Lower body negative pressure identifies altered central vein characteristics without accompanying changes to baroreflexes in astronauts within hours of landing.

Cardiovascular deconditioning and altered baroreflexes predispose returning astronauts to Orthostatic Intolerance. We assessed 7 astronauts (1 female) before and following long-duration spaceflight (146 ± 43 days) with minimal upright posture prior to testing. We applied lower body negative pressure (LBNP) of up to - 30 mmHg to supine astronauts instrumented for continual synchronous measurements of cardiovascular variables, and intermittent imaging the Portal Vein (PV) and Inferior Vena Cava (IVC). During supine rest without LBNP, postflight elevations to total peripheral resistance (TPR; 15.8 ± 4.6 vs. 20.8 ± 7.1 mmHg min/l, p < 0.05) and reductions in stroke volume (SV; 104.4 ± 16.7 vs. 87.4 ± 11.5 ml, p < 0.05) were unaccompanied by changes to heart rate (HR) or estimated central venous pressure (CVP). Small increases to systolic blood pressure (SBP) and diastolic blood pressure (DBP) were not statistically significant. Autoregressive moving average modelling (ARMA) during LBNP did not identify differences to either arterial (DBP → TPR and SBP → HR) or cardiopulmonary (CVP → TPR) baroreflexes consistent with intact cardiovascular control. On the other hand, IVC and PV diameter-CVP relationships during LBNP revealed smaller diameter for a given CVP postflight consistent with altered postflight venous wall dynamics.

Bone marrow mesenchymal/fibroblastic stromal cells induce a distinctive EMT-like phenotype in AML cells.

The development of epithelial-to-mesenchymal transition (EMT) like features is emerging as a critical factor involved in the pathogenesis of acute myeloid leukaemia (AML). However, the extracellular signals and the signalling pathways in AML that may regulate EMT remain largely unstudied. We found that the bone marrow (BM) mesenchymal/fibroblastic cell line HS5 induces an EMT-like migratory phenotype in AML cells. AML cells underwent a strong increase of vimentin (VIM) levels that was not mirrored to the same extent by changes of expression of the other EMT core proteins SNAI1 and SNAI2. We validated these particular pattern of co-expression of core-EMT markers in AML cells by performing an in silico analysis using datasets of human tumours. Our data showed that in AML the expression levels of VIM does not completely correlate with the co-expression of core EMT markers observed in epithelial tumours. We also found that vs epithelial tumours, AML cells display a distinct patterns of co-expression of VIM and the actin binding and adhesion regulatory proteins that regulate F-actin dynamics and integrin-mediated adhesions involved in the invasive migration in cells undergoing EMT. We conclude that the BM stroma induces an EMT related pattern of migration in AML cells in a process involving a distinctive regulation of EMT markers and of regulators of cell adhesion and actin dynamics that should be further investigated. Understanding the tumour specific signalling pathways associated with the EMT process may contribute to the development of new tailored therapies for AML as well as in different types of cancers.

Long-Chain Omega-3 Fatty Acid Intake Is Associated with Age but not Cognitive Performance in an Older Australian Sample.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) are essential nutrients and may be capable of delaying age-related cognitive decline. However, previous studies indicate that Australians are not meeting recommendations for LCn-3 PUFA intake. The current study therefore examined LCn-3 PUFA intake in an older Australia sample, as well as associations between LCn-3 PUFA intake and cognitive function. METHODS: Cross-sectional data were collected from 90 adults aged 50 to 80 years. LCn-3 PUFA intake was assessed using a food frequency questionnaire and red blood cell fatty acid profiles were used to calculate the Omega-3 Index (RBC n-3 index). Cognitive function was measured using Addenbrooke's Cognitive Examination-III. RESULTS: Positive associations were observed between age and RBC n-3 index (b=0.06, 95% CI: 0.01 - 0.10, P=0.01), and age and LCn-3 PUFA intake from fish oil capsules (b=17.5, 95% CI: 2.4 - 32.5 mg/day, P=0.02). When adjusting for LCn-3 PUFA from fish oil capsules, the association between age and RBC n-3 index was no longer significant. No associations were observed between LCn-3 PUFA intake and cognitive function. CONCLUSION: LCn-3 PUFA and fish oil consumption increased with age in this sample of older Australians, particularly due to supplement intake. However, LCn-3 PUFA intake was not associated with cognitive function.

Effects of exercise countermeasure on myocardial contractility measured by 4D speckle tracking during a 21-day head-down bed rest.

OBJECTIVE: To evaluate functional myocardial contractility after 21 days of head-down bed rest (HDBR) in sedentary control (CON) or with a resistive vibration exercise (RVE) countermeasure (CM) applied, by using 4D echocardiographic (4D echo) imaging and speckle tracking strain quantification. METHODS: Twelve volunteers were enrolled in a crossover HDBR design, and 4D echo was performed in supine position (REST) at BDC-2 and at R + 2, and in - 6° HDT at day 18, and during the first and the last minute of the 80° head-up step of tilt test performed at both BDC-2 and R + 2. Radial (Rad-Str), longitudinal (Lg-Str) and twist (Tw-Str) strains were measured by 4D speckle tracking, as well as left ventricle diastolic volume (LVDV) and mass (LVmass). RESULTS: On HDT 18: in the CON group, LVDV and LVmass were reduced (p < 0.05), the Rad-Str decreased (p < 0.05) and Tw-Str showed a tendency to increase (p < 0.11), with no changes in Lg-Str. In RVE group, LVDV and LV mass, as well as all the strain parameters remained unchanged. On R + 2: in the CON group, LVDV and LVmass were not recovered in all subjects compared to pre-HDBR (p < 0.08) and Rad-Str was still decreased (p < 0.05), while Tw-Str tended to increase (p < 0.09). These parameters remained unchanged in the RVE group. Tilt 80°: Rad-Str and Lg-Str values at 80° tilt were similar post-HDT in both groups. CONCLUSION: The 4D echo and speckle tracking analysis showed that in the CON group, Rad-Str decreased concomitant with LVmass and LVDV with HDBR, but this observation did not allow concluding if HDBR induced a real remodeling or a muscle atrophy. RVE was able to preserve LVmass, LVDV and contractility during HDBR, thus proving its effectiveness to this aim. Nevertheless, the significant HDBR-induced changes observed in the CON group had only a limited effect on the cardiac contractile response as observed during post-HDBR tilt test. The level of contractility at 80° Tilt position was not affected either by HDBR or by RVE CM.

Wave energy absorption by a submerged air bag connected to a rigid float.

A new wave energy device features a submerged ballasted air bag connected at the top to a rigid float. Under wave action, the bag expands and contracts, creating a reciprocating air flow through a turbine between the bag and another volume housed within the float. Laboratory measurements are generally in good agreement with numerical predictions. Both show that the trajectory of possible combinations of pressure and elevation at which the device is in static equilibrium takes the shape of an S. This means that statically the device can have three different draughts, and correspondingly three different bag shapes, for the same pressure. The behaviour in waves depends on where the mean pressure-elevation condition is on the static trajectory. The captured power is highest for a mean condition on the middle section.

Glutaredoxin 2a overexpression in macrophages promotes mitochondrial dysfunction but has little or no effect on atherogenesis in LDL-receptor null mice.

AIMS: Reactive oxygen species (ROS)-mediated formation of mixed disulfides between critical cysteine residues in proteins and glutathione, a process referred to as protein S-glutathionylation, can lead to loss of enzymatic activity and protein degradation. Since mitochondria are a major source of ROS and a number of their proteins are susceptible to protein-S-glutathionylation, we examined if overexpression of mitochondrial thioltranferase glutaredoxin 2a (Grx2a) in macrophages of dyslipidemic atherosclerosis-prone mice would prevent mitochondrial dysfunction and protect against atherosclerotic lesion formation. METHODS AND RESULTS: We generated transgenic Grx2aMac(LDLR-/-) mice, which overexpress Grx2a as an EGFP fusion protein under the control of the macrophage-specific CD68 promoter. Transgenic mice and wild type siblings were fed a high fat diet for 14 weeks at which time we assessed mitochondrial bioenergetic function in peritoneal macrophages and atherosclerotic lesion formation. Flow cytometry and Western blot analysis demonstrated transgene expression in blood monocytes and peritoneal macrophages isolated from Grx2aMac(LDLR-/-) mice, and fluorescence confocal microscopy studies confirmed that Grx2a expression was restricted to the mitochondria of monocytic cells. Live-cell bioenergetic measurements revealed impaired mitochondrial ATP turnover in macrophages isolated from Grx2aMac(LDLR-/-) mice compared to macrophages isolated from non-transgenic mice. However, despite impaired mitochondrial function in macrophages of Grx2aMac(LDLR-/-) mice, we observed no significant difference in the severity of atherosclerosis between wildtype and Grx2aMac(LDLR-/-) mice. CONCLUSION: Our findings suggest that increasing Grx2a activity in macrophage mitochondria disrupts mitochondrial respiration and ATP production, but without affecting the proatherogenic potential of macrophages. Our data suggest that macrophages are resistant against moderate mitochondrial dysfunction and rely on alternative pathways for ATP synthesis to support the energetic requirements.

Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight.

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO(2). Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BP(MCA)) and expired CO(2) were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BP(MCA)/CBFV). Cerebrovascular autoregulation and CO(2) reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO(2) were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BP(MCA) (P = 0.017). The postflight responses to CO(2) were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO(2) reactivity.

Cardiovascular regulation during long-duration spaceflights to the International Space Station.

Early evidence from long-duration flights indicates general cardiovascular deconditioning, including reduced arterial baroreflex gain. The current study investigated the spontaneous baroreflex and markers of cardiovascular control in six male astronauts living for 2-6 mo on the International Space Station. Measurements were made from the finger arterial pressure waves during spontaneous breathing (SB) in the supine posture pre- and postflight and during SB and paced breathing (PB, 0.1 Hz) in a seated posture pre- and postflight, as well as early and late in the missions. There were no changes in preflight measurements of heart rate (HR), blood pressure (BP), or spontaneous baroreflex compared with in-flight measurements. There were, however, increases in the estimate of left ventricular ejection time index and a late in-flight increase in cardiac output (CO). The high-frequency component of RR interval spectral power, arterial pulse pressure, and stroke volume were reduced in-flight. Postflight there was a small increase compared with preflight in HR (60.0 ± 9.4 vs. 54.9 ± 9.6 beats/min in the seated posture, P < 0.05) and CO (5.6 ± 0.8 vs. 5.0 ± 1.0 l/min, P < 0.01). Arterial baroreflex response slope was not changed during spaceflight, while a 34% reduction from preflight in baroreflex slope during postflight PB was significant (7.1 ± 2.4 vs. 13.4 ± 6.8 ms/mmHg), but a smaller average reduction (25%) during SB (8.0 ± 2.1 vs. 13.6 ± 7.4 ms/mmHg) was not significant. Overall, these data show no change in markers of cardiovascular stability during long-duration spaceflight and only relatively small changes postflight at rest in the seated position. The current program routine of countermeasures on the International Space Station provided sufficient stimulus to maintain cardiovascular stability under resting conditions during long-duration spaceflight.

Evaluation of macrophage-specific promoters using lentiviral delivery in mice.

In gene therapy, tissue-specific promoters are useful tools to direct transgene expression and improve efficiency and safety. Macrophage-specific promoters (MSPs) have previously been published using different delivery systems. In this study, we evaluated five different MSPs fused with green fluorescent protein (GFP) to delineate the one with highest specificity using lentiviral delivery. We compared three variants of the CD68 promoter (full length, the 343-bp proximal part and the 150-bp proximal part) and two variants (in forward and reverse orientation) of a previously characterized synthetic promoter derived from elements of transcription factor genes. We transduced a number of cell lines and primary cells in vitro. In addition, hematopoietic stem cells were transduced with MSPs and transferred into lethally irradiated recipient mice. Fluorescence activated cell sorting analysis was performed to determine the GFP expression in different cell populations both in vitro and in vivo. We showed that MSPs can efficiently be used for lentiviral gene delivery and that the 150-bp proximal part of the CD68 promoter provides primarily macrophage-specific expression of GFP. We propose that this is the best currently available MSP to use for directing transgene expression to macrophage populations in vivo using lentiviral vectors.

Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition.

CC-chemokines are important mediators in the pathogenesis of atherosclerosis. Atherosclerosis progression is reduced by high-level, short-term inhibition of CC-chemokine activity, for example by adenoviral gene transfer. However, atherosclerosis is a chronic condition where short-term effects, while demonstrating proof-of-principle, are unlikely to provide maximum therapeutic benefit. Accordingly, we generated a recombinant lentivirus, lenti35K, encoding the broad-spectrum CC chemokine inhibitor, 35K, derived from the vaccinia virus. To investigate the effects of prolonged broad-spectrum chemokine inhibition on atherosclerosis, lenti35K, or lentiGFP or PBS were delivered to 6-week-old ApoE knockout (ApoE-KO) mice by hydrodynamic injection. Sustained lentiviral transduction and transgene expression were demonstrated by 35K mRNA and viral DNA in liver tissue, and recombinant 35K protein circulating in the plasma, 3 months after gene transfer. Plasma from lenti35K animals had reduced chemokine activity compared with plasma from lentiGFP or PBS-treated animals. Histologic analysis of aortic sinus sections revealed that atherosclerotic plaque area in lenti35K mice was significantly reduced compared with both lentiGFP and PBS controls. Furthermore, plaque macrophage content was substantially reduced in lenti35K mice. Lentiviral 35K gene transfer is a promising experimental strategy to reduce atherosclerosis progression, and demonstrates the potential of long-term CC-chemokine inhibition as a potential therapeutic target in atherosclerosis.

Heterogeneity of responses to orthostatic stress in homozygous twins.

Early analysis into the role of genetics on cardiovascular regulation has been accomplished by comparing blood pressure and heart rate in homozygous twins during unstressed, resting physiological conditions. However, many variables, including cognitive and environmental factors, contribute to the regulation of cardiovascular hemodynamics. Therefore, the purpose of this study was to determine the hemodynamic response of identical twins to an orthostatic stress, ranging from supine rest to presyncope. Heart rate, arterial blood pressure, middle cerebral artery blood velocity, an index of cerebrovascular resistance, cardiac output, total peripheral resistance, and end-tidal carbon dioxide were measured in 16 healthy monozygotic twin pairs. Five minutes of supine resting baseline data were collected, followed by 5 min of 60 degrees head-up tilt. After 5 min of head-up tilt, lower body negative pressure was applied in increments of 10 mmHg every 3 min until the onset of presyncope, at which time the subject was returned to the supine position for a 5-min recovery period. The data indicate that cardiovascular regulation under orthostatic stress demonstrates a significant degree of variance between identical twins, despite similar orthostatic tolerance. As the level of stress increases, so does the difference in the cardiovascular response within a twin pair. The elevated variance with increasing stress may be due to an increase in the role of environmental factors, as the influential role of genetics nears a functional limit. Therefore, although orthostatic tolerance times were very similar between identical twins, the mechanism involved in sustaining cardiovascular function during increasing stress was different.

Arterial and venous response to Tilt with LBNP test after a 60 day HDT bedrest (WISE study).

UNLABELLED: The objective was to quantify the Cerebral, and Femoral arterial hemodynamics as well as the calf vein section changes induced by a Tilt up test continuing with a Tilt plus LBNP after a 60 day HDT (WISE). METHOD: 24 healthy volunteers (25-40 y) underwent a 60 day HDT (-6 degree) bedrest: 8 as Control (Co), 8 with Exercise (Ex: treadmill under LBNP and flywheel), 8 with Nutrition (Nut: daily protein supplement). At R+0 all of them underwent a 10 min 80 degree Tilt up test, to which several LBNP period of 3 min were added (from -10 to -50 mmHg by steps of 10 mmHg) until presyncopal stage. Cerebral and Femoral flow changes were assessed by Doppler. Posterior Tibial, and Gastrocnemian vein were investigated by echography. RESULTS: At Post HDT 10 min Tilt: cerebral flow decreased similarly in the 3 groups, but more in the non finishers than in the finishers, while the femoral decreased similarly in all groups. Leg vascular resistance and cerebral/femoral flow ratio increased less in the Co and Nut gr than in the Ex gr, and also in the non finishers than in the finishers. Percent increase in Gastrocnemian and Tibial section was higher in Co and Nut gr than in Ex gr, and in non finishers than in finishers. CONCLUSION: Non exercise and non finisher subjects showed a lack of leg vasoconstriction, and a higher calf vein distensibility at post HDT Tilt test.

WISE 2005: vascular responses to 60-day bed rest in women.

WISE-2005 studied 24 women during a 60-day head down bed rest (HDBR) who look part in an exercise countermeasure (LBNP-treadmill plus flywheel, EX) and no-exercise (No-EX). We conducted a series of experiments to explore changes in cardiovascular function and the ability of EX to prevent these changes. Resting arterial diameter in the arm was not affected but the leg arteries (femoral and popliteal) were significantly reduced in Np-EX, but was increased in EX. In this study we report on drug stimulated responses with sublingual nitroglycerin and infused isoproterenol. Heart rate increased in response to nitroglycerin with larger increases in No-EX after HDBR. Likewise during isoproterenol infusion the HR increase was greater after HDBR in the No-EX group. In all cases, the higher HR was associated with lower stroke volume in No-EX while stroke volume was protected in EX. These data do not support a change in sensitivity of beta-adrenergic receptors after HDBR. The leg vascular resistance decreased in response to isoproterenol and it decreased to a greater extent in No-EX than EX. These data were consistent with observations of lower leg vascular resistance during orthostatic challenge tests after HDBR. We conclude that consistent changes in cardiovascular function in the No-EX were detected by different methods that point to mechanisms contributing to orthostatic intolerance after HDBR.

WISE-2005: orthostatic tolerance is poorly predicted by acute changes in cardiovascular variables.

Twenty-four (24) healthy women from 25-40 years of age underwent orthostatic tolerance tests consisting of passive tilt and lower body negative pressure before and after completing 60-days of continuous -6 degree head down tilt bed rest (HDBR). Prior to HDBR, participants were assigned to one of three groups: control, exercise or nutrition. We aimed to identify any acute head up tilt changes in mean arterial pressure, pulse pressure, total peripheral resistance, cardiac output, stroke volume, or heart rate, which might predict tolerance or changes in tolerance with HDBR. Generally, these attempts were largely unsuccessful. The results indicate that the mechanisms of orthostatic failure are not strongly related to the way in which the body responds to the initial challenge. Additionally, the observation that some variables were predictive of tolerance before and not after tilt may indicate a change in the strategies used to maintain blood pressure, or differential adaptations to HDBR.

WISE 2005: altered cerebrovascular autoregulation after 60 day head-down bed rest.

We tested the hypothesis that 60 days of head-down bed rest (HDBR) would affect cerebrovascular autoregulation and that this change would be correlated with changes in tolerance to the upright posture. Twenty-four healthy women (32 +/- 4 yrs) participated in a 60-d bed rest study at the MEDES Clinic in Toulouse, France. End tidal CO2 (ETCO2), continuous blood pressure (BP), middle cerebral artery (MCA) velocity and time to presyncope (endpoint) were measured during an orthostatic tolerance test conducted before/after bed rest. Given the large range of change in tolerance even within assigned countermeasure groups, we separated subjects for this analysis on the basis of the change in endpoint (Delta endpoint) pre- to post-bed rest. Autoregulation and CO2 responsiveness were evaluated on a different day from a two-breath test with intermittent hypercapnic exposure. Autoregressive moving average (ARMA) modeled the two confounding inputs, BP and CO2, on cerebrovascular blood flow. The cerebrovascular resistance index (CVRi) was expected to decrease following a decrease in BP at the MCA to assist in maintenance of cerebral blood flow. Subjects with the smallest Delta endpoint after bed rest had a 78% increase in the gain of the BP --> CVRi response. Meanwhile, the groups with greater decline in orthostatic tolerance post-HDBR had no change in the gain of this response. ETCO2 was lower overall following HDBR, decreasing from 41.8 +/- 3.4 to 40.2 +/- 3.0 in supine rest, 37.9 +/- 3.4 to 33.3 +/- 4.0 in early tilt, and 29.5 +/- 4.4 to 27.1 +/- 5.1 at pre-syncope. There was however, higher MCA velocity at any ETCO2 for post- compared to pre-HDBR. In summary, changes in autoregulation were found only in those subjects who had the smallest change from pre- to post-HDBR orthostatic tolerance. The changes may assist in buffering changes in cerebral blood flow during orthostatic hypotension post-HDBR. The reduction in ETCO2 after bed rest might be due to a change in chemoreceptor response to blood CO2, but the cerebrovascular system seems to have completely compensated.

WISE-2005: reduced cerebral blood flow velocity with nitroglycerin--comparison with common carotid artery blood flow.

During the WISE-2005 study of 24 women, we observed a reduction (21.6 +/- 0.89%, mean +/- SEM) in cerebral blood flow velocity (CBV) measured by transcranial Doppler ultrasound, following 0.3 mg sublingual nitroglycerin (NG). In parallel, we observed quantitative reductions in leg blood flow (47.3 +/- 7.0%) and corresponding reductions in calculated conductance (Conductance = Femoral Flow / Mean Arterial Pressure; 45.7 +/- 7.2%). To determine if the reduction in CBV was the result of reduced cerebral blood flow or dilation of the middle cerebral artery (MCA), the change in CBV in the MCA was compared with changes in quantitative flow measured in the common carotid artery (CCA). The relationship between CBV and CCA blood flow was tested in five men and four women using hyper- and hypo-ventilation to manipulate arterial PCO2. Changes in CCA blood flow were positively correlated with changes in CBV (p<0.001). We then investigated the CBV and CCA flow responses to sublingual NG in an additional two men and six women. Concurrent with the reduction in CBV there was no change in blood flow through the CCA (p>0.05). These results indicate that the decrease in CBV observed in response to NG was probably the result of dilation of the MCA and that total cerebral blood flow was similar after administration of NG. These results suggest regional differences in the vascular responses to NG during the WISE bed rest. Conduit vessels of both the peripheral and cerebral vasculature dilated; however, the resistance vessels in skeletal muscle constricted causing a reduction in blood flow, while the resistance vessels of the brain appeared to be unaffected by NG so that cerebral blood flow remained constant. These results highlight the need to obtain quantitative measures of cerebral blood flow if there is reason to suspect that the diameter of the MCA might not remain constant.

WISE-2005: developing a non-invasive method to monitor cardiovascular deconditioning.

We have determined the gain of the cardiopulmonary baroreflex (CPBR) by measuring the central venous pressure (CVP) by venous catheter and calculating the total peripheral resistance (TPR) from mean arterial pressure (MAP) by Finometer and cardiac output (QD) by Doppler ultrasound. We tested the hypothesis that the BeatScope software of the Finometer, which calculates cardiac stroke volume (SVF) and cardiac output (QF) from the arterial pulse wave, could provide data with which to estimate CVP and TPR. The estimate of QF was linearly related to QD with a correction factor. Further, we found linear relationships between CVP and SVF that allowed us to establish a prediction of CVP from the SVF as the new input to the CPBR. To test the ability of this method to monitor changes in CPBR we are testing the subjects of the WISE-2005 study before and after 50-days of bed rest. We conclude that the TPR can be assessed with the Finometer and without any invasive method to record the CVP.

Transient paralysis after administration of a single dose of cyclizine.

Two patients with underlying neuromuscular disorders developed varying degrees of paralysis after a single dose of cyclizine, one necessitating full mechanical ventilation. These cases appear to be unique in the literature and represent an increasing spectrum of adverse reactions seen with the greater use of cyclizine.