Weeks Of Survival Research Articles

Abstract 564: Xenograft of Human Mesenchymal Stem Cells to Canine Myocardial Infarction Model with or without Epicardial Pacing has no Immune Rejection, But Proarrhythmia and Sympathetic Nerve Sprouting

Background Cardiac resynchronization therapy reduces morbidity and mortality in patients with heart failure, and mesenchymal stem cells (MSC) transplantation has a potential for the improvement of ventricular function, especially in acute stage of myocardial infarction. However, the safety of combined left ventricular (LV) epicardial pacing (EpiP) and MSC transplantation in acute myocardial infarction (AMI) has not been studied. Methods and Results We explored the safety of human MSC (hMSC) transplantation in 15 canine model of with or without AMI or LV EpiP. AMI was made by ligation of proximal left circumflex coronary artery in open chest canine model, and positioned EpiP electrode on the peri-infarct zone (DDD mode, 3.5 V, minimal AV delay 150 ms). Implantable cardioverter defibrillator (ICD) was implanted in right ventricular endocardium to monitor ventricular arrhythmia. hMSC (1x10 7 in 1 mL, 5 sites) were injected subepicardially 15 mm separated from pacing electrode. We compared hMSC+EpiP+AMI (n=5), hMSC+EpiP (n=5), hMSC only (n=5), and sham operation (n=1) by ICD egm analysis and immunohistochemistry after 4 weeks of survival. Results: 1. 80% of hMSC+EpiP+AMI group, 60% of hMSC+EpiP group, 40% of hMSC only group, and none of control revealed spontaneous ventricular tachyarrhythmia (VT) episodes in stored ICD egm, and 60%, 40%, 20%, and 0% of each group died suddenly at 5.3±6.6 days after surgery. 2. Human nucleolin positive hMSC with vimenting positive meosdermal differentiation were observed at the subepicardial peri-infarct zone without any evidence of immune rejection. 3. The hMSC transplanted hearts expressed higher density of tyrosine hydroxylase positive cardiac nerves compared with control dog. Conclusion Although hMSC xenograft to canine AMI and EpiP model showed successful engraftment of hMSC without immune rejection, VT and sudden death with sympathetic hyper-innervation happened frequently.

Cognitive Change in Special Forces Personnel following Stressful Survival Training

Understanding the deterioration in cognitive functioning produced by stress continues to gain in importance due to the increasing demands imposed by technologically sophisticated systems. Although the general deleterious effects of stress are well established, the relative sensitivity of different cognitive functions to stress and the pattern of cognitive recovery with rest have not been fully distinguished. In this paper, we examined the cognitive performance of Special Forces soldiers immediately prior to and immediately following one week of Survival, Evasion, Resistance and Escape (SERE) School training at Ft. Bragg, NC. Post-stress cognitive performance was characterized by significantly increased response time with minimal change in response accuracy. While response time increased for all tasks, memory appears to be most sensitive to stress. Performance returned to pre-stress levels the next morning following one night of sleep. The tasks affected most in the current study differed from changes which follow primarily upon physical stress, implying that the effects of combined psychological and physical stress on cognitive performance differ substantively from the effects of physical demand alone.

Persistence ofStreptococcus pyogenesin Stationary-Phase Cultures

In addition to causing fulminant disease, Streptococcus pyogenes may be asymptomatically carried between recurrent episodes of pharyngitis. To better understand streptococcal carriage, we characterized in vitro long-term stationary-phase survival (>4 weeks) of S. pyogenes. When grown in sugar-limited Todd-Hewitt broth, S. pyogenes cells remained culturable for more than 1 year. Both Todd-Hewitt supplemented with excess glucose and chemically defined medium allowed survival for less than 1 week. After 4 weeks of survival in sugar-limited Todd-Hewitt broth, at least 10(3) CFU per ml remained. When stained with fluorescent live-dead viability stain, there were a number of cells with intact membranes that were nonculturable. Under conditions that did not support persistence, these cells disappeared 2 weeks after loss of culturability. In persistent cultures, these may be cells that are dying during cell turnover. After more than 4 weeks in stationary phase, the culturable cells formed two alternative colony phenotypes: atypical large colonies and microcolonies. Protein expression in two independently isolated microcolony strains, from 14-week cultures, was examined by use of two-dimensional electrophoresis. The proteomes of these two strains exhibited extensive changes compared to the parental strain. While some of these changes were common to the two strains, many of the changes were unique to a single strain. Some of the common changes were in metabolic pathways, suggesting a possible alternate metabolism for the persisters. Overall, these data suggest that under certain in vitro conditions, S. pyogenes cells can persist for greater than 1 year as a dynamic population.

Optimal blood glucose levels while using insulin to minimize the size of infarction in focal cerebral ischemia.

Insulin has been shown to ameliorate cerebral necrosis in global and, more recently, in focal cerebral ischemia. The goal of this study was to determine the relationship between this neuroprotective effect and blood sugar levels in a rat model of focal ischemia. Thirty-four rats were subjected to 80 minutes of transient middle cerebral artery occlusion at a mean arterial blood pressure of 60 mm Hg and a temperature of 37 degrees C. Insulin (3.5 IU/kg) was administered 1 hour before (12 rats) and 20 minutes after (12 rats) ischemia; 10 animals served as controls. A quantitative histopathological study conducted after 1 week of survival showed that insulin was not beneficial in reducing the size of the infarction or selective neuronal necrosis in the penumbra when administered before or after ischemia. In addition to infarction, six animals from the insulin-treated groups had bilateral selective neuronal necrosis in the hippocampus or the neocortex. A nonlinear regression analysis in which glucose levels were compared with both cortical necrosis and total infarction yielded a U-shaped curve with a nadir for cerebral necrosis that lay in the 6- to 7-mM blood glucose range. The increased brain damage induced by insulin occurred in animals with very low blood sugar values in the range of 2 to 3 mM. These results in rats indicate that if insulin is used following ischemia, blood glucose levels should be maintained at approximately 6 to 7 mM. From these data one can infer that hypoglycemia of less than 3 mM should be avoided in situations of focal cerebral ischemia in which insulin is used. Additional animal studies and clinical trials in humans are needed to study the effects of insulin on ischemia.

NERVE SPARING RADICAL PROSTATECTOMY: EFFECTS OF HEMOSTATIC ENERGY SOURCES ON THE RECOVERY OF CAVERNOUS NERVE FUNCTION IN A CANINE MODEL

To preserve sexual function following radical prostatectomy, one must avoid injury to the neurovascular bundles (NVBs). In the conventional open surgical technique, the use of energy sources for hemostasis is avoided to prevent damage to the cavernous nerves. In contrast, during laparoscopic radical prostatectomy, electrosurgical and ultrasonic energy sources are frequently used for hemostasis during dissection of the prostate. In this study, we evaluated the acute and chronic physiological effects of various hemostatic energy sources on cavernous nerve function in the canine model. A total of 12 dogs were divided into 4 groups based on the type of energy source used for hemostasis during unilateral dissection of the NVB. The groups included conventional dissection with suture ligatures (group 1), monopolar (group 2) or bipolar (group 3) electrosurgery and ultrasonic shears (group 4). The contralateral NVB was left undissected as a control. Erectile function was assessed acutely and after 2 weeks of survival by measuring peak intracavernous pressures in response to cavernous nerve stimulation. Following conventional techniques of nerve sparing, the erectile response to nerve stimulation was unaffected. In contrast, the use of energy sources in proximity to the NVB during nerve preservation was associated with a substantial decrease in erectile response both acutely (74% to 91% decrease compared to controls) and after 2 weeks (93% to 96% decrease). In the chronic canine model, use of hemostatic energy sources in proximity to the prostate during dissection of the neurovascular bundle is associated with a significantly decreased erectile response to cavernous nerve stimulation.

Debris of “dark” (compacted) neurones are removed from an otherwise undamaged environment mainly by astrocytes via blood vessels

By means of a condenser-discharge electric shock paradigm, "dark" granule neurones were momentarily produced in a sporadic distribution among normal ones in the otherwise undamaged (non-necrotic, non-excitotoxic, non-inflammatory or non-contused) hippocampal dentate gyri of the rat brain. In the electron microscope, the ultrastructural elements of the affected neurones remained undamaged but turned markedly electron-dense and the distances between them became strikingly reduced (compaction). A proportion of such neurones recovered in 1 day while others died. During the first week of survival, the dead "dark" granule neurones retained the compacted and electron-dense ultrastructure, but underwent cytoplasmic convolution and fragmentation. The fragments were enclosed by membranes and separated from each other and from the intact neuropil by astrocytic processes containing an excess of glycogen particles. Neither proliferation of microglial cells nor infiltration of haematogenous macrophages was observed. A few fragments were taken over by resting microglial cells, while the majority was engulfed by astrocytes. The latter transported the engulfed fragments, either unchanged or digested to various degrees, to capillaries, arterioles and venules. Thereafter, the astrocyte-engulfed neuronal fragments, as well as their partly or completely digested remnants, were either transferred to phagocytotic pericytes or discharged into vascular lumina.

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat amygdala

BackgroundVolumetric changes and glial pathology have been reported in the amygdala in patients with major depressive disorder. Here we report an analysis of glial cell proliferation in response to electroconvulsive seizures (ECS), clinically used for the treatment of severe depression. MethodsMale Wistar rats were subjected to five ECS-treatments and then injected with bromodeoxyuridine (BrdU) to detect cell proliferation in the amygdala. The animals were transcardially perfused either 12 hours or 3 weeks after the last BrdU injection. Tissue sections were double-stained for BrdU and the cell-type markers NG2, OX-42, RIP, S-100β, Doublecortin, or NeuN. ResultsElectroconvulsive seizures dramatically increased the proliferation of amygdala cells expressing the oligodendrocyte progenitor marker NG2. Bromodeoxyuridine-labeled NG2-expressing cells were still present after 3 weeks of survival, and a small proportion of the proliferating cells had differentiated into mature oligodendrocytes. ConclusionsMajor depression has been associated with a reduction of glial cells. Our results show that ECS, an antidepressant treatment, significantly increases the number of NG2+ glial cells and mature oligodendrocytes in the adult rat amygdala.

Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla

Ethacrynic acid (EA) is known to interact with aminoglycoside antibiotics such as gentamicin (GM). In the chinchilla, co-administration of GM and EA can produce hair cell lesions ranging from a small loss of outer hair cells (OHCs) in the base of the cochlea to complete destruction of all hair cells, depending on dosing parameters. Although hair cell loss has been characterized, little is known about the fate of efferent fibers or spiral ganglion neurons (SGNs) in this model. To study the time course of efferent fiber and SGN loss, chinchillas were injected with GM (125 mg/kg IM) followed immediately by EA (40 mg/kg IV). Estimates of efferent fiber loss and density changes were made after 3 days or 1, 2, 3, or 4 weeks of survival. Estimates of SGN loss and density changes were made after 15 days or 1, 2, 4, or 6 months of survival. Cochlear function was rapidly abolished and all cochlear hair cells were missing within 24 h after treatment. Inner hair cells (IHCs) in the middle turn of the cochlea died earlier than cells in the apex or base, and OHCs in Rows 1 and 2 died earlier than OHCs in Row 3. Degeneration of efferent nerve fibers began 3–7 days post-injection, versus 15–30 days for SGNs, and the loss of efferent fibers was essentially complete within 1 month, versus 2–4 months for SGNs. The rapid time course of efferent fiber and SGN loss in the chinchilla may make it a practical model for studying mechanisms of neural loss and survival in the mammalian inner ear.

Deep circumflex iliac cutaneous free flap in cats.

To develop and assess the survival of a microvascular cutaneous free flap based on the ventral branch of the deep circumflex iliac (DCI) artery and vein in cats. Experimental study. Phase 1: 6 feline cadavers; Phase 2: 2 adult cats; Phase 3: 10 adult cats. Phase 1: Selective angiographic study of the deep circumflex iliac artery was completed in 6 feline cadavers. After injection of the DCI artery with barium, high-detail radiographs were made of skin flaps harvested from the lateral flank and thigh region. The extent of the cutaneous angiosome was mapped with regard to the underlying anatomical landmarks. Phase 2: An island flap based on anatomic boundaries of the DCI angiosome derived from phase 1 of the study was elevated in 2 cats. Flaps were observed for 3 weeks for survival. Phase 3: Free skin flaps based on the DCI vessels were harvested in 10 cats and transferred to the dorsal interscapular region. Flaps were evaluated for 2 weeks for survival. Tissue samples were collected for histopathology, and angiograms of the flaps were completed. Phase 1: Angiograms revealed a large primary cutaneous angiosome of the DCI artery located over the lateral femoral region, which extended from the iliac crest to the level of the patella. Phase 2: All island flaps survived for 3 weeks. Phase 3: Six free flaps survived for 2 weeks, and 4 flaps failed completely. Failure of 1 flap occurred because of avulsion of the venous and arterial anastomosis postoperatively. Another cat had intraoperative hemorrhage, which resulted in anemia and hypovolemia and likely caused the flap to fail. The other 2 flaps that failed had poor perfusion intraoperatively and had the longest ischemia times. The cutaneous DCI free flap in cats may be clinically useful in reconstruction of large cutaneous wounds. The length of ischemia time for successful cutaneous free flap transfer in the cat may be shorter than in other species. Large wounds created by trauma or oncologic ablative surgery in cats could be reconstructed with cutaneous microvascular free flap. Additional studies assessing the critical ischemia time of cutaneous flaps in cats and evaluating the use of this flap clinically are needed.

Activation of mitogen-activated protein kinases in experimental cerebral ischemia.

Mitogen-activated protein kinases (MAPK) regulate cell survival and differentiation. The aim of the present study is to investigate the activation pattern of different MAPKs [extracellular signal-regulated kinase (ERK), c-jun-N-terminal kinase (JNK) and p38] after cerebral ischemia. Rats were subjected to cerebral ischemia using a model for transient (2 h) and permanent middle cerebral artery occlusion (MCAO). The rats were allowed 6 h to 1 week of survival before immunohistochemical evaluation with phospho-specific antibodies, recognizing activated MAPKs. ERK was activated in ipsilateral blood vessels, neurons and glia, but also in contralateral vessels. JNK activation was absent in neurons but appeared in arterial blood vessels and glia at the lesion side. Active p38 was observed in macrophages in maturing infarcts. ERK and JNK may participate in the angiogenic response to cerebral ischemia. ERK, but not JNK, was activated in neurons, possibly indicating a pathophysiologic role. Active p38 might be involved in the inflammatory reaction.

New Patterns of Intracortical Projections after Focal Cortical Stroke

Cortical strokes alter functional maps but associated changes in connections have not been documented. The neuroanatomical tracer biotinylated dextran amine (BDA) was injected into cortex bordering infarcts 3 weeks after focal strokes in rat whisker barrel (somatosensory) cortex. The mirror locus in the opposite hemisphere was injected as a control. After 1 week of survival, brains were processed for cytochrome oxidase (CO)-, Nissl-, and BDA-labeled neurons. Cortex bordering the infarct (peri-infarct cortex) had abnormal CO and Nissl structure. BDA-labeled neurons were plotted and projections were analyzed quantitatively. Animals with small strokes had intracortical projections, arising from peri-infarct cortex, not seen in normal hemispheres: the overall orientation was statistically significantly different from and rotated 157° relative to the controls. Compared to the controls, significantly fewer cells were labeled in the thalamus. Thus, after focal cortical stroke, the peri-infarct cortex is structurally abnormal, loses thalamic connections, and develops new horizontal cortical connections by axonal sprouting.

Changes of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors in layer v of epileptogenic, chronically isolated rat neocortex

In vivo chronic partial isolation of neocortical islands results in epileptogenesis that involves pyramidal neurons of layer V. To test whether an alteration in glutamate receptors might contribute to the epileptiform activity, we analysed the time-course of light microscopic changes in expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors using subunit-specific antibodies. The isolation caused a rapid down-regulation of immunoreactivity for GluR1 and GluR2/3 subunits in deep layer V pyramidal neurons within the neocortical island which was evident 24 h post-lesion, and within three days was reduced to about 40–60% of the control level. Many pyramidal cells in deep layer V completely lacked GluR2. Between one and four weeks of survival, down-regulation of GluR2/3 and GluR2 involved the majority of pyramidal layer V neurons, except for cells in the upper part of layer V, and those within narrow areas of all sub-laminae of layer V (“micro-islands”). Initial down-regulation was also observed one to three days post-lesion for subunits 1 and 2 of the N-methyl- d-aspartate receptor, but in contrast to GluR2/3 immunoreactivity, NMDAR2A/B immunoreactivity was enhanced three weeks post-lesion. The present data provide evidence for plastic changes in glutamate receptors in neurons of partially isolated neocortical island. A sub-population of layer V neurons remains relatively unaffected, and would presumably be capable of generating fast glutamatergic synaptic potentials necessary for the development of synchronous epileptiform activity.

Induced hypothermia during emergency department thoracotomy: an animal model.

Induced hypothermia is used clinically to prevent ischemic injury during elective procedures. We present an animal model of asanguinous hypothermic (10 degrees C) circulatory arrest, induced through a left anterior lateral thoracotomy after exsanguinating uncontrolled hemorrhage. Through a left anterior thoracotomy, 26 swine (45-70 kg) sustained a laceration of the descending thoracic aorta, producing exsanguinating uncontrolled hemorrhage. After 5 minutes of severe hypotension (systolic BP <20 mm Hg), a 22 French Foley catheter was directed cephalad through the enlarged aortic wound. A solution (containing 42.5 mmol/L K+ and precooled to 1 degrees C) was infused to arrest/preserve the heart and brain. A second 24 French Foley catheter was then directed caudally through the same wound. The right atrium was opened to drain the venous system. The animal was cooled with a cardiopulmonary bypass pump (>5L/min) through the Foley catheters. Once 10 degree C was reached, a cannula was placed to the aortic root and the aortic laceration repaired. The animal was maintained at 10 degree C for a total of 90 minutes. Before the rewarming process, the circulation was rinsed with a solution containing normal levels of electrolytes followed by infusion of whole blood. Rewarming was performed by maintaining a 10-degree gradient on the heat exchanger. The first 16 animals were used in nonsurvival experiments to develop the technique and to record dural temperatures and electroencephalogram tracings. The last 10 animals were used to determine long-term survival and neurologic outcome. Group I: seven animals were kept at < 10 degrees C with flows less than 2L/min. Group II: three animals underwent 20, 30, and 40 minutes of no flow once they were cooled to 10 degrees C. After 6 weeks of survival and neurologic examinations, the brains were fixed for histologic evaluations. The average time to cool the head to 18 degrees C and 10 degrees C was 6 minutes and 12 minutes, respectively. The hematocrit fell below 2% by the end of the cooling period. A total of 7 of the 10 animals from the long-term study survived. Group I: five of seven animals survived. Four of the survivors had no appreciable neurologic deficits, were fully functional at 6 weeks, and had no evidence of histologic injury. One of the five survivors in this group had moderate neurologic disability. Of the two animals that died, one died from air embolism from the i.v. line. The second death was in an animal for which maximal cooling to 2.7 degrees C was attempted. Group II: The first two animals that had "no flow" for 20 and 30 minutes were fully functional and had normal neurologic examinations. However, the second animal was found to have brain injury on histologic examination. The last animal in this group died of accidental extubation during recovery. Induction of hypothermic arrest through the chest after exsanguination is possible. The further development of this technique may provide an extended state of "suspended animation" to allow for repairs of hemorrhaging injuries in trauma patients who require emergency department thoracotomy.

Cadmium Levels in Feed Components and Kidneys of Growing/Finishing Pigs

Cadmium (Cd) concentrations in pig feeds (one control feed and one feed with reduced nitrogen content), straw, water, and pig kidney cortex were determined in 2 breeds of growing/finishing pigs (n = 96). The total Cd intake from feed was calculated. Feed mixtures and components, straw and kidney cortex samples, and certified reference samples were microwave-digested and analyzed by atomic absorption spectrometry with graphite furnace technique. Total Cd concentration in the control feed was 37.1 micrograms/kg wet weight (w.wt). The highest Cd levels were found in nonlocally produced feed components: vitamin-mineral mixture, lime, dicalcium phosphate, soybean meal, and rapeseed meal. These components contributed 70% of the Cd content in the feed. The main component, barley, which was locally produced, contributed 30% of the total Cd content in feed. The feed with reduced nitrogen content contained less soybean and rapeseed meal and a lower Cd level than the control feed. The Cd levels in kidney cortex varied from 38.0 to 105 micrograms/kg w.wt, with a mean level of 70.9 micrograms/kg. The levels differed between breeds and feeds, but not between gender. There was a significant correlation between Cd level in kidney cortex and age at slaughter, with an increase of 2.8 micrograms/kg w.wt in the kidney for each additional week of survival. The contribution of Cd from nonlocally produced feed components could have environmental effects through application of farmyard manure to local soils.

Nitric oxide synthase and growth-associated protein are coexpressed in primary sensory neurons after peripheral injury

A possible role for nitric oxide in growth and regeneration of dorsal root ganglion (DRG) afferents has been explored in lesion experiments by comparing immunocytochemistry for nitric oxide synthase (NOS) with that for the growth-associated phosphoprotein 43 (GAP-43). Sciatic nerve ligature induced a progressive increase in the number of small DRG cell profiles immunopositive for NOS between 2 days and 4 weeks of survival. In the proximal stump of the ligature, NOS-immunopositive fibers began to appear 2 days after injury and their growth cones were especially evident after 7 days. NOS-immunopositive fibers appeared past (i.e., distal to) the ligature at 14 days of survival and extended for at least 6 mm in either direction 4 weeks after the lesion. Dorsal root ligature alone at L4-L5 did not result in expression of NOS in DRG neurons or in the appearance of NOS-immunopositive fibers. In rats with dorsal root ligature and nerve ligature, the results were similar to those with nerve ligature only. DRG cell profiles immunopositive for GAP-43 kept increasing from 2 days to 4 weeks after sciatic nerve ligature and included small neurons initially and large neurons subsequently. Numerous axons became GAP-43 immunopositive on both sides of the ligature from 2 days after injury. In double-labeled material, about 80% of DRG cell profiles immunopositive for NOS were also immunopositive for GAP-43. The two antigens co-occurred in peripheral nerve axons proximal to the ligature starting at about 7 days and distal to it at about 2 weeks after ligature. Thus, in response to nerve lesion, nitric oxide may not only provide an injury signal to the central nervous system but may also contribute to the growth and regeneration of injured axons.

Neurogenesis and migration of receptor neurons in the vomeronasal sensory epithelium in the opossum, Monodelphis domestica.

The sensory epithelium of the vomeronasal organ (VNO) contains primary chemosensory receptor neurons that project to the accessory olfactory bulb (AOB). In the present study, neurogenesis and cell migration in the sensory epithelium of the VNO were analyzed in opossums (Monodelphis domestica) by using bromodeoxyuridine (BrdU) labeling. 1) In the VNO of normal adult opossums, BrdU labeled a small number of cells localized in the basal region of the sensory epithelium. After 1 or 2 weeks of survival, the labeled cells appeared in the receptor cell layers and became receptor neurons, as indicated by coexpression of the G proteins G(i alpha2) or G(o alpha). 2) In the VNO in which the receptor neurons had been destroyed by removing the AOB, the number of BrdU-labeled cells in the reconstituting sensory epithelium was greatly increased compared with that in the intact VNO. The labeled cells were also located in the basal region of the sensory epithelium. 3) In the developing VNO (at postnatal day 10), more cells in the basal region of the sensory epithelium were labeled than in the adult VNO, indicating rapid cell proliferation; and there appeared to be more labeled cells in the basal region near the margins of the sensory epithelium where it meets the nonsensory epithelium. These observations demonstrate that, in the opossum VNO, there is a population of proliferating cells in the basal region close to the basal lamina in the sensory epithelium. The newly generated neurons in the basal region migrate vertically into the receptor cell layer.

The costs of managing patients with malignant glioma at a neuro-oncology clinic*

Malignant glioma (glioblastoma and anaplastic astrocytoma) remain incurable despite extensive resection, radiotherapy, chemotherapy and experimentaltherapies. Few studieshave addressed either the costsofvarious treatmentsfor malignant glioma or their cost effectiveness. The aims of this study were to identify direct hospital costs of treating patients with biopsy proven malignant glioma. The study was carried out within the setting of a dedicated neuro-oncology clinic at a university teaching hospital and included 236 patients treated between 1989 and 1995. The study used the unit costing of each item of treatment according to NHS National Costing Project. The cost of treatment was broken down into its various components: bed days, investigations, surgery, radiotherapy, chemotherapy and neuro-oncology out-patient follow-ups. The mean costs for each of the items based on 1995 figures for the 157 patients having surgery followed by radiotherapy were neuroradiological investigations ( 442), neurosurgical bed days ( 2407), neurosurgery ( 2068), neuropathology ( 434), radiotherapy ( 8832), out-patients( 1078) and chemotherapy ( 440). Totaltreatmentcosts per patient ranged from 1978 to 26980. Median costs of care decreased sequentially with worsening MRC Brain Tumour prognostic group. Management of patients with the best prognosis (MRC index score of 1-10) cost a median of 16550 (range 4572-26,090) whilst the median management cost of those in the worst prognostic group (MRC score 34-38) was 6514(range 1978-18,360). The median costofeach week of survivalin the patients with the bestoutcome (MRC score 1-10) was 150 compared to 232 for each week of survival for patients in the worst prognostic group (MRC score 34-38). This study made no attempt to collect costs of supportive or community-based care. Prospective studies are required to collect such data, as well as assessing the costs effectiveness of alternative treatment strategies.

A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases

The median survival of well-selected patients with single-brain metastases treated with whole-brain irradiation and resection or radiosurgery is comparable, although a randomized trial of these two modalities has not been performed. In this era of cost containment, it is imperative that health-care professionals make fiscally prudent decisions. The present environment necessitates a critical appraisal of apparently equi-efficacious therapeutic modalities, and it is within this context that we present a comparison of the actual costs of resection and radiosurgery for brain metastases. Survival and quality of life outcome data for radiation alone or with surgery were obtained from two randomized trials, and radiosurgical results were obtained from a multiinstitutional analysis that specifically evaluated patients meeting surgical criteria. Only linear accelerator radiosurgery data were considered. Cost analysis was performed from a societal view point, and the following parameters were evaluated: actual cost, cost ratios, cost effectiveness, incremental cost effectiveness, cost utility, incremental cost utility, and national cost burden. The computerized billing records for all patients undergoing resection or radiosurgery for single-brain metastases from January 1989 to July 1994 were reviewed. A total of 46 resections and 135 radiosurgery procedures were performed. During the same time period, 454 patients underwent whole-brain radiation alone. An analysis of the entire bill was performed for each procedure, and each itemized cost was assigned a proportionate figure. The relative cost ratios of resection and radiosurgery were compared using the Wilcoxon rank sum test. Cost effectiveness of each modality, defined as the cost per year of median survival, was evaluated. Incremental cost effectiveness, defined as the additional cost per year of incremental gain in median survival, compared to the next least expensive modality, was also determined. To calculate the societal or national impact of these practices, the proportion of patients potentially eligible for aggressive management was estimated and the financial impact was determined using various utilization ratios for radiosurgery and surgery. Both resection and radiosurgery yielded superior survival and functional independence, compared to whole brain radiotherapy alone, with minor differences in outcome between the two modalities; resection resulted in a 1.8-fold increase in cost, compared to radiosurgery. The latter modality yielded superior cost outcomes on all measures, even when a sensitivity analysis of up to 50% was performed. A reversal estimate indicated that in order for surgery to yield equal cost effectiveness, its cost would have to decrease by 48% or median survival would have to improve by 108%. The average cost per week of survival was $310 for radiotherapy, $524 for resection plus radiation, and $270 for radiosurgery plus radiation. For selected patients, aggressive strategies such as resection or radiosurgery are warranted, as they result in improved median survival and functional independence. Radiosurgery appears to be the more cost-effective procedure.

A population of nicotinic receptors is associated with thalamocortical afferents in the adult rat: laminal and areal analysis.

In the adult rat brain, a prominent population of nicotinic cholinoceptors binds 3H-nicotine with nanomolar affinity. These receptors are abundant in most thalamic nuclei and in neocortical layers 3/4, which receive a major thalamic input. To test whether cortical nicotinic receptors are associated with thalamocortical afferents, unilateral excitotoxic (N-methyl-D-aspartate) lesions were made in one of four thalamic nuclear groups (anterior, ventral, medial geniculate, or dorsal lateral geniculate) or in temporal cortex. After 1 or 4 weeks of survival, cortical 3H-nicotine binding was quantified via autoradiography. Thalamic lesions resulted in a partial loss of 3H-nicotine binding in ipsilateral cerebral cortex. In each thalamic lesion group, the greatest decrease (35-45%) occurred within the cortical layers and area (i.e., cingulate, parietal, temporal, or occipital cortex) receiving the densest thalamocortical innervation. Binding of 3H-nicotine was also reduced within the thalamus local to the lesion, particularly at the longer survival time. Saturation analysis, performed in frontoparietal cortical tissue homogenates following ventral thalamic lesions, revealed a significant (34%) reduction in receptor density but not affinity. Direct excitotoxic lesions of the neocortex (temporal cortex) tended to preserve 3H-nicotine binding in layers 3/4, despite local neuronal loss. These results, taken with other published findings, suggest that some nicotinic cholinoceptors in adult rat cerebral cortex are located on thalamocortical terminals. This organizing principle appears to apply not only to sensory and motor relay projections but also to association nuclei that project to allocortical areas. These receptors may provide a local mechanism for nicotinic cholinergic modulation of thalamocortical input.

Effect of Age and Sex on N -Methyl- d -Aspartate Antagonist-Induced Neuronal Necrosis in Rats

Although N-methyl-D-aspartate (NMDA) antagonism may be a useful therapeutic approach in stroke treatment, it has been found that these pharmacological agents cause neuronal necrosis in restricted cortical regions of the rodent brain. To test the hypothesis that age and sex influence NMDA antagonist-induced neuronal necrosis, male and female rats were studied at 2 months (young), 12 months (middle-aged), and 24 months (old) of age. A dose of 5 mg/kg MK-801 was administered, followed by quantitation of neuronal necrosis at nine coronal levels in the cingulate and retrosplenial cortex at 1 week of survival. Mortality was dependent on age but not sex and was higher in the old rats (P<.01). The number of necrotic neurons per hemisphere was greater in female than in male rats at all ages (P<.0001). Female rats also showed increasing neuronal necrosis with age (P<.05). The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susceptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in human stroke.