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Object: The management of intractable epilepsy remains a challenge, despite advances in its surgical and nonsurgical treatment. The identification of low-risk, low-cost therapeutic strategies that lead to improved outcome is therefore an important ongoing goal of basic and clinical research. Single-dose focal ionizing beam radiation delivered at necrosis-inducing and subnecrotic levels was investigated for its effects on seizure activity by using an established model of chronic recurrent spontaneous limbic seizures in rats., Methods: A single 90-minute period of repetitive electrical stimulation (inducing stimulus) of the hippocampus in rats elicited a single episode of status epilepticus, followed by a 2- to 4-week seizure-free period. Spontaneous recurrent seizures developed subsequently and persisted for the duration of monitoring (2-10 months). Simultaneous computerized electroencephalography and video recording were used to monitor the animals. After the establishment of spontaneous recurrent seizures, bilateral radiation centered in the ventral hippocampal formation was administered with the Leksell gamma knife, aided by a stereotactic device custom made for small animals. A center dose of 10, 20, or 40 Gy was administered using a 4-mm collimator. Control animals were subjected to the same seizure-inducing stimulus but underwent a sham treatment instead of gamma irradiation. In a second experiment, the authors examined the effects of gamma irradiation on the proclivity of hippocampal neurons to display epileptiform discharges. Naive animals were irradiated with a single 40-Gy dose, as already described. Slices of the hippocampus were prepared from animals killed between 1 and 178 days postirradiation. Sensitivity to penicillin-induced epileptiform spiking was examined in vitro in slices prepared from control and irradiated rat brains., Conclusions: In the first experiment, single doses of 20 or 40 Gy (but not 10 Gy) reduced substantially, and in some cases eliminated, behaviorally and electrographically recognized seizures. Significant reductions in both the frequency and duration of spontaneous seizures were observed during a follow-up period of up to 10 months postradiation. Histological examination of the targeted region did not reveal signs of necrosis. These findings indicate that single-dose focal ionizing beam irradiation at subnecrotic dosages reduces or eliminates repetitive spontaneous seizures in a rat model of temporal lobe epilepsy. In the second experiment, synaptically driven neuronal firing was shown to be intact in hippocampal neurons subjected to 40-Gy doses. However, the susceptibility to penicillin-induced epileptiform activity was reduced in the brain slices of animals receiving 40-Gy doses, compared with those from control rats that were not irradiated. The results provide rational support for the utility of subnecrotic gamma irradiation as a therapeutic strategy for treating epilepsy. These findings also provide evidence that a functional increase in the seizure threshold of hippocampal neurons contributes to the anticonvulsant influence of subnecrotic gamma irradiation.

Expression of cholines terases and muscarinic acetylcholine receptors in the jejunal mucosa has been investigated during infection of rats with the nematode parasite Nippostrongylus brasiliensis. Selective expression of m3 receptors was observed on epithelial cells from uninfected rats and animals 7 days postinfection, and saturation binding with [(3)H]quinuclidinyl benzilate indicated that receptor expression on cell membranes was unaltered by infection. Butyrylcholinesterase was highly expressed in mucosal epithelia, but acetylcholinesterase was present at low levels in uninfected animals. In contrast, discrete foci of intense acetylcholinesterase activity were observed on the basement membrane of intestinal epithelial cells in animals infected with N. brasiliensis. This was demonstrated to be due to upregulation of expression of endogenous enzyme, which peaked at Day 10 postinfection and subsequently declined to preinfection levels. It is suggested that this occurs in response to hyper-activation of the enteric nervous system as a result of infection, and may benefit the host by limiting excessive fluid secretion due to cholinergic stimulation., (Copyright 2000 Academic Press.)

Background: Routine toxicology screening of seriously injured patients has become the standard of care in most trauma centers. However, the benefit of drug screening in acute trauma is unproven. We reviewed the impact of positive drug screening results on patient care within the first 3 days of treatment., Methods: We retrospectively reviewed the charts of seriously injured patients admitted to an American College of Surgeons-certified level I trauma center over a 5-year period. Modifications of therapeutic regimens based on positive toxicology results were noted. Using current financial data, charges for toxicology were calculated., Results: Between January 1, 1990, and December 31, 1995, 2,678 trauma patients had drug screening. Of these, 414 (15%) had detectable quantities of the following intoxicants: opiates, barbiturates, amphetamines, phencyclidine hydrochloride (PCP), cocaine, marijuana, or benzodiazepines. Review of all 401 available charts failed to identify any cases in which treatment was altered by a positive toxicology result. Hospital costs related to routine screening were $138,587, while charges to patients amounted to $538,278., Conclusions: Routine toxicology does not alter or improve the immediate care of the injured patient. Routine drug screening is expensive, and benefits were not easily documented. The policy of routine toxicology screening in trauma centers should be reevaluated.

Mathematical models predict that a population which oscillates in the absence of time-dependent factors can develop multiple attracting final states in the advent of periodic forcing. A periodically-forced, stage-structured mathematical model predicted the transient and asymptotic behaviors of Tribolium (flour beetle) populations cultured in periodic habitats of fluctuating flour volume. Predictions included multiple (2-cycle) attractors, resonance and attenuation phenomena, and saddle influences. Stochasticity, combined with the deterministic effects of an unstable 'saddle cycle' separating the two stable cycles, is used to explain the observed transients and final states of the experimental cultures. In experimental regimes containing multiple attractors, the presence of unstable invariant sets, as well as stochasticity and the nature, location, and size of basins of attraction, are all central to the interpretation of data.

A continuous age-structured model of cannibalistic insect populations is constructed and analyzed. The model is a continuous analog of the model used in the recent work of Costantino et al. in which discrete modeling, mathematical analysis, statistical techniques, and laboratory experiments were used to demonstrate the presence of nonlinear dynamics, including chaos, in laboratory Tribolium cultures. A special case of the continuous model (no larva-on-egg cannibalism) is analyzed and the results are compared to the analogous special case of the discrete model.

Expression of the ectoenzyme gamma-glutamyl transpeptidase (GGT) is regulated on T lymphocytes. It is present at a low level on naive T cells, at a high level on activated T cells, and at an intermediate level on resting memory T cells. GGT cleaves the glutamyl group from glutathione, which is the first step in the uptake of extracellular glutathione. In vitro, purified GGT also metabolizes the naturally occurring nitrosothiol, S-nitrosoglutathione (GSNO). Because of this relationship, the effects of cellular GGT on the metabolism of and cellular response to GSNO were tested. The GGT-negative lymphoblasts Ramos and SupT1 were transfected with cDNA for human GGT. In the presence of cells lacking GGT, GSNO is extremely stable. In contrast, GGT-expressing cells rapidly metabolize GSNO leading to nitric oxide release. The nitric oxide causes a rapid (<2-h) inhibition of DNA synthesis. There is a concomitant decrease in the concentration of intracellular deoxyribonucleotides, suggesting that one effect of the nitric oxide generated from GSNO is the previously described inactivation of the enzyme ribonucleotide reductase. GSNO also caused a rapid, GGT-dependent cytostatic effect in Hut-78, a human T cell lymphoma, as well as in activated peripheral blood T cells. Although DNA synthesis was decreased to 16% of control values in anti-CD3-stimulated Hut-78, the production of IL-2 was unchanged by GSNO. These data show that GGT, a regulated ectoenzyme on T cells, controls the rate of nitric oxide production from GSNO and thus markedly affects the physiological response to this biologically active nitrosothiol.

The role of beta3- and other putative atypical beta-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine beta3-adrenoceptor (beta3AR) agonists with varying intrinsic activities and selectivities for human cloned betaAR subtypes. The ability to demonstrate beta1/2AR antagonist-insensitive (beta3 or other atypical betaAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective beta3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited beta1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full beta3AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta1/2AR antagonism, despite it having very low efficacies at cloned beta1- and beta2ARs. A component of the response to another phenylethanolamine selective beta3AR agonist (SB-215691) was insensitive to beta1/2AR antagonism in some experiments. Because no [corrected] novel aryloxypropanolamine had a beta1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that beta3ARs mediate lipolysis in human white adipocytes, and suggest that putative 'beta4ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned betaARs which betaARs will mediate responses to agonists in tissues that have a high number of beta1- and beta2ARs or a low number of beta3ARs.

Experiments with the flour beetle Tribolium have revealed that animal numbers were larger in cultures grown in a periodically fluctuating volume of medium than in cultures grown in a constant volume of the same average size. In this paper we derive and analyze a discrete stage-structured mathematical model that explains this phenomenon as a kind of resonance effect. Habitat volume is incorporated into the model by the assumption that all rates of cannibalism (larvae on eggs, adults on eggs and pupae) are inversely proportional to the volume of the culture medium. We tested this modeling assumption by conducting and statistically analyzing laboratory experiments. For parameter estimates derived from experimental data, our model indeed predicts, under certain circumstances, a larger (cycle-average) total population abundance when the habitat volume periodically fluctuates than when the habitat volume is held constant at the average volume. The model also correctly predicts certain phase relationships and transient dynamics observed in data. The analyses involve a thorough integration of mathematics, statistical methods, biological details and experimental data.

Two types of adult-on-juvenile cannibalism are discussed and differentiated: those with "mean yield of cannibalism" greater than one, and those with mean yield less than one. Two extant models--one continuous and one discrete--in which cannibalism is beneficial only when the mean yield exceeds one are reviewed and compared. The discrete model is modified and analyzed to demonstrate that cannibalism can be beneficial even when the mean yield is less than one.

1. Chronic treatment of patients with beta-blockers causes atrial inotropic hyperresponsiveness through beta 2-adrenoceptors, 5-HT4 receptors and H2-receptors but apparently not through beta 1-adrenoceptors despite data claiming an increased beta 1-adrenoceptor density from homogenate binding studies. We have addressed the question of beta 1-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the beta 1-adrenoceptor selective partial agonist (-)-RO363 and by carrying out both homogenate binding and quantitative beta-adrenoceptor autoradiography in atria obtained from patients treated or not treated with beta-blockers. In the course of the experiments it became apparent that (-)-RO363 also may cause agonistic effects through the third atrial beta-adrenoceptor. To assess whether (-)-RO363 also caused agonistic effects through beta 3-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human beta 3-adrenoceptors. 2. beta-Adrenoceptors were labelled with (-)-[125I]-cyanopindolol. The density of both beta 1- and beta 2-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (-)-RO363 for beta 1-adrenoceptors (pKi = 8.0-7.7) and beta 2-adrenoceptors (pKi = 6.1-5.8) were not significantly different in the two groups. 3. (-)-RO363 increased atrial force with a pEC50 of 8.2 (beta-blocker treated) and 8.0 (non-beta-blocker treated) and intrinsic activity with respect to (-)-isoprenaline of 0.80 (beta-blocker treated) and 0.54 (non-beta-blocker treated) (P < 0.001) and with respect to Ca2+ (7 mM) of 0.65 (beta-blocker treated) and 0.45 (non-beta-blocker treated) (P < 0.01). The effects of (-)-RO363 were resistant to antagonism by the beta 2-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3-10 nM (-)-RO363 were antagonized by 3-10 nM of the beta 1-adrenoceptor selective antagonist CGP 20712A. The effects of 20-1000 nM (-)-RO363 were partially resistant to antagonism by 30-300 nM CGP 20712A. 4. (-)-RO363 relaxed the rat colon, partially precontracted by 30 mM KCl, with an intrinsic activity of 0.97 compared to (-)-isoprenaline. The concentration-effect curve to (-)-RO363 revealed 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.5 and fraction 0.66, the other resistant to (-)-propranolol (200 nM) with pEC50 = 5.6 and fraction 0.34 of maximal relaxation. 5. (-)-RO363 relaxed the longitudinal muscle of guinea-pig ileum, precontracted by 0.5 microM histamine, with intrinsic activity of 1.0 compared to (-)-isoprenaline and through 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.7 and fraction 0.67, the other resistant to (-)-propranolol with pEC50 = 4.9 and fraction 0.33 of maximal relaxation. 6. (-)-RO363 stimulated the adenylyl cyclase of CHO cells expressing human beta 3-adrenoceptors with pEC50 = 5.5 and intrinsic activity 0.74 with respect to (-)-isoprenaline (pEC50 = 5.9). (-)-RO363 competed for binding with [125I]-cyanopindolol at human beta 3-adrenoceptors transfected into CHO cells with pKi = 4.5. (-)-Isoprenaline (pKi = 5.2) and (-)-CGP 12177A (pKi = 6.1) also competed for binding at human beta 3-adrenoceptors. 7. We conclude that under conditions used in this study, (-)-RO363 is a potent partial agonist for human beta 1- and beta 3-adrenoceptors and appears also to activate the third human atrial beta-adrenoceptor. (-)-RO363 relaxes mammalian gut through both beta 1- and beta 3-adrenoceptors. (-)-RO363, used as a beta 1-adrenoceptor selective tool, confirms previous findings with (-)-noradrenaline that beta 1-adrenoceptor-mediated atrial effects are only slightly enhanced by chronic treatment of patients with beta-blockers. Chronic treatment with

Objective: Cranioplasty using acrylic is a common procedure in patients with cranial defects secondary to trauma, infection, or tumor. The limitations of this technique include poor adherence of the acrylic to surrounding bone and difficulty in achieving a proper cosmetic contour in complicated cranial defects, especially those involving the orbital rim. The authors have been continually developing techniques of cranioplasty., Methods: Ten consecutive cranioplasties were performed over the past 5 years using this new technique., Technique: The authors describe a technique using miniplates as struts to which the acrylic is applied using a "reinforced concrete" principle., Results/conclusion: All patients achieved excellent cosmetic results with no complications. This technique allows contour of the repair site while the acrylic is curing and provides a more resilient resulting prosthesis.

A new surgical technique for the treatment of lumbar spinal stenosis features extensive unilateral decompression with undercutting of the spinous process and, to preserve stability, uses contralateral autologous bone fusion of the spinous processes, laminae, and facets. The operation was performed in 29 patients over a 19-month period ending in December of 1991. All individuals had been unresponsive to conservative treatment and presented with low-back pain in addition to signs and symptoms consistent with neurogenic claudication or radiculopathy. Nine had undergone previous lumbar decompressive surgery. The minimum and mean postoperative follow-up times were 2 and 2 1/2 years, respectively. The mean patient age was 64 years; only two patients were younger than 50 years of age. Of the patients with neurogenic claudication, 69% reported complete pain relief at follow-up review. Of those with radicular symptoms, 41% had complete relief and 23% had mild residual pain that was rated 3 or less on a pain-functionality scale of 0 to 10. For the entire sample, this surgery decreased pain from 9.2 to 3.3 (p < 0.0001) on the scale. Sixty-nine percent of patients were satisfied with surgery. Low-back pain was significantly relieved in 62% of all patients (p < 0.0001). Low-back pain relief correlated negatively with number of levels decompressed (p < 0.05). To assess fusion, follow-up flexion/extension radiographs were obtained, and no motion was detected at the surgically treated levels in any patient. The results suggest that this decompression procedure safely and successfully treats not only the radicular symptoms caused by lateral stenosis but also the neurogenic claudication symptoms associated with central stenosis. In addition, the procedure, by using contralateral autologous bone fusion along the laminae and spinous processes, can preserve stability without instrumentation.

N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) and N-formyl-L-methionyl-L-phenylalanine (FMP) were used to investigate neutrophil (PMN) aggregation. Neutrophils were isolated from healthy adult volunteers and term newborn cord blood. Neutrophil aggregation was measured after the addition of FMLP and FMP. Adult PMN aggregation curves demonstrated initial aggregation with slow deaggregation. Newborn neutrophil aggregation curves showed slow aggregation with no deaggregation. These results were identical to the adult and newborn neutrophil aggregation curves produced by C5a. Newborn PMN aggregates examined by scanning electromicrography showed frequent, dense aggregates compared with fewer, less dense aggregates of adult PMNs. Adult and newborn PMN aggregates differed when compared by transmission electromicrographs (EM). Newborn PMNs were tightly bound with cell membrane projections; adult PMNs were loosely bound with no cell membrane projections. Cytochalasin-B pretreated adult and newborn PMN aggregates displayed close approximation of cell membranes with large numbers of cytoplasmic projections. Newborn neutrophils are irreversibly aggregated by FMLP and FMP whereas adult neutrophils display an aggregation-deaggregation reaction. EM studies suggest that this irreversible aggregation of untreated newborn neutrophils may differ from the irreversible aggregation of cytochalasin-B pretreated neutrophils.

The respiratory syncytial virus (RSV) is a common cause of bronchiolitis and pneumonia in infants and young children. Throughout the world annual RSV epidemics result in numerous hospitalizations, substantial morbidity and some mortality. Until the recent introduction of ribavirin only supportive therapy has been available for treating these infections. The development of animal models of RSV infection and the observation that some lots of immunoglobulin prepared for intravenous administration contained substantial RSV-neutralization antibody titers, prompted a series of studies examining the safety and efficacy of immunoglobulin prepared for intravenous administration in the prophylaxis and treatment of RSV infections. This discussion will review our published, or soon to be published, studies on the use of Sandoglobulin for both immunoprophylaxis and immunotherapy of RSV infections in cotton rats. It will summarize studies utilizing both parenteral and topical (tracheal) Sandoglobulin therapy for RSV infections in owl monkeys. Finally the results of a small double blind trial of parenteral albumin or Sandoglobulin in the therapy of RSV bronchiolitis and/or pneumonia in hospitalized children will be reviewed. The data show that immunoprophylaxis and immunotherapy of RSV infections in laboratory animals was well-tolerated, was safe and induced highly significant reductions in RSV shedding from the lower respiratory tract. Further, immunotherapy of RSV infections in children was also well-tolerated, induced no short or long term evidence of toxicity or injury and caused significant improvements in oxygenation and reductions in RSV shed from the respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant fibrous histiocytomas are an unusual neoplasm in the head and neck, and only six cases involving the maxillary sinus have been reported. The combination of an anaplastic storiform "fibroblastic" stroma with xanthomatous tumor giant cells histologically identifies this tumor. The high incidence of local recurrence of this neoplasm necessitates wide surgical resection. Regional lymph node and distant metastases, although not previously reported in maxillary sinus fibrous histiocytomas, occurred in this case.

Three techniques combining the shaping of calvarial and facial bone with onlay of methyl methacrylate are presented for use in the late treatment of unilateral coronal synostosis deformities. The procedures described are suggested as possible alternatives to extensive bone repositioning procedures. They have the advantage of being quicker and are therefore potentially safer operations. Acrylic is malleable and does not resorb; thus, permanent superior esthetic results may be achieved. The two most serious risks when using this technique are infection and limitation of growth. The risk of infection may be reduced by attaching the acrylic implant securely to surrounding bone, under sterile conditions, beneath well-vascularized skin. Growth limitation may be obviated by not placing acrylic across sutures in children with enlarging skulls.