Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs

OBJECTIVE: Outcome after prolonged normovolemic cardiac arrest is poor, and new resuscitation strategies have to be found. We hypothesized that the induction of deep hypothermia for emergency preservation and resuscitation (EPR) during prolonged cardiac arrest, before the start of reperfusion, will mitigate the deleterious cascades leading to neuronal death and will thus improve outcome. DESIGN: Prospective experimental study. SETTING: University research laboratory. SUBJECTS: Thirteen pigs, Large White breed (27-37 kg). INTERVENTIONS: After 15 mins of ventricular fibrillation, pigs were subjected to 1) EPR (n = 6), 20 mins of hypothermic stasis induced with a cold saline aortic flush; or 2) 20 mins of conventional resuscitation (n = 7). Then cardiopulmonary bypass was initiated in both groups, followed by defibrillation. Controlled ventilation and mild hypothermia were continued for 20 hrs; survival was for 9 days. For neurologic evaluation, neurologic deficit score (100% = brain dead, 0-10% = normal), overall performance category (1 = normal, 5 = dead or brain dead), and brain histologic damage score were used. MEASUREMENTS AND MAIN RESULTS: In the EPR group, brain temperature decreased from 38.5 degrees C +/- 0.2 degrees C to 16.7 degrees C +/- 2.5 degrees C within 235 +/- 27 secs. Five animals achieved restoration of spontaneous circulation and survived to 9 days: two pigs with overall performance category 2 and three pigs with overall performance category 3. Their neurologic deficit score was 45% (interquartile range 35, 50) and histologic damage score was 142 (interquartile range 109, 159). In the control group, four pigs achieved restoration of spontaneous circulation: one survived to 9 days with overall performance category 3, neurologic deficit score 45%, and histologic damage score 226 (restoration of spontaneous circulation, p = .6; survival, p = .03; overall performance category, p = .02). CONCLUSIONS: EPR is feasible in an experimental pig model and improves survival after prolonged cardiac arrest in pigs. Further experimental studies are needed before this concept can be brought into clinical practice.     

Role of transforming growth factor beta in rat bladder smooth muscle cell proliferation

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor (TGF) beta in both rats and patients. Because TGFbeta can have both growth-promoting and -inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGFbeta1, TGFbeta2, or TGFbeta3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC(50) of approximately 0.1 ng/ml) and efficacy. Such inhibition was antagonized by a specific TGFbeta receptor antagonist and independent of the presence of serum. Mitogen-activated protein kinases (MAPKs) are involved in the control of cell growth, and all three TGFbeta isoforms inhibited activation of the extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGFbeta isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGFbeta did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGFbeta is a mediator of rat bladder hypertrophy.     

Proposal of a guanine-based purinergic system in the mammalian central nervous system

Guanine-based purines have been traditionally studied as modulators of intracellular processes, mainly G-protein activity. However, they also exert several extracellular effects not related to G proteins, including modulation of glutamatergic activity, trophic effects on neural cells, and behavioral effects. In this article, the putative roles of guanine-based purines on the nervous system are reviewed, and we propose a specific guanine-based purinergic system in addition to the well-characterized adenine-based purinergic system. Current evidence suggest that guanine-based purines modulate glutamatergic parameters, such as glutamate uptake by astrocytes and synaptic vesicles, seizures induced by glutamatergic agents, response to ischemia and excitotoxicity, and are able to affect learning, memory and anxiety. Additionally, guanine-based purines have important trophic functions affecting the development, structure, or maintenance of neural cells. Although studies addressing the mechanism of action (receptors and second messenger systems) of guanine-based purines are still insufficient, these findings point to the guanine-based purines (nucleotides and guanosine) as potential new targets for neuroprotection and neuromodulation.     

Biomechanical comparison of extended trochanteric osteotomy and slot osteotomy for femoral component revision in total hip arthroplasty

BACKGROUND: Depending upon the clinical presentation and need for exposure in revision hip arthroplasty, an extended trochanteric osteotomy or slot osteotomy could be used for removal of an inaccessible distal cement mantle, infected material, or distal fragment of a broken stem. This study is a biomechanical comparison of these two osteotomy techniques. METHODS: A press-fit femoral component with a 20-cm straight stem was implanted in each of ten synthetic femurs. The stiffness of these components implanted in the femurs was measured for a compressive load condition simulating the stance phase of level walking. Half of the femurs then received an extended trochanteric osteotomy, and the other half a slot osteotomy. Stiffness testing was repeated both after the osteotomized bone was removed, and after it was fixed back in place by cerclage wiring. FINDINGS: The stiffness of the femoral component/synthetic femur constructs in the slot osteotomy group was significantly greater than in the extended trochanteric osteotomy group. INTERPRETATION: This study demonstrated that in the laboratory setting, the slot osteotomy was significantly stiffer than the more traditional extended trochanteric osteotomy. However, the clinical implications of this increased stiffness are unknown. The ultimate choice of the type of osteotomy depends upon the exposure requirements for a given clinical situation.     

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin‐dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose–insulin–glucagon model was used to describe seven virtual patients with insulin pump‐treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba‐insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre‐defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125‐μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba‐insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model‐based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin‐dependent glucagon dosing regimen for treatment of insulin‐induced mild hypoglycaemia in patients with type 1 diabetes.     

PKCbeta regulates ischemia/reperfusion injury in the lung

Activation of PKCbetaII is associated with the response to ischemia/reperfusion (I/R), though its role, either pathogenic or protective, has not been determined. In a murine model of single-lung I/R, evidence linking PKCbeta to maladaptive responses is shown in the following studies. Homozygous PKCbeta-null mice and WT mice fed the PKCbeta inhibitor ruboxistaurin subjected to I/R displayed increased survival compared with controls. In PKCbeta-null mice, phosphorylation of extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38 MAPK was suppressed in I/R. Expression of the immediate early gene, early growth response-1 (Egr-1), and its downstream target genes was significantly increased in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this expression was attenuated in PKCbeta-null mice or WT mice fed ruboxistaurin. In vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by inhibition of PKCbeta, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These findings elucidate key roles for PKCbetaII activation in I/R by coordinated activation of MAPKs (ERK1/2, JNK) and Egr-1.     

Rehabilitation therapy for patients with long-term spinal cord injuries

The functional effects of three types of therapy for subjects with long-term incomplete cervical spinal cord injuries were investigated. Men and women, aged 18 to 45 years, were assigned to one of four groups using a restricted randomization process. The training period was divided into two consecutive eight-week time blocks where subjects received either (1) supervised physical exercise therapy (PET), (2) neuromuscular stimulation (NMS), or (3) electromyographic (EMG) biofeedback. Group 1 received EMG biofeedback followed by PET; Group 2 received EMG biofeedback followed by NMS; Group 3 received NMS followed by PET; and Group 4 received 16 weeks of PET. Dependent measures (manual muscle tests, self-care scores, mobility measures, and voluntary EMG activity) were assessed before training, at eight weeks, and after 16 weeks of training. A significant improvement (p less than .05) across time was found on all dependent measures except voluntary EMG. No difference was found on comparisons between groups.     

Estimating the potential pool of uncontrolled DCD donors in the United States

Organs from uncontrolled DCD donors (uDCDs) have expanded donation in Europe since the 1980s, but are seldom used in the United States. Cited barriers include lack of knowledge about the potential donor pool, lack of robust outcomes data, lack of standard donor eligibility criteria and preservation methods, and logistical and ethical challenges. To determine whether it would be appropriate to invest in addressing these barriers and building this practice, we sought to enumerate the potential pool of uDCD donors. Using data from the Nationwide Emergency Department Sample, the largest all‐payer emergency department (ED) database, between 2013 and 2016, we identified patients who had refractory cardiac arrest in the ED. We excluded patients with contraindications to both deceased donation (including infection, malignancy, cardiopulmonary disease) and uDCD (including hemorrhage, major polytrauma, burns, and poisoning). We identified 9828 (range: 9454‐10 202) potential uDCDs/y; average age was 32 years, and all were free of major comorbidity. Of these, 91.1% had traumatic deaths, with major causes including nonhead blunt injuries (43.2%) and head injuries (40.1%). In the current era, uDCD donors represent a significant potential source of unused organs. Efforts to address barriers to uDCD in the United States should be encouraged.