Decompression scenarios in a new underground transportation system

BACKGROUND: The risks of a public exposure to a sudden decompression, until now, have been related to civil aviation and, at a lesser extent, to diving activities. However, engineers are currently planning the use of low pressure environments for underground transportation. This method has been proposed for the future Swissmetro, a high-speed underground train designed for inter-urban linking in Switzerland. HYPOTHESIS: The use of a low pressure environment in an underground public transportation system must be considered carefully regarding the decompression risks. Indeed, due to the enclosed environment, both decompression kinetics and safety measures may differ from aviation decompression cases. METHOD: A theoretical study of decompression risks has been conducted at an early stage of the Swissmetro project. A three-compartment theoretical model, based on the physics of fluids, has been implemented with flow processing software (Ithink 5.0). Simulations have been conducted in order to analyze "decompression scenarios" for a wide range of parameters, relevant in the context of the Swissmetro main study. RESULTS: Simulation results cover a wide range from slow to explosive decompression, depending on the simulation parameters. Not surprisingly, the leaking orifice area has a tremendous impact on barotraumatic effects, while the tunnel pressure may significantly affect both hypoxic and barotraumatic effects. Calculations have also shown that reducing the free space around the vehicle may mitigate significantly an accidental decompression. CONCLUSION: Numeric simulations are relevant to assess decompression risks in the future Swissmetro system. The decompression model has proven to be useful in assisting both design choices and safety management.

New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.

BACKGROUND: Lactate protects mice against the ischaemic damage resulting from transient middle cerebral artery occlusion (MCAO) when administered intracerebroventricularly at reperfusion, yielding smaller lesion sizes and a better neurological outcome 48 h after ischaemia. We have now tested whether the beneficial effect of lactate is long-lasting and if lactate can be administered intravenously. METHODS: Male ICR-CD1 mice were subjected to 15-min suture MCAO under xylazine + ketamine anaesthesia. Na L-lactate (2 µl of 100 mmol/l) or vehicle was administered intracerebroventricularly at reperfusion. The neurological deficit was evaluated using a composite deficit score based on the neurological score, the rotarod test and the beam walking test. Mice were sacrificed at 14 days. In a second set of experiments, Na L-lactate (1 µmol/g body weight) was administered intravenously into the tail vein at reperfusion. The neurological deficit and the lesion volume were measured at 48 h. RESULTS: Intracerebroventricularly injected lactate induced sustained neuroprotection shown by smaller neurological deficits at 7 days (median = 0, min = 0, max = 3, n = 7 vs. median = 2, min = 1, max = 4.5, n = 5, p < 0.05) and 14 days after ischaemia (median = 0, min = 0, max = 3, n = 7 vs. median = 3, min = 0.5, max = 3, n = 7, p = 0.05). Reduced tissue damage was demonstrated by attenuated hemispheric atrophy at 14 days (1.3 ± 4.0 mm(3), n = 7 vs. 12.1 ± 3.8 mm(3), n = 5, p < 0.05) in lactate-treated animals. Systemic intravenous lactate administration was also neuroprotective and attenuated the deficit (median = 1, min = 0, max = 2.5, n = 12) compared to vehicle treatment (median = 1.5, min = 1, max = 8, n = 12, p < 0.05) as well as the lesion volume at 48 h (13.7 ± 12.2 mm(3), n = 12 vs. 29.6 ± 25.4 mm(3), n = 12, p < 0.05). CONCLUSIONS: The beneficial effect of lactate is long-lasting: lactate protects the mouse brain against ischaemic damage when supplied intracerebroventricularly during reperfusion with behavioural and histological benefits persisting 2 weeks after ischaemia. Importantly, lactate also protects after systemic intravenous administration, a more suitable route of administration in a clinical emergency setting. These findings provide further steps to bring this physiological, commonly available and inexpensive neuroprotectant closer to clinical translation for stroke.

Limited role of the c-Jun N-terminal kinase pathway in a neonatal rat model of cerebral hypoxia-ischemia

D-JNKI1, a cell-permeable peptide inhibitor of the c-Jun N-terminal kinase (JNK) pathway, has been shown to be a powerful neuroprotective agent after focal cerebral ischemia in adult mice and young rats. We have investigated the potential neuroprotective effect of D-JNKI1 and the involvement of the JNK pathway in a neonatal rat model of cerebral hypoxia-ischemia. Seven-day-old rats underwent a permanent ligation of the right common carotid artery followed by 2h of hypoxia (8% oxygen). Treatment with D-JNKI1 (0.3mg/kg intraperitoneally) significantly reduced early calpain activation, late caspase-3 activation and, in the thalamus, autophagosome formation, indicating an involvement of JNK in different types of cell death: necrotic, apoptotic and autophagic. However the size of the lesion was unchanged. Further analysis showed that neonatal hypoxia-ischemia induced an immediate decrease in JNK phosphorylation (reflecting mainly P-JNK1) followed by a slow progressive increase (including P-JNK3 54kDa), whereas c-jun and c-fos expression were both strongly activated immediately after hypoxia-ischemia. In conclusion, unlike in adult ischemic models, JNK is only moderately activated after severe cerebral hypoxia-ischemia in neonatal rats and the observed positive effects of D-JNKI1 are insufficient to give neuroprotection. Thus, for perinatal asphyxia, D-JNKI1 can only be considered in association with other therapies.

Cerebral oxygenation during the Richalet hypoxia sensitivity test and cycling time-trial performance in severe hypoxia.

BACKGROUND: The Richalet hypoxia sensitivity test (RT), which quantifies the cardiorespiratory response to acute hypoxia during exercise at an intensity corresponding to a heart rate of ~130 bpm in normoxia, can predict susceptibility of altitude sickness. Its ability to predict exercise performance in hypoxia is unknown. OBJECTIVES: Investigate: (1) whether cerebral blood flow (CBF) and cerebral tissue oxygenation (O2Hb; oxygenated hemoglobin, HHb; deoxygenated hemoglobin) responses during RT predict time-trial cycling (TT) performance in severe hypoxia; (2) if subjects with blunted cardiorespiratory responses during RT show greater impairment of TT performance in severe hypoxia. STUDY DESIGN: Thirteen men [27 ± 7 years (mean ± SD), Wmax: 385 ± 30 W] were evaluated with RT and the results related to two 15 km TT, in normoxia and severe hypoxia (FIO2 = 0.11). RESULTS: During RT, mean middle cerebral artery blood velocity (MCAv: index of CBF) was unaltered with hypoxia at rest (p > 0.05), while it was increased during normoxic (+22 ± 12 %, p < 0.05) and hypoxic exercise (+33 ± 17 %, p < 0.05). Resting hypoxia lowered cerebral O2Hb by 2.2 ± 1.2 μmol (p < 0.05 vs. resting normoxia); hypoxic exercise further lowered it to -7.6 ± 3.1 μmol below baseline (p < 0.05). Cerebral HHb, increased by 3.5 ± 1.8 μmol in resting hypoxia (p < 0.05), and further to 8.5 ± 2.9 μmol in hypoxic exercise (p < 0.05). Changes in CBF and cerebral tissue oxygenation during RT did not correlate with TT performance loss (R = 0.4, p > 0.05 and R = 0.5, p > 0.05, respectively), while tissue oxygenation and SaO2 changes during TT did (R = -0.76, p < 0.05). Significant correlations were observed between SaO2, MCAv and HHb during RT (R = -0.77, -0.76 and 0.84 respectively, p < 0.05 in all cases). CONCLUSIONS: CBF and cerebral tissue oxygenation changes during RT do not predict performance impairment in hypoxia. Since the changes in SaO2 and brain HHb during the TT correlated with performance impairment, the hypothesis that brain oxygenation plays a limiting role for global exercise in conditions of severe hypoxia remains to be tested further.

Dynamic model of the left ventricle for use in simulation of myocardial perfusion SPECT and gated SPECT

Simulation is a useful tool in cardiac SPECT to assess quantification algorithms. However, simple equation-based models are limited in their ability to simulate realistic heart motion and perfusion. We present a numerical dynamic model of the left ventricle, which allows us to simulate normal and anomalous cardiac cycles, as well as perfusion defects. Bicubic splines were fitted to a number of control points to represent endocardial and epicardial surfaces of the left ventricle. A transformation from each point on the surface to a template of activity was made to represent the myocardial perfusion. Geometry-based and patient-based simulations were performed to illustrate this model. Geometry-based simulations modeled ~1! a normal patient, ~2! a well-perfused patient with abnormal regional function, ~3! an ischaemic patient with abnormal regional function, and ~4! a patient study including tracer kinetics. Patient-based simulation consisted of a left ventricle including a realistic shape and motion obtained from a magnetic resonance study. We conclude that this model has the potential to study the influence of several physical parameters and the left ventricle contraction in myocardial perfusion SPECT and gated-SPECT studies.

Predicting neurological outcome after cardiac arrest.

Purpose of reviewTherapeutic hypothermia and aggressive management of postresuscitation disease considerably improved outcome after adult cardiac arrest over the past decade. However, therapeutic hypothermia alters prognostic accuracy. Parameters for outcome prediction, validated by the American Academy of Neurology before the introduction of therapeutic hypothermia, need further update.Recent findingsTherapeutic hypothermia delays the recovery of motor responses and may render clinical evaluation unreliable. Additional modalities are required to predict prognosis after cardiac arrest and therapeutic hypothermia. Electroencephalography (EEG) can be performed during therapeutic hypothermia or shortly thereafter; continuous/reactive EEG background strongly predicts good recovery from cardiac arrest. On the contrary, unreactive/spontaneous burst-suppression EEG pattern, together with absent N20 on somatosensory evoked potentials (SSEP), is almost 100% predictive of irreversible coma. Therapeutic hypothermia alters the predictive value of serum markers of brain injury [neuron-specific enolase (NSE), S-100B]. Good recovery can occur despite NSE levels >33 mu g/l, thus this cut-off value should not be used to guide therapy. Diffusion MRI may help predicting long-term neurological sequelae of hypoxic-ischemic encephalopathy.SummaryAwakening from postanoxic coma is increasingly observed, despite early absence of motor signs and frank elevation of serum markers of brain injury. A new multimodal approach to prognostication is therefore required, which may particularly improve early prediction of favorable clinical evolution after cardiac arrest.

A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland.

OBJECTIVE: To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS). METHODS: Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age ≥75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label. RESULTS: After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel. CONCLUSIONS: In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel. CLINICAL TRIAL REGISTRATION NUMBER: SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416.

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

Prooxidant/Antioxidant Balance in Hypoxia: A Cross-Over Study on Normobaric vs. Hypobaric "Live High-Train Low".

"Live High-Train Low" (LHTL) training can alter oxidative status of athletes. This study compared prooxidant/antioxidant balance responses following two LHTL protocols of the same duration and at the same living altitude of 2250 m in either normobaric (NH) or hypobaric (HH) hypoxia. Twenty-four well-trained triathletes underwent the following two 18-day LHTL protocols in a cross-over and randomized manner: Living altitude (PIO2 = 111.9 ± 0.6 vs. 111.6 ± 0.6 mmHg in NH and HH, respectively); training "natural" altitude (~1000-1100 m) and training loads were precisely matched between both LHTL protocols. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP) and nitrotyrosine] and antioxidant markers [ferric-reducing antioxidant power (FRAP), superoxide dismutase (SOD) and catalase], NO metabolism end-products (NOx) and uric acid (UA) were determined before (Pre) and after (Post) the LHTL. Cumulative hypoxic exposure was lower during the NH (229 ± 6 hrs.) compared to the HH (310 ± 4 hrs.; P<0.01) protocol. Following the LHTL, the concentration of AOPP decreased (-27%; P<0.01) and nitrotyrosine increased (+67%; P<0.05) in HH only. FRAP was decreased (-27%; P<0.05) after the NH while was SOD and UA were only increased following the HH (SOD: +54%; P<0.01 and UA: +15%; P<0.01). Catalase activity was increased in the NH only (+20%; P<0.05). These data suggest that 18-days of LHTL performed in either NH or HH differentially affect oxidative status of athletes. Higher oxidative stress levels following the HH LHTL might be explained by the higher overall hypoxic dose and different physiological responses between the NH and HH.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial.

BACKGROUND: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. METHODS: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. RESULTS: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). CONCLUSION: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.

Is altitude training an efficient treatment for obesity?

Worldwide, about half the adult population is considered overweight as defined by a body mass index (BMI - calculated by body weight divided by height squared) ratio in excess of 25 kg.m-2. Of these individuals, half are clinically obese (with a BMI in excess of 30) and these numbers are still increasing, notably in developing countries such as those of the Middle East region. Obesity is a disorder characterised by increased mass of adipose tissue (excessive fat accumulation) that is the result of a systemic imbalance between food intake and energy expenditure. Although factors such as family history, sedentary lifestyle, urbanisation, income and family diet patterns determine obesity prevalence, the main underlying causes are poor knowledge about food choice and lack of physical activity3. Current obesity treatments include dietary restriction, pharmacological interventions and ultimately, bariatric surgery. The beneficial effects of physical activity on weight loss through increased energy expenditure and appetite modulation are also firmly established. Another viable option to induce a negative energy balance, is to incorporate hypoxia per se or combine it with exercise in an individual's daily schedule. This article will present recent evidence suggesting that combining hypoxic exposure and exercise training might provide a cost-effective strategy for reducing body weight and improving cardio-metabolic health in obese individuals. The efficacy of this approach is further reinforced by epidemiological studies using large-scale databases, which evidence a negative relationship between altitude of habitation and obesity. In the United States, for instance, obesity prevalence is inversely associated with altitude of residence and urbanisation, after adjusting for temperature, diet, physical activity, smoking and demographic factors.

Comparison of Griffiths-II and Bayley-II tests for the developmental assessment of high-risk infants.

INTRODUCTION: Two important risk factors for abnormal neurodevelopment are preterm birth and neonatal hypoxic ischemic encephalopathy. The new revisions of Griffiths Mental Development Scale (Griffiths-II, [1996]) and the Bayley Scales of Infant Development (BSID-II, [1993]) are two of the most frequently used developmental diagnostics tests. The Griffiths-II is divided into five subscales and a global development quotient (QD), and the BSID-II is divided into two scales, the Mental scale (MDI) and the Psychomotor scale (PDI). The main objective of this research was to establish the extent to which developmental diagnoses obtained using the new revisions of these two tests are comparable for a given child. MATERIAL AND METHODS: Retrospective study of 18-months-old high-risk children examined with both tests in the follow-up Unit of the Clinic of Neonatology of our tertiary care university Hospital between 2011 and 2012. To determine the concurrent validity of the two tests paired t-tests and Pearson product-moment correlation coefficients were computed. Using the BSID-II as a gold standard, the performance of the Griffiths-II was analyzed with receiver operating curves. RESULTS: 61 patients (80.3% preterm, 14.7% neonatal asphyxia) were examined. For the BSID-II the MDI mean was 96.21 (range 67-133) and the PDI mean was 87.72 (range 49-114). For the Griffiths-II, the QD mean was 96.95 (range 60-124), the locomotors subscale mean was 92.57 (range 49-119). The score of the Griffiths locomotors subscale was significantly higher than the PDI (p<0.001). Between the Griffiths-II QD and the BSID-II MDI no significant difference was found, and the area under the curve was 0.93, showing good validity. All correlations were high and significant with a Pearson product-moment correlation coefficient >0.8. CONCLUSIONS: The meaning of the results for a given child was the same for the two tests. Two scores were interchangeable, the Griffiths-II QD and the BSID-II MDI.

Corticosteroids and the retina: a role for the mineralocorticoid receptor.

PURPOSE OF REVIEW: Long-lasting devices releasing steroids have been approved recently for macular edema of various origins. Identification of the retina as a novel mineralo-sensitive tissue also raises new therapeutic options. RECENT FINDINGS: Recently, the over activation of the mineralocorticoid receptor (MR) pathway has been shown to cause fluid accumulation in the retina, choroidal vasodilation, and to promote retinal neovascularization in hypoxic conditions. These findings indicate that MR antagonists could have beneficial effects in the treatment of retinal diseases. Central serous chorioretinopathy is a retinal disease associated with choroidal vasodilation and subretinal fluid that affects mostly men with type A personality and occurrence has been associated with steroid intake. In several independent studies, MR antagonists have shown beneficial effects, significantly reducing subretinal fluid in eyes of chronic central serous chorioretinopathy patients. SUMMARY: The role of MR in retinal disorder is emerging and the potential association with psychological traits is considered. The place of MR antagonists for retinal diseases treatment is discussed.