Influence of brain death and associated trauma on solid organ histological characteristics

PURPOSE: To evaluate histopathological alterations triggered by brain death and associated trauma on different solid organs in rats. METHODS: Male Wistar rats (n=37) were anesthetized with isoflurane, intubated and mechanically ventilated. A trepanation was performed and a balloon catheter inserted into intracraninal cavity and rapidly inflated with saline to induce brain death. After induction, rats were monitored for 30, 180, and 360 min for hemodynamic parameters and exsanguinated from abdominal aorta. Heart, lung, liver, and kidney were removed and fixed in paraffin to evaluation of histological alterations (H&E). Sham-operated rats were trepanned only and used as control group. RESULTS: Brain dead rats showed a hemodynamic instability with hypertensive episode in the first minute after the induction followed by hypotension for approximately 1 h. Histological analyses showed that brain death induces vascular congestion in heart (p<0.05), and lung (p<0.05); lung alveolar edema (p=0.001), kidney tubular edema (p<0.05); and leukocyte infiltration in liver (p<0.05). CONCLUSIONS: Brain death induces hemodynamic instability associated with vascular changes in solid organs and compromises most severely the lungs. However, brain death associated trauma triggers important pathophysiological alterations in these organs.

Inhibition of Autonomic Storm by Epidural Anesthesia Does Not Influence Cardiac Inflammatory Response After Brain Death in Rats

Background. After brain death (BD) donors usually experience cardiac dysfunction, which is responsible for a considerable number of unused organs. Causes of this cardiac dysfunction are not fully understood. Some authors argue that autonomic storm with severe hemodynamic instability leads to inflammatory activation and myocardial dysfunction. Objectives. To investigate the hypothesis that thoracic epidural anesthesia blocks autonomic storm and improves graft condition by reducing the inflammatory response. Methods. Twenty-eight male Wistar rats (250-350 g) allocated to four groups received saline or bupivacaine via an epidural catheter at various times in relation to brain-death induction. Brain death was induced by a sudden increase in intracranial pressure by rapid inflation of a ballon catheter in the extradural space. Blood gases, electrolytes, and lactate analyses were performed at time zero, and 3 and 6 hours. Blood leukocytes were counted at 0 and 6 hours. After 6 hours of BD, we performed euthanasia to measure vascular adhesion molecule (VCAM)-1, intracellular adhesion molecule (ICAM)-1, interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, Bcl-2 and caspase-3 on cardiac tissue. Results. Thoracic epidural anesthesia was effective to block the autonomic storm with a significant difference in mean arterial pressure between the untreated (saline) and the bupivacaine group before BD (P < .05). However, no significant difference was observed for the expressions of VCAM-1, ICAM-1, TNF-alpha, IL-1 beta, Bcl-2, and caspase-3 (P > .05). Conclusion. Autonomic storm did not seem to be responsible for the inflammatory changes associated with BD; thoracic epidural anesthesia did not modify the expression of inflammatory mediators although it effectively blocked the autonomic storm.

Paradoxical effects of brain death and associated trauma on rat mesenteric microcirculation: an intravital microscopic study

OBJECTIVE: Experimental findings support clinical evidence that brain death impairs the viability of organs for transplantation, triggering hemodynamic, hormonal, and inflammatory responses. However, several of these events could be consequences of brain death-associated trauma. This study investigated microcirculatory alterations and systemic inflammatory markers in brain-dead rats and the influence of the associated trauma. METHOD: Brain death was induced using intracranial balloon inflation; sham-operated rats were trepanned only. After 30 or 180 min, the mesenteric microcirculation was observed using intravital microscopy. The expression of P-selectin and ICAM-1 on the endothelium was evaluated using immunohistochemistry. The serum cytokine, chemokine, and corticosterone levels were quantified using enzyme-linked immunosorbent assays. White blood cell counts were also determined. RESULTS: Brain death resulted in a decrease in the mesenteric perfusion to 30%, a 2.6-fold increase in the expression of ICAM-1 and leukocyte migration at the mesentery, a 70% reduction in the serum corticosterone level and pronounced leukopenia. Similar increases in the cytokine and chemokine levels were seen in the both the experimental and control animals. CONCLUSION: The data presented in this study suggest that brain death itself induces hypoperfusion in the mesenteric microcirculation that is associated with a pronounced reduction in the endogenous corticosterone level, thereby leading to increased local inflammation and organ dysfunction. These events are paradoxically associated with induced leukopenia after brain damage.

A graph-theoretical approach in brain functional networks. Possible implications in EEG studies

Abstract Background Recently, it was realized that the functional connectivity networks estimated from actual brain-imaging technologies (MEG, fMRI and EEG) can be analyzed by means of the graph theory, that is a mathematical representation of a network, which is essentially reduced to nodes and connections between them. Methods We used high-resolution EEG technology to enhance the poor spatial information of the EEG activity on the scalp and it gives a measure of the electrical activity on the cortical surface. Afterwards, we used the Directed Transfer Function (DTF) that is a multivariate spectral measure for the estimation of the directional influences between any given pair of channels in a multivariate dataset. Finally, a graph theoretical approach was used to model the brain networks as graphs. These methods were used to analyze the structure of cortical connectivity during the attempt to move a paralyzed limb in a group (N=5) of spinal cord injured patients and during the movement execution in a group (N=5) of healthy subjects. Results Analysis performed on the cortical networks estimated from the group of normal and SCI patients revealed that both groups present few nodes with a high out-degree value (i.e. outgoing links). This property is valid in the networks estimated for all the frequency bands investigated. In particular, cingulate motor areas (CMAs) ROIs act as ‘‘hubs’’ for the outflow of information in both groups, SCI and healthy. Results also suggest that spinal cord injuries affect the functional architecture of the cortical network sub-serving the volition of motor acts mainly in its local feature property. In particular, a higher local efficiency El can be observed in the SCI patients for three frequency bands, theta (3-6 Hz), alpha (7-12 Hz) and beta (13-29 Hz). By taking into account all the possible pathways between different ROI couples, we were able to separate clearly the network properties of the SCI group from the CTRL group. In particular, we report a sort of compensatory mechanism in the SCI patients for the Theta (3-6 Hz) frequency band, indicating a higher level of “activation” Ω within the cortical network during the motor task. The activation index is directly related to diffusion, a type of dynamics that underlies several biological systems including possible spreading of neuronal activation across several cortical regions. Conclusions The present study aims at demonstrating the possible applications of graph theoretical approaches in the analyses of brain functional connectivity from EEG signals. In particular, the methodological aspects of the i) cortical activity from scalp EEG signals, ii) functional connectivity estimations iii) graph theoretical indexes are emphasized in the present paper to show their impact in a real application.

Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy

Postmortem decomposition of brain tissue was investigated by (1)H-magnetic resonance spectroscopy (MRS) in a sheep head model and selected human cases. Aiming at the eventual estimation of postmortem intervals in forensic medicine, this study focuses on the characterization and identification of newly observed metabolites. In situ single-voxel (1)H-MRS at 1.5 T was complemented by multidimensional homo- and heteronuclear high-resolution NMR spectroscopy of an extract of sheep brain tissue. The inclusion of spectra of model solutions in the program LC Model confirmed the assignments in situ. The first postmortem phase was characterized mainly by changes in the concentrations of metabolites usually observed in vivo and by the appearance of previously reported decay products. About 3 days postmortem, new metabolites, including free trimethylammonium, propionate, butyrate, and iso-butyrate, started to appear in situ. Since the observed metabolites and the time course is comparable in sheep and human brain tissue, the model system seems to be appropriate.

Comprehensive rehabilitation in chronic heart failure - better psycho-emotional status related to quality of life, brain natriuretic peptide concentrations, and clinical severity of disease

To evaluate the effects of a comprehensive outpatient rehabilitation program in chronic heart failure (CHF) on quality of life (QoL) in relation to emotional status and clinical severity of disease.

Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice

BACKGROUND There is an urgent need for preclinical models of prostate cancer; however, clinically relevant patient-derived prostate cancer xenografts (PDXs) are demanding to establish. METHODS Sixty-seven patients who were undergoing palliative transurethral surgery or radical prostatectomy for histologically confirmed, clinically relevant prostate cancer were included in the study. Fresh prostate cancer tissue was identified by frozen analysis in 48 patients. The cancer tissue was transplanted subcutaneously and under the renal capsule of NSG and NOG mice supplemented with human testosterone. All growing PDXs were evaluated by histology and immunohistochemistry. RESULTS Early assessment of the animals at least three months after transplantation included 27/48 (56.3%) eligible PDX cohorts. PDX growth was detected in 10/27 (37%) mouse cohorts. Eight of the ten PDXs were identified as human donor derived lymphomas, including seven Epstein Barr virus (EBV)-positive diffuse large B-cell lymphomas and one EBV-negative peripheral T-cell lymphoma. One sample consisted of benign prostatic tissue, and one sample comprised a benign epithelial cyst. Prostate cancer was not detected in any of the samples. CONCLUSIONS Tumors that arise within the first three months after prostate cancer xenografting may represent patient-derived EBV-positive lymphomas in up to 80% of the early growing PDXs when using triple knockout NSG immunocompromised mice. Therefore, lymphoma should be excluded in prostate cancer xenografts that do not resemble typical prostatic adenocarcinoma. Prostate 9999: XX-XX, 2014. © 2015 Wiley Periodicals, Inc.

Development and validation of the Neuro Symptom Inventory in the primary brain tumor patient population

Symptoms has been shown to predict quality of life, treatment course and survival in solid tumor patients. Currently, no instrument exists that measures both cancer-related symptoms and the neurologic symptoms that are unique to persons with primary brain tumors (PBT). The aim of this study was to develop and validate an instrument to measure symptoms in patients who have PBT. A conceptual analysis of symptoms and symptom theories led to defining the symptoms experience as the perception of the frequency, intensity, distress, and meaning that occurs as symptoms are produced, perceived, and expressed. The M.D. Anderson Symptom Inventory (MDASI) measures both symptoms and how they interfere with daily functioning in patients with cancer, which is similar to the situational meaning defined in the analysis. A list of symptoms pertinent to the PBT population was added to the core MDASI and reviewed by a group of experts for validity. As a result, 18 items were added to the core MDASI (the MDASI-BT) for the next phase of instrument development, establishing validity and reliability through a descriptive, cross-sectional approach with PBT patients. Data were collected with a patient completed demographic data sheet, an investigator completed clinician checklist, and the MDASI-BT. Analysis evaluated the reliability and validity of the MDASI-BT in PBT patients. Data were obtained from 201 patients. The number of items was reduced to 22 by evaluation of symptom severity as well as cluster analysis. Regression analysis showed more than half (56%) of the variability in symptom severity was explained by the brain tumor module items. Factor analysis confirmed that the 22 item MDASI-BT measured six underlying constructs: (a) affective; (b) cognitive; (c) focal neurologic deficits; (d) constitutional symptoms; (e) treatment-related symptoms; and (f) gastrointestinal symptoms. The MDASI-BT was sensitive to disease severity and if the patient was hospitalized. The MDASI-BT is the first instrument to measure symptoms in PBT patients that has demonstrated reliability and validity. It is the first step in a program of research to evaluate the occurrence of symptoms and plan and evaluate interventions for PBT patients. ^

Neurite, a finite difference large scale parallel program for the simulation of the electrical signal propagation in neurites under mechanical loading

With the growing body of research on traumatic brain injury and spinal cord injury, computational neuroscience has recently focused its modeling efforts on neuronal functional deficits following mechanical loading. However, in most of these efforts, cell damage is generally only characterized by purely mechanistic criteria, function of quantities such as stress, strain or their corresponding rates. The modeling of functional deficits in neurites as a consequence of macroscopic mechanical insults has been rarely explored. In particular, a quantitative mechanically based model of electrophysiological impairment in neuronal cells has only very recently been proposed (Jerusalem et al., 2013). In this paper, we present the implementation details of Neurite: the finite difference parallel program used in this reference. Following the application of a macroscopic strain at a given strain rate produced by a mechanical insult, Neurite is able to simulate the resulting neuronal electrical signal propagation, and thus the corresponding functional deficits. The simulation of the coupled mechanical and electrophysiological behaviors requires computational expensive calculations that increase in complexity as the network of the simulated cells grows. The solvers implemented in Neurite-explicit and implicit-were therefore parallelized using graphics processing units in order to reduce the burden of the simulation costs of large scale scenarios. Cable Theory and Hodgkin-Huxley models were implemented to account for the electrophysiological passive and active regions of a neurite, respectively, whereas a coupled mechanical model accounting for the neurite mechanical behavior within its surrounding medium was adopted as a link between lectrophysiology and mechanics (Jerusalem et al., 2013). This paper provides the details of the parallel implementation of Neurite, along with three different application examples: a long myelinated axon, a segmented dendritic tree, and a damaged axon. The capabilities of the program to deal with large scale scenarios, segmented neuronal structures, and functional deficits under mechanical loading are specifically highlighted.

Purified inositol hexakisphosphate kinase is an ATP synthase: diphosphoinositol pentakisphosphate as a high-energy phosphate donor.

Diphosphoinositol pentakisphosphate (PP-IP5) and bis(diphospho)inositol tetrakisphosphate (bis-PP-IP4) are recently identified inositol phosphates that possess pyrophosphate bonds. We have purified an inositol hexakisphosphate (IP6) kinase from rat brain supernatants. The pure protein, a monomer of 54 kDa, displays high affinity (Km = 0.7 microM) and selectivity for inositol hexakisphosphate as substrate. It can be dissociated from bis(diphospho)inositol tetrakisphosphate synthetic activity. The purified enzyme transfers a phosphate from PP-IP5 to ADP to form ATP. This ATP synthase activity indicates the high phosphate group transfer potential of PP-IP5 and may represent a physiological role for PP-IP5.

DUI program as OEF/OIF Veterans Outreach: Descriptive Data from Two Community-Based Outpatient Clinics

Although initially conceived as providing simply the preventive portion of an extended continuum of care for veterans, the Driving Under the Influence (DUI) program has turned out to be an important outreach service for active duty or recently discharged OEF/OIF (Operation Enduring Freedom/Operation Iraqi Freedom) veterans. Veterans receive empirically-based, state-mandated education and therapy under the only Department of Veterans Affairs (VA) - sponsored DUI program in the State of Colorado, with the advantage of having providers who are sensitive to symptoms of Post-Traumatic Stress Disorder (PTSD) and other relevant diagnoses specific to this population, including Traumatic Brain Injury (TBI). In this paper, the rapid growth of this program is described, as well as summary data regarding the completion, discontinuation, and augmentation of services from the original referral concern. Key results indicated that for nearly one third (31.9%) of the OEF/OIF veterans who were enrolled in the DUI program, this was their initial contact with the VA health care system. Furthermore, following their enrollment in the DUI program, more than one fourth (27.6%) were later referred to and attended other VA programs including PTSD rehabilitation and group therapy, anger management, and intensive inpatient or outpatient dual diagnosis programs. These and other findings from this study suggest that the DUI program may be an effective additional pathway for providing treatment that is particularly salient to the distinctive OEF/OIF population; one that may also result in earlier intervention for problem drinking and other problems related to combat. Relevant conclusions discussed herein primarily aim to improve providers' understanding of effective outreach, and to enhance the appropriate linkages between OEF/OIF veterans and existing VA services.

The Role of Hope in Rehabilitation and Long-term Outcomes among patients with Comorbid Spinal Cord and Traumatic Brain Injuries.

Spinal cord injury (SCI) and traumatic brain injury (TBI) are two potentially devastating conditions alone; when they co-occur in an individual they can be doubly so. The role of hope in rehabilitating oneself and recovering emotionally is examined in this paper. More specifically, Snyder's Model of Hope (1991) is examined as a tool that can aid in the rehabilitative process and help treatment providers, their patients, and the families of patients keep hope alive during a time of physical and emotional upheaval. This paper further examines the roles of hope in a rehabilitation program at Craig Hospital, a private, non-profit hospital dedicated exclusively to the rehabilitation of SCIs and TBIs and designated as a TBI and SCI Model Systems Center.

Stroke = brain attack : every minute counts! : stroke rehabilitation resource and information guide.

"8/06"--Colophon.

Encephalomeningocele (protrusion of brain substance, covered with membranes, through a defect in the skull), drawn by Jean Young, ca. 1935

Carbon dust on Ross Stipple Board with water color added