Cerebral MRI on fetuses submitted to repeated cocaine administration during the gestation: an ovine model

The aim of this study was to determine the role of Magnetic Resonance Imaging (MRI) in investigating fetal cerebral lesions induced by long term exposure to cocaine during sheep pregnancy. Cerebral Magnetic Resonance Imaging was performed on two groups of fetuses at 125 days of gestation (normal gestation: 145 days). The control group consisted of eight fetuses of four pregnant ewes. The study group consisted of eight fetuses of four pregnant ewes receiving daily 140 mg/kg injection of cocaine from day 60 until delivery. The following MR sequences were applied: T1-weighted FLASH, and T2-weighted Fast-Spin-Echo. Cerebral images were evaluated semi quantitatively using the following criteria: Heterogenicity, contrast between grey and white matter, contours irregularity, hyposignal, lateral ventricle sizes. The brightness distribution and homogenicity of the images were analysed by means of edge pair distributions using a new computerized method originally designed for ultrasound images analysis developed by Ultrasight inc (USA). (1) Flash T1: Heterogenic areas and irregular contours were more frequent in cocaine exposed fetuses. The contrast between grey and white matter was more important in the cocaine group. Hyposignal was found only in the cocaine group. Enlarged lateral ventricle occurred more frequently in the cocaine group. (2) Spin echo T2: The contrast between grey and white matter was higher and the contours of the brain more irregular in the cocaine group. Heterogenicity and hyposignal were also more frequent in this group but the difference with the control group was not significant. The computerized analysis of the contrast density on the cerebral images showed that 88% of the areas exceeding the reference level concerned the cocaine group, while only 14% of the areas exceeding the reference level concerned the control group. Long term exposure to cocaine induces cerebral tissue modifications, in favor of an advanced maturation and the development of hypoxic lesions. The histology of the brains confirmed in the cocaine group, the existence of hypoxic lesions with gliosis, perivascular edema and hemorrhages, and neuronal death

Peripheral Arterial and Venous Response to Tilt Test after a 60-Day Bedrest with and without Countermeasures (ES-IBREP)

We quantified the impact of 60-day head-down bed rest (HDBR) with countermeasures on arterial and venous response to tilt. Methods: Twenty-one males: 7 control (Con), 7 resistive vibration exercise (RVE) and 7 Chinese herb (Herb) were assessed. Subjects were identified as finisher (F) or non-finishers (NF) at the post-HDBR 20-min tilt test. The cerebral (MCA), femoral (FEM) arterial flow velocity and leg vascular resistance (FRI), the portal vein section (PV), the flow redistribution ratios (MCA/FEM; MCA/PV), the tibial (Tib), gastrocnemius (Gast), and saphenous (Saph) vein sections were measured by echography and Doppler ultrasonography. Arterial and venous parameters were measured at 3-min pre-tilt in the supine position, and at 1 min before the end of the tilt. Results: At post-HDBR tilt, MCA decreased more compared with pre-HDBR tilt in the Con, RVE, and Herb groups, the MCA/FEM tended to decrease in the Con and Herb groups (not significant) but remained stable in the RVE gr. FRI dropped in the Con gr, but remained stable in the Herb gr and increased in the RVE gr. PV decreased less in the Con and Herb groups but remained unchanged in the RVE gr. MCA/PV decreased in the Con and Herb groups, but increased to a similar extent in the RVE gr. Gast section significantly increased more in the Con gr only, whereas Tib section increased more in the Con and Herb groups but not in the RVE gr. The percent change in Saph section was similar at pre- and post-HDBR tilt. Conclusion: In the Con gr, vasoconstriction was reduced in leg and splanchnic areas. RVE and Herb contributed to prevent the loss of vasoconstriction in both areas, but the effect of RVE was higher. RVE and Herb contributed to limit Gast distension whereas only RVE had a protective effect on the Tib

Fluid Shifts

NASA is focusing on long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but more than 30% of ISS astronauts experience more profound, chronic changes with objective structural and functional findings such as papilledema and choroidal folds. Globe flattening, optic nerve sheath dilation, and optic nerve tortuosity also are apparent. This pattern is referred to as the visual impairment and intracranial pressure (VIIP) syndrome. VIIP signs and symptoms, as well as postflight lumbar puncture data, suggest that elevated intracranial pressure (ICP) may be associated with the space flight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration space flight, and to correlate these findings with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during space flight, as well as the VIIP-related effects of those shifts, is predicted by the crewmember's pre-flight condition and responses to acute hemodynamic manipulations (such as head-down tilt). Lastly, we will evaluate the patterns of fluid distribution in ISS astronauts during acute reversal of fluid shifts through application of lower body negative pressure (LBNP) interventions to characterize and explain general and individual responses. We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the Figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography, intraocular pressure, 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness, Doppler ultrasound of ophthalmic and retinal arteries, and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, distortion-product otoacoustic emissions, and ICP calculated by MRI). On the ground, acute head-down tilt will induce cephalad fluid shifts, whereas LBNP will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome. This study has been selected for flight implementation and is one of the candidate investigations being considered for the one year mission

Fluid Shifts

INTRODUCTION: Mechanisms responsible for the ocular structural and functional changes that characterize the visual impairment and intracranial pressure (ICP) syndrome (VIIP) are unclear, but hypothesized to be secondary to the cephalad fluid shift experienced in spaceflight. This study will relate the fluid distribution and compartmentalization associated with long-duration spaceflight with VIIP symptoms. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as the VIIP-related effects of those shifts, can be predicted preflight with acute hemodynamic manipulations, and also if lower body negative pressure (LBNP) can reverse the VIIP effects. METHODS: Physiologic variables will be examined pre-, in- and post-flight in 10 International Space Station crewmembers including: fluid compartmentalization (D2O and NaBr dilution); interstitial tissue thickness (ultrasound); vascular dimensions and dynamics (ultrasound and MRI (including cerebrospinal fluid pulsatility)); ocular measures (optical coherence tomography, intraocular pressure, ultrasound); and ICP measures (tympanic membrane displacement, otoacoustic emissions). Pre- and post-flight measures will be assessed while upright, supine and during 15 deg head-down tilt (HDT). In-flight measures will occur early and late during 6 or 12 month missions. LBNP will be evaluated as a countermeasure during HDT and during spaceflight. RESULTS: The first two crewmembers are in the preflight testing phase. Preliminary results characterize the acute fluid shifts experienced from upright, to supine and HDT postures (increased stroke volume, jugular dimensions and measures of ICP) which are reversed with 25 millimeters Hg LBNP. DISCUSSION: Initial results indicate that acute cephalad fluid shifts may be related to VIIP symptoms, but also may be reversible by LBNP. The effect of a chronic fluid shift has yet to be evaluated. Learning Objectives: Current spaceflight VIIP research is described, including novel hardware and countermeasures

Fluid Shifts

NASA is focusing on long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low-Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but more than 50% of ISS astronauts experienced more profound, chronic changes with objective structural and functional findings such as papilledema and choroidal folds. Globe flattening, optic nerve sheath dilation, and optic nerve tortuosity also are apparent. This pattern is referred to as the visual impairment and intracranial pressure (VIIP) syndrome. VIIP signs and symptoms, as well as postflight lumbar puncture data, suggest that elevated intracranial pressure (ICP) may be associated with the spaceflight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration spaceflight, and to correlate these findings with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as the VIIP-related effects of those shifts, is predicted by the crewmember's preflight conditions and responses to acute hemodynamic manipulations (such as head-down tilt). Lastly, we will evaluate the patterns of fluid distribution in ISS astronauts during acute reversal of fluid shifts through application of lower body negative pressure (LBNP) interventions to characterize and explain general and individual responses. METHODS: We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the Figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography, intraocular pressure, 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness, Doppler ultrasound of ophthalmic and retinal arteries, and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, distortion-product otoacoustic emissions, and ICP calculated by MRI). On the ground, acute head-down tilt will induce cephalad fluid shifts, whereas LBNP will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome

Carotid artery plaque composition : Relationship to clinical presentation and ultrasound B-mode imaging

Objective: To correlate B-mode ultrasound findings to carotid plaque histology. Design: European multicentre study (nine centres). Material and Methods: Clinical presentation and risk factors were recorded and preoperative ultrasound Duplex scanning with special emphasis on B-mode imaging studies was performed in 270 patients undergoing carotid endarterectomy. Perioperatively macroscopic plaque features were evaluated and the removed specimens were analysed histologically for fibrous tissue, calcification and 'soft tissue' (primarily haemorrhage and lipid). Results: Males had more soft tissue than females (p = 0.0006), hypertensive patients less soft tissue than normotensive (p = 0.01) and patients with recent symptoms more soft tissue than patients with earlier symptoms (p = 0.004). There was no correlation between surface description on ultrasound images compared to the surface judged intraoperatively by the surgeon. Echogenicity on B-mode images was inversely related to soft tissue (p=0.005) and calcification ions directly related to echogenicity (p < 0.0001). Heterogeneous plaques contained more calcification than homogeneous (p = 0.003), however there was no difference in content of soft tissue. Conclusion: Ultrasound B-mode characteristics are related to the histological composition of carotid artery plaques and to patient's history. These results may imply that patients with distant symptoms may be regarded and treated as asymptomatic patients whereas asymptomatic patients with echolucent plaques should be considered for carotid endarterectomy

Fetal cerebrovascular response to chronic hypoxia - implications for the prevention of brain damage

Fetal hypoxia is one of the leading causes of perinatal morbidity and mortality. One of the most severe sequels of fetal hypoxic insult is the development of perinatal brain lesions resulting in a spectrum of neurological disabilities, from minor cerebral disorders to cerebral palsy. One of the most important fetal adaptive responses to hypoxia is redistribution of blood flow towards the fetal brain, known as the 'brain sparing effect'. The fetal blood flow redistribution in favor of the fetal brain can be detected and quantified by the Doppler cerebral/umbilical ratio (C/U ratio = cerebral resistance index (CRI)/umbilical resistance index (URI)). Our studies on animal models and human fetuses have demonstrated clearly that this phenomenon cannot prevent the development of perinatal brain lesions in the case of severe or prolonged hypoxia. Fetal deterioration in chronic and severe hypoxia is characterized by the disappearance of the physiological cerebral vascular variability (vasoconstriction and vasodilatation), followed by an increase in cerebral vascular resistance. However, our latest study on growth-restricted and hypoxic human fetuses has shown that perinatal brain lesions can develop even before the loss of cerebrovascular variability. The fetal exposure to hypoxia can be quantified by using a new vascular score, the hypoxia index. This parameter, which takes into account the degree as well as duration of fetal hypoxia, can be calculated by summing the daily % C/U ratio reduction from the cut-off value 1 over the period of observation. According to our results, the use of this parameter, which calculates the cumulative, relative oxygen deficit, could allow for the first time the sensitive and reliable prediction and even prevention of adverse neurological outcome in pregnancies complicated by fetal hypoxia

Brain damage and hypoxia in an ovine fetal chronic cocaine model1

OBJECTIVE: To assess the development of brain damage in an ovine fetal chronic cocaine model. To evaluate the effect of isolated hypoxic tests on this model and to correlate hemodynamic findings (brain-sparing effect) following fetal hypoxia and the occurrence of brain damage. STUDY DESIGN: Fifteen ewes were divided into a control group (n=7) and a cocaine treated group (n=8). From day 65 to day 134 the cocaine treated animals received a daily (5 days per week) intramuscular injection (2 mg/kg cocaine) and the control animals a placebo injection (2 ml of isotonic solution). Both groups underwent hypoxic tests (cord compression (3 min) and aortic compression (1 min)) at 90 and 134 days. In addition, anesthesia for magnetic resonance imaging (MRI) examination was carried out at 125 days. Fetal blood samples were collected during both series of hypoxic tests and the cerebral and umbilical flows were monitored by Doppler. Samples from 25 brains (control n = 10; cocaine n= 15) were processed for light and electron microscopic examination. Quantification of brain damage was done on semithin sections from six areas of cortex and germinal matrix on each fetus. RESULTS: Similar forms of brain damage (selective neuronal loss limited to the parasaggital cortex, striatum, hippocampus and Purkinje cells) was present in both groups but lesions were more frequent in the cocaine treated group as shown by quantitative analysis for the proportion of abnormal capillaries (65% vs. 35%), capillary edema (61% vs. 34%) and abnormal neurons showing delayed neuronal degeneration (DND) (66% vs. 36%) in the cocaine and control group respectively. There was no significant difference in immunoreactivity for glial fibrillary acidic protein (GFAP) but it was more marked in the cerebellum of cocaine treated animals. Fetal blood samples showed a moderate sustained hypoxia and Doppler findings demonstrated the presence of a brain sparing effect associated with increased uterine and umbilical vascular resistance in the cocaine treated group. Nevertheless, the amplitude of the heart rate increase and cerebral dilatation was significantly lower in the cocaine treated animals. CONCLUSION: This ovine fetal chronic cocaine model showed the presence of brain damage. Cocaine treatment seems to potentiate the effect of the hypoxic tests. Independent of the cause, the brain damage developed in the presence of brain sparing effect, strongly suggesting that this phenomenon is a sign of a pathological fetal condition and no guarantee that it will prevent tissue damag