pronounced when subjects exercise in hypoxia compared to resting conditions. Twenty males were studied before and after an eight hour passive (PHE) and active (plus exercise) hypoxic exposure (AHE) (F(i)O(2) = 11.0%, P(i)O(2)∼80 mmHg). Cerebral edema formation was investigated with a 1.5 Tesla magnetic resonance scanner and analyzed by voxel based morphometry (VBM), AMS was assessed using the Lake Louise Score. During PHE and AHE AMS was diagnosed in 50% and 70% of participants, respectively (p>0.05). While PHE slightly increased gray and white matter volume and the apparent diffusion coefficient, these changes were clearly more pronounced during AHE but were unrelated to AMS. In conclusion, our findings indicate that rest and especially exercise in normobaric hypoxia are associated with accumulation of water in the extracellular space, however independent of AMS development. Thus, it is suggested that AMS and HACE do not share a common pathophysiological mechanism.

Cardiac troponins in young marathon runners.

Cardiac troponin increases are common in adult marathon finishers. However, data on troponin values for young marathon runners are scarce. Forty young runners (20 healthy male and 20 female) 13 to 17 years old participated in this study. Blood samples were taken before, immediately after, and 24 hours after the race for determination of cardiac troponin T (cTnT) and troponin I (cTnI). Thirty-seven runners completed the race with a mean finishing time of 4 hours 53 minutes. No participant developed an adverse medical event during or after the race. In 30 of 37 participants, levels of cTnT and/or cTnI exceeded upper reference limits of 0.01 and 0.1 ng/ml immediately after the race, and in 3 participants these levels were even higher than the reference range for acute myocardial infarction (>0.1 and >0.5 ng/ml for cTnT and cTnI, respectively). Twenty-four hours after the race no participant had troponin levels exceeding the upper reference limits. Average increases of troponin levels did not differ between sexes. In conclusion, this is the first study to show that cardiac troponin levels increase to a similar extent in male and female adolescent marathon runners as observed in adults. Rapid recovery of troponin levels after a race is indicative of a physiologic rather than a pathologic response.

Short-term exposure to hypoxia for work and leisure activities in health and disease: which level of hypoxia is safe?

INTRODUCTION: Exposures to natural and simulated altitudes entail reduced oxygen availability and thus hypoxia. Depending on the level of hypoxia, the duration of exposure, the individual susceptibility, and preexisting diseases, health problems of variable severity may arise. Although millions of people are regularly or occasionally performing mountain sport activities, are transported by airplanes, and are more and more frequently exposed to short-term hypoxia in athletic training facilities or at their workplace, e.g., with fire control systems, there is no clear consensus on the level of hypoxia which is generally well tolerated by human beings when acutely exposed for short durations (hours to several days). CONCLUSIONS: Available data from peer-reviewed literature report adaptive responses even to altitudes below 2,000 m or corresponding normobaric hypoxia (F(i)O(2) > 16.4%), but they also suggest that most of exposed subjects without severe preexisting diseases can tolerate altitudes up to 3,000 m (F(i)O(2) > 14.5%) well. However, physical activity and unusual environmental conditions may increase the risk to get sick. Large interindividual variations of responses to hypoxia have to be expected, especially in persons with preexisting diseases. Thus, the assessment of those responses by hypoxic challenge testing may be helpful whenever possible.

Risk factors for high-altitude headache in mountaineers.

AIM: The aim was to identify most relevant risk factors of high-altitude headache within a broad mountaineering population through a prospective, observational, rater-blinded study. METHODS: A total of 506 mountaineers were enrolled after their first overnight stay in one of seven alpine huts between 2200-3817 m. Structured interview including information on mountaineering histories, caffeine intake, smoking habits, alcohol consumption, intake of medication, rate of ascent, physical fitness, the level of exertion and the amount of fluids intake at the day of ascent were recorded along with a standardized medical examination. RESULTS: High-altitude headache occurred in 31% of study participants. Logistic regression analysis revealed a migraine history, low arterial oxygen saturation, high ratings of perceived exertion and fluid intake below 2 l to be independent risk factors for the development of high-altitude headache. CONCLUSION: Given the high prevalence, high-altitude headache is a relevant medical condition and a better understanding of risk factors has important impact and may facilitate patient behaviour and future study design.

The prevalence of and risk factors for acute mountain sickness in the Eastern and Western Alps.

Acute mountain sickness (AMS) is the most common condition of high altitude illnesses. Its prevalence varies between 15% and 80% depending on the speed of ascent, absolute altitude reached, and individual susceptibility. Additionally, we assumed that the more experienced mountaineers of the Western Alps are less susceptible to developing AMS than recreational mountaineers of the Eastern Alps or tourist populations. Therefore, the main goals of the present study were the collection of data regarding the AMS prevalence and triggers in both the Eastern and Western Alps using identical methods. A total of 162 mountaineers, 79 in the Eastern Alps (3454 m) and 83 in the Western Alps (3817 m) were studied on the morning after their first night at high altitude. A diagnosis of AMS was based on a Lake Louise Score (LLS) ≥4, the presence of headache, and at least one additional symptom. Thirty of 79 subjects (38.0%) suffered from AMS at 3454 m in the Eastern Alps as did 29 of 83 (34.9%) at 3817 m in the Western Alps. After adjustment for altitude, the prevalence in the Western Alps constituted 24.5%, which differed significantly (p = 0.04) from that found in the Eastern Alps. The lower mountaineering experience of mountaineers in the Eastern Alps turned out to be the only factor for explaining their higher AMS prevalence. Thus, expert advice by mountain guides or experienced colleagues could help to reduce the AMS risk in these subjects.

Prevalence of acute mountain sickness in the Eastern Alps.

Little information is available on the prevalence of acute mountain sickness (AMS) in the Eastern Alps compared with the Western Alps. Because of differences regarding the populations of mountaineers, we hypothesized that the prevalence differs between the Eastern and Western Alps. Thus, we determined the prevalence and risk factors of AMS at four different altitudes in the Eastern Alps of Austria. Four hundred and thirty-one recreational hikers were studied using questionnaires on the morning of their first night at high altitude. A diagnosis of AMS was based on a Lake Louise Score > or =4, the presence of headache, and at least one additional symptom. Overall 16.2% of the subjects met the criteria for AMS, and the prevalence of AMS increased significantly with altitude (2200 m: 6.9%; 2500 m: 9.1%; 2800 m: 17.4%; 3500 m: 38.0%). Heavy perceived exertion, a history of migraine, the absolute altitude reached, little mountaineering experience, and inadequate water intake (< or =2 L) were independent AMS risk factors. The reported altitude-related AMS prevalence in the Western Alps is 4% to 8% lower compared with that found in this study for the Eastern Alps. In conclusion, the prevalence of AMS is higher in the tourist population of the Eastern Alps compared to the more experienced mountaineers of the Western Alps. Consideration of easily modifiable risk factors such as individual exertion and water intake could markedly reduce AMS and contribute to the enjoyment of mountaineering.

Ansiedade de separacao e Sindrome Borderline

O artigo apresenta um estudo sobre a Sindrome Borderline e busca um melhor entendimento da mesma para a pratica clinica. A fundamentacao teorica esta centrada na teoria do desenvolvimento emocional de Margareth Mahler, entre outros autores, que elucidam a genese dos estados limitrofes. Enfatiza a influencia da ansiedade de separacao no relacionamento mae/filho, o nao-estimulo a individuacao nos seus primeiros anos de vida. A experiencia pratica foi desenvolvida em um hospital-escola da Grande Porto Alegre.