The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are ...associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two
models of PD (PD
and PD
), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PD
). PD
worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PD
worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PD
worms compared to PD
and PD
worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PD
and PD
worms, but had less marked effects in PD
. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PD
, PD
and PD
worms. These results illustrate the use of these two
models in fundamental and applied PD research.
To compare resuscitation outcomes and myocardial function among intra-arrest head cooling, delayed surface cooling, and uncooled controls.
Prospective animal study.
University-affiliated animal ...research laboratory.
Twenty-four male domestic pigs.
Ventricular fibrillation remained untreated for 10 mins after which animals were assigned into three groups: 1) intra-arrest head cooling, 2) postresuscitation surface cooling, and 3) uncooled controls. Head cooling by evaporative perfluorochemical began coincident with the start of cardiopulmonary resuscitation and continued for a total of 4 hrs. Surface cooling using a cooling blanket began at 2 hrs after return of spontaneous circulation and continued for 8 hrs. Control animals were treated identically with the exception for cooling.
Return of spontaneous circulation was achieved in eight of eight head-cooled animals, in seven of eight surface-cooled animals, and in seven of eight of controls. Myocardial functions measured by transthoracic echocardiography were significantly better in the head-cooled animals than in surface-cooled and controls. All head-cooled animals survived for more than 96 hrs. This contrasted with six of eight survivors after surface cooling, and only two of eight among controls.
Both intra-arrest head cooling and delayed surface cooling improved postresuscitation myocardial dysfunction. The beneficial effects were greatest with head cooling initiated with cardiopulmonary resuscitation.
Employing transnasal head-cooling in a pig model of prolonged ventricular fibrillation, we compared the effects of 4 hrs of head-cooling started during cardiopulmonary resuscitation with those of 8 ...hrs of surface-cooling started at 2 hrs after resuscitation on 96-hr survival and neurologic outcomes.
Prospective controlled animal study.
University-affiliated research laboratory.
Domestic pigs.
Twenty-four male pigs were subjected to 10 min of untreated ventricular fibrillation followed by 5 min of cardiopulmonary resuscitation. In the head-cooling group, hypothermia was started with cardiopulmonary resuscitation and continued for 4 hrs after resuscitation. In the surface-cooling group, systemic hypothermia with a cooling blanket was started, in accord with current clinical practices, at 2 hrs after resuscitation and continued for 8 hrs. Methods in the control animal studies were identical except for temperature interventions.
All animals were resuscitated except for one animal in each of the surface-cooling and control groups. After 5 min of cardiopulmonary resuscitation, jugular vein temperature was significantly decreased in the head-cooled animals. However, there were no differences in pulmonary artery temperatures among the three groups at that time. Nevertheless, both head-cooled and surface-cooled animals had an improved 96-hr survival after resuscitation. Significantly better neurologic outcomes were observed in early head-cooled animals in the first 3 days after resuscitation.
Early head-cooling during cardiopulmonary resuscitation continuing for 4 hrs after resuscitation produced favorable survival and neurologic outcomes in comparison with delayed surface-cooling of 8 hrs duration.
Background The objective of this randomized clinical trial of elective coronary artery bypass grafting was to investigate whether intraoperative mean arterial pressure below autoregulatory limits of ...the coronary and cerebral circulations was a principal determinant of postoperative complications. The trial compared the impact of two strategies of hemodynamic management during cardiopulmonary bypass on outcome. Patients were randomized to a low mean arterial pressure of 50 to 60 mm Hg or a high mean arterial pressure of 80 to 100 mm Hg during cardiopulmonary bypass.
Methods A total of 248 patients undergoing primary, nonemergency coronary bypass were randomized to either low (
n = 124) or high (
n = 124) mean arterial pressure during cardiopulmonary bypass. The impact of the mean arterial pressure strategies on the following outcomes was assessed: mortality, cardiac morbidity, neurologic morbidity, cognitive deterioration, and changes in quality of life. All patients were observed prospectively to 6 months after the operation.
Results The overall incidence of combined cardiac and neurologic complications was significantly lower in the high pressure group at 4.8% than in the low pressure group at 12.9% (
p = 0.026). For each of the individual outcomes, the trend favored the high pressure group. At 6 months after coronary bypass for the high and low pressure groups, respectively, total mortality rate was 1.6% versus 4.0%, stroke rate 2.4% versus 7.2%, and cardiac complication rate 2.4% versus 4.8%. Cognitive and functional status outcomes did not differ between the groups.
Conclusion Higher mean arterial pressures during cardiopulmonary bypass can be achieved in a technically safe manner and effectively improve outcomes after coronary bypass. (J T
HORAC C
ARDIOVASC S
URG 1995;110:1302-14
)
Introduction
Hypothermic brain protection has been linked to how rapidly cooling is initiated and how quickly and uniformly the therapeutic hypothermic zone (THZ) is reached. The nasopharyngeal (NP) ...approach is uniquely suited for preferential brain cooling due to anatomic proximity to the cerebral circulation, cavernous sinus, and carotid arteries. This study explores a novel NP cooling approach employing evaporative characteristics of aerosolized perfluorochemical (PFC).
Methods
Anesthetized, normotensive sheep (
n
= 30) were instrumented with temperature probes and vascular catheters, then randomized to NP approach (NP-PFC: PFC spray device;
n
= 24) or whole body surface (WBS:
n
= 6) cooling. Regional temperatures, vital signs, and blood chemistries were assessed serially. Two animals were exposed to double PFC flow rates and PFC was measured in blood during NP-PFC cooling to assess PFC uptake and elimination. Cooling rates were evaluated (ANOVA) as a function of method (NP-PFC versus WBS) and time to reach the brain THZ (i.e., ≤−3.5°C below baseline).
Results
Independent of region, brain cooling was faster during NP-PFC versus WBS (
P
< 0.001). During NP-PFC, brain > vascular > rectal cooling rates (
P
< 0.001), brain to systemic temperature gradients were maintained, the brain THZ was reached within 15 min, and the NP epithelial surface appeared histologically intact. During WBS, brain versus systemic cooling rates were not significantly different and the brain THZ could not be reached within 2 h.
Conclusions
The NP-PFC procedure more rapidly induced preferential brain cooling as compared to WBC without adverse effects.
When systemic hypothermia was maintained before inducing cardiac arrest, the likelihood of successful defibrillation and meaningful survival was increased. When hypothermia is induced during ...cardiopulmonary resuscitation, mortality is also improved. With the introduction of the amplitude spectrum area as a predictor of the success of electrical defibrillation, we investigated the effect of preferential head cooling initiated coincident with cardiopulmonary resuscitation on amplitude spectrum area as a predictor. We hypothesized that rapid head cooling initiated coincident with cardiopulmonary resuscitation improves amplitude spectrum area, and therefore is predictive of successful defibrillation.
Prospective randomized controlled study.
University-affiliated research institute.
Domestic pigs.
Sixteen pigs, weighing 40.6 +/- 1.4 kg, were randomized to the hypothermia (n = 8), or control (n = 8) group. Ventricular fibrillation was induced and untreated for 10 mins. Cardiopulmonary resuscitation was then initiated for 5 mins followed by attempted defibrillation with a biphasic 150-J electric shock. Coincident with starting cardiopulmonary resuscitation, hypothermia was induced with evaporative intranasal cooling using a perfluorochemical. If spontaneous circulation was not restored after defibrillation, cardiopulmonary resuscitation was resumed for 1 min before the next defibrillation attempt until the animal was either successfully resuscitated or for a total of 15 mins. The target core temperature was 34 degrees C. Control animals were identically treated except for hypothermia.
Five seconds of ventricular fibrillation waveform were recorded immediately preceding delivery of a shock. The ventricular fibrillation waveforms were analyzed using the amplitude spectrum area algorithm. A smaller epinephrine dose (60 +/- 32.1 vs. 30 +/- 0 mg/mL, p = .01) and shorter cardiopulmonary resuscitation duration (365 +/- 42 sec vs. 600 +/- 243 sec, p = .01) were required to achieve return of spontaneous circulation in the hypothermia group, compared with control. Five minutes after starting cardiopulmonary resuscitation, head temperature was reduced from 38 degrees C to 34 degrees C in the hypothermia group (p = .028). Hypothermia improved the success of electrical shocks before return of spontaneous circulation (88 +/- 18% vs. 66 +/- 19%, p = .034). Both the amplitude spectrum area values of initial shock (26.1 +/- 5.3 vs. 21.4 +/- 2.16 mV-Hz, p = .049) and total shocks (26.1 +/- 5.3 vs. 21.4 +/- 2.16 mV-Hz, p = .006) were significantly higher in the hypothermia group than control.
Amplitude spectrum area served as a useful predictor for improved resuscitation and facilitated defibrillation in the setting of rapid head cooling initiated coincident with cardiopulmonary resuscitation.
Abstract only
Methods
We assessed safety and feasibility of trans-nasal cooling in a multi-centre, single-arm descriptive study of comatose patients who had been successfully resuscitated after ...cardiac arrest. Forty three patients were treated with a non-invasive cooling device through which cooling was achieved via trans-nasal delivery of an evaporative coolant into the nasopharynx. Initial temperatures, course of cooling, and systemic and local adverse events during cooling were documented. Patients were treated with nasal cooling until they either reached target temperature or were transitioned to treatment according to local standard protocols. Primary outcome was speed of cooling. Survival and cerebral performance category (CPC) at hospital discharge were recorded.
Results
Data are presented as mean ± SD or median (interquartile range (25, 75%)). Mean age was 71.1 ± 10.8 years. VF was the first documented rhythm in 52.4% of the patients, asystole in 31.0%. Temperatures at admission were 35.2±1.2°C tympanic, 35.5±1.1°C, core (arterial or esophageal), and 35.9±1.0°C, bladder. Time from the start of cooling to target temperature (33°C) was 50.0 (35.0 – 68.3) minutes tympanic, and 72.5 (17.3–146.3) minutes, core. Cooling rate of tympanic temperature was 2.4°C/hr., core cooling rate was 1.4°C/hr and bladder 0.9°C/hr. Adverse events affecting the nasal area occurred in 9/43 patients, resolved in 8 (78%) patients spontaneously. One had persistent damage at death, 18 hours later. Systemic adverse events were consistent with the patient population being treated. Twelve patients (30%) had a CPC of 1–2. Twenty-three patients (57.5%) died, none related to the hypothermia procedure, and five patients (12.5%) had a poor outcome. In patients with VF, eight patients (40%) had a CPC of 1–2, eight patients died and four patients had poor outcome.
Conclusions
Trans-nasal cooling for induction of therapeutic hypothermia in patients after successful resuscitation from cardiac arrest is feasible and effective in lowering temperature rapidly in a hospital emergency setting. This method of cooling offers the possibility for immediate introduction and needs now to be investigated in the field setting.
Embolic signals have been detected within both the aortic lumen and the intracranial vasculature during coronary artery bypass grafting. Total numbers of these emboli have been reported. The present ...study examined the size of individual emboli and the total volume of embolization.
Using transesophageal echocardiography, we continuously monitored the aortic lumen of 10 patients undergoing isolated coronary artery bypass grafting. We manually analyzed 720,000 individual echo frames over a 4-minute period after the release of aortic clamps to track and to calculate the volume of 657 individual particles. The embolic load for the entire procedure was calculated from mean volume based on analysis of 1,508 particles. We simultaneously monitored the middle cerebral artery using transcranial Doppler ultrasonography and compared numbers of emboli detected by the two techniques.
Particle diameter ranged from 0.3 to 2.9 mm (mean, 0.8 mm), and particle volume from 0.01 to 12.5 mm
3 (mean, 0.8 mm
3). Twenty-eight percent of particles measured 1 mm or more, 44% measured 0.6 to 1.0 mm, and only 27% measured 0.6 mm or less in diameter. Aortic embolic load for the procedure ranged from 0.6 cm
3 to 11.2 cm
3 (mean, 3.7 cm
3). Estimated cerebral embolic load for the procedure ranged from 60 to 510 mm
3 (mean, 276 mm
3). The fraction of aortic emboli entering the cerebral circulation was very variable (3.9% to 18.1%). Seventy-six percent of the embolic volume after the release of clamps occurred over a 20-second period. Only 1 patient was encephalopathic perioperatively. This patient had the largest estimated cerebral embolic load (510 mm
3) and the second largest aortic embolic load (8.4 cm
3).
We determined the size of individual intraaortic embolic particles and the total volume of embolization during coronary artery bypass grafting, and found the proportion entering the cerebral circulation to be very variable. The constitution of these particles and the neurologic impairment resulting from such embolization remains to be determined.
Fat embolism to the pulmonary circulation is known to occur during total hip arthroplasty, especially during insertion of a cemented femoral component. Fat and air bubbles may enter the systemic ...circulation via a patent foramen ovale or through pulmonary circulation.
To determine whether microemboli to the brain were occurring during total hip arthroplasty, 23 patients underwent transcranial Doppler assessment of emboli to the middle cerebral artery during total hip arthroplasty. Surgery was performed with the patient in the lateral decubitus position so that the probe recorded from the nondependent side.
Successful recordings were made in 20 patients, in 8 of 20 patients there were embolic signals, which ranging from 1 to 200. In all eight patients, signals were recorded during impaction of a cemented component or after relocation of the hip. Only one patient showed evidence of emboli with impaction of the acetabulum component. In two patients there were 150 and 200 embolic signals: in both mild respiratory symptoms developed. One patient became overtly agitated during a flurry of emboli.
Cerebral microemboli can occur during total hip arthroplasty. Whether this contributes to changes in postoperative cognitive function is unknown.
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