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To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations.

Immunotherapy is an attractive option for patients with high risk neuroblastoma due to their poor long-term survival rates after conventional treatment. Neuroblastoma cells are derived from the embryonic neural crest and therefore express tumor antigens not widely seen in normal cells, making them potential targets for immunologic attack. There is already considerable experience with monoclonal antibodies that target these tumor associated antigens, and in this review we focus on more exploratory approaches, using tumor vaccines and adoptive transfer of tumor-directed T cells.

Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both.

Serial blood draws for the assessment of trauma patients' hemoglobin (sHgb) and hematocrit (sHct) is standard practice. A device that would allow for continuous real-time, non-invasive monitoring of hemoglobin and tissue perfusion would potentially improve recognition, monitoring and resuscitation of blood loss. We developed a device utilizing diffuse optical spectroscopy (DOS) technology that simultaneously measures tissue scattering and near-infrared (NIR) absorption to obtain non-invasive measurements of oxy- (Hb-O2), deoxyhemoglobin (Hb-R) concentrations and tissue hemoglobin concentration (THC) in an animal model of hypovolemic shock induced by successive blood withdrawals. Intubated New Zealand White rabbits (N= 16) were hemorrhaged via a femoral arterial line every 20 min until a 20% blood loss (10-15 cc kg?1) was achieved to attain hypovolemia. A broadband DOS probe placed on the inner thigh was used to measure muscle concentrations of Hb-O2and Hb-R, during blood withdrawal. THC and tissue hemoglobin saturation (STO2) were calculated from DOS [Hb-O2] and [Hb-R]. Broadband DOS-measured values were compared against traditional invasive measurements: systemic sHgb, arterial oxygen saturation (SaO2) and venous oxygen saturation (SvO2) drawn from arterial and central venous blood. DOS and traditional invasive measurements versus blood loss were closely correlated (r2= 0.96) showing a decline with removal of blood. STO2and [Hb-O2] followed similar trends with hemorrhage, while [Hb-R] remained relatively constant. These measurements may be limited to some extent by the inability to distinguish between hemoglobin and myoglobin contributions to DOS signals in tissue at this time. Broadband DOS provides a potential platform for reliable non-invasive measurements of tissue oxygenated and deoxygenated hemoglobin and may accurately reflect the degree of systemic hypovolemia and compromised tissue perfusion.

The power handling of HTS thin films was accurately characterized in an 8.15 GHz HTS/Sapphire resonator as a function of temperature. The surface resistance of a superconductor depends upon the level of the surface magnetic field especially if the value exceeds the lower critical magnetic field. A four-film power “round robin” was performed, which allowed for both the power handling of each of the HTS films and the statistics about the measurement repeatability to be calculated. A highly nonlinear empirically derived formula was identified and used to interpolate the measurement data. These four HTS films can now be used as power-qualified reference films for future HTS/Sapphire resonator measurements.

Introduction.: Over the past 30 years, a multidisciplinary approach com-bining surgery, chemotherapy, and radiation has led to a dramatic improvement in survival for patients affected by malignant diseases. Cellular therapies, such as stem cell transplantation, have also made a significant contribution. Nonetheless, many patients are still resistant to standard therapies, which also have high and often unacceptable acute and chronic organ toxicity, with an increased risk for secondary malignancies. Therefore new strategies are needed to improve overall survival and decrease treatment-asso-ciated morbidity. Immunotherapy represents one of the most appealing of these approaches, and active immunization in particular has proved to be amongst the most important of these new cellular strategies because of its ability to stimulate the immune system to actively recognize and kill the malignant cells. Identification of antigens expressed on tumor cells (Table 1), together with a better understanding of the molecular and cellular mechanisms involved in the immune response against cancer, have given investigators tools to manipulate the immune system to induce an efficient immune response in the tumor-bearing host [1-5]. The present review describes the approaches used in cancer vaccination that are intended not only to optimize antitu-mor immunity, but also to overcome tumor immune escape. Examples of how these approaches are being applied clinically are also given.

Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAPgene sequencing as the confirmatory assay.

Glutamate receptors of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype and voltage‐gated Na+channels are associated with diseases of the central nervous system characterized by neuronal over‐excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na+channel blockers provide protection in these conditions.Dimethyl‐{2‐[2‐(3‐phenyl‐[1,2,4]oxadiazol‐5‐yl)‐phenoxyl]‐ethyl}‐amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor – and Na+channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo.BIIR 561 CL protected mice against AMPA‐induced toxicity with an ED50value of 4.5 mg kg−1following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED50value of 3.0 mg kg−1s.c. In amygdala‐kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg−1following intraperitoneal (i.p.) injection.The data show that the combination of blocking AMPA receptor‐ and voltage‐gated Na+channels in one molecule induces effective protection in animal models of neuronal over‐excitation.

Background.Emphysema is a chronic disease of the lungs with destruction of terminal alveoli and airway obstruction. Lung volume reduction surgery (LVRS) is being investigated for the treatment of emphysema. Increasing resection volumes with LVRS may lead to worsening of carbon monoxide diffusing capacity (Dlco) despite improvement in compliance and flow. We hypothesized that the pulmonary circulation-related parameters, pulmonary artery pressure (PAP) and diffusing capacity (Dlco), may be used as indicators of the maximally tolerated LVRS resection volume.

Objective: The purpose of this study was to investigate in an elastase-induced emphysema rabbit model the effects of increasing resection volumes during lung volume reduction surgery on pulmonary compliance, forced expiratory air flow, and diffusing capacity to assess factors limiting optimal resection. Methods: Emphysema was induced in 68 New Zealand White rabbits with 15,000 units of aerosolized elastase. Static respiratory system compliance, forced expiratory flow, and single-breath diffusing capacity were measured before the induction of emphysema, after the induction of emphysema, and 1 week after a bilateral upper and middle lobe lung volume reduction operation. Results: Static respiratory system compliance with 60 mL insufflation above functional residual capacity increased with emphysema induction and then decreased progressively with resection of larger volumes of lung tissue (P = .001 by analysis of variance). Expiratory flow improved after lung resection in the rabbits with large resection volumes. In contrast, diffusing capacity tended to deteriorate with larger resection volumes (P = .18). Conclusion: Improvements in respiratory system compliance and forced expiratory flow after lung volume reduction operations may account for the improvements seen clinically. Declines in diffusing capacity with extensive lung reduction may limit the clinical benefits associated with greater tissue resection volumes. Future investigations with animal models may reveal other physiologic parameters that may further guide optimal lung volume reduction procedures. (J Thorac Cardiovasc Surg 1999;117:728-35)

Objective: Bilateral staple lung volume reduction surgery (LVRS) immediately improves pulmonary function and dyspnea symptoms in patients with advanced heterogeneous emphysema to a greater degree than do unilateral procedures. However, the long-term outcome after these surgical procedures needs to be critically evaluated. We compare 2-year survival of patients who underwent unilateral versus bilateral video-assisted LVRS in a large cohort treated by a single surgical group. Methods: The cases of all 260 patients who underwent video-assisted thoracoscopic stapled LVRS from April 1994 to March 1996 were analyzed to compare results after unilateral versus bilateral procedures. Overall survival was calculated by Kaplan-Meier methods; Cox proportional hazard methods were used to adjust for patient heterogeneity and baseline differences between groups. Results: Overall survival at 2 years was 86.4% (95% CI 80.9%-91.8%) after bilateral LVRS versus 72.6% (95% CI 64.2%-81.2%) after unilateral LVRS (P = .001 for overall survival comparison). Improved survival after bilateral LVRS was seen among high- and low-risk subgroups as well. Average follow-up time was 28.5 months (range, 6 days to 46.6 months) for the bilateral LVRS group and 29.3 months (range, 6 days to 45.0 months) for the unilateral LVRS patients. Conclusions: Comparison of unilateral versus bilateral thoracoscopic LVRS procedures for the treatment of emphysema reveals that bilateral LVRS by video-assisted thoracoscopy resulted in better overall survival at 2-year follow-up than did unilateral LVRS. This survival study, together with other studies demonstrating improved lung function after bilateral LVRS, suggests that bilateral surgery appears to be the procedure of choice for patients undergoing LVRS for most eligible patients with severe heterogeneous emphysema. (J Thorac Cardiovasc Surg 1999;118:1101-9)

Lung volume reduction surgery (LVRS) has shown promising results in severe emphysema. However, intraoperative indicators are needed to define optimal resection volumes. Diffusing capacity (DLCO) worsens with larger LVRS and may correlate with pulmonary artery (PA) pressure. We hypothesized that there would be a greater increase in PA pressures with larger volume LVRS in an inhaled elastase animal emphysema model. Twenty-one rabbits were induced with 15,000 units of elastase via an endotracheal tube. Four weeks later, bilateral LVRS was performed through a median sternotomy using an endoscopic stapler. PA pressures were measured prior to LVRS, immediately after LVRS, and at sacrifice. Single-breath DLCO, static pressure–volume relationships, and forced expiratory flows were measured prior to induction and at corresponding times to PA pressures. Systolic PA pressures increased in both groups immediately after LVRS (small: 2.67 ± 9.2 mm Hg, ANOVA,P= 0.023; large: 3.8 ± 8.5 mm Hg,P= 0.002), and then decreased at time of sacrifice 1 week later (small: 9.43 ± 4.8 mm Hg, ANOVA,P= 0.053; large: 5.2 ± 7.3 mm Hg,P= 0.552). The decrease, at sacrifice, in PA pressures was greater for small LVRS animals than large LVRS animals. The mortality rate (MR) for the small resection group was 0%, whereas that for the large resection group was 24%. The MR associated with larger LVRS was appreciably greater than that associated with small LVRS. These studies suggest that PA pressures may prove to be a useful intraoperative indicator for limits of resection.

Ca(2+)-dependent cell-cell adhesion is mediated by the cadherin family of transmembrane proteins. Adhesion is achieved by homophilic interaction of the extracellular domains of cadherins on adjacent cells, with the cytoplasmic regions serving to couple the complex to the cytoskeleton. IQGAP1, a novel RasGAP-related protein that interacts with the cytoskeleton, binds to actin, members of the Rho family, and E-cadherin. Calmodulin binds to IQGAP1 and regulates its association with Cdc42 and actin. Here we demonstrate competition between calmodulin and E-cadherin for binding to IQGAP1 both in vitro and in a normal cellular milieu. Immunocytochemical analysis in MCF-7 (E-cadherin positive) and MDA-MB-231 (E-cadherin negative) epithelial cells revealed that E-cadherin is required for accumulation of IQGAP1 at cell-cell junctions. The cell-permeable calmodulin antagonist CGS9343B significantly increased IQGAP1 at areas of MCF-7 cell-cell contact, with a concomitant decrease in the amount of E-cadherin at cell-cell junctions. Analysis of E-cadherin function revealed that CGS9343B significantly decreased homophilic E-cadherin adhesion. On the basis of these data, we propose that disruption of the binding of calmodulin to IQGAP1 enhances the association of IQGAP1 with components of the cadherin-catenin complex at cell-cell junctions, resulting in impaired E-cadherin function.

This paper discusses a first-stage analysis of the link of unemployment rates, as well as other economic, social and environmental health risk factors, to mortality rates in postwar Britain. The results presented represent part of an international study of the impact of economic change on mortality patterns in industrialized countries. The mortality patterns examined include total and infant mortality and (by cause) cardiovascular (total), cerebrovascular and heart disease, cirrhosis of the liver, and suicide, homicide and motor vehicle accidents. Among the most prominent factors that beneficially influence postwar mortality patterns in England/Wales and Scotland are economic growth and stability and health service availability. A principal detrimental factor to health is a high rate of unemployment. Additional factors that have an adverse influence on mortality rates are cigarette consumption and heavy alcohol use and unusually cold winter temperatures (especially in Scotland). The model of mortality that includes both economic changes and behavioral and environmental risk factors was successfully applied to infant mortality rates in the interwar period. In addition, the “simple” economic change model of mortality (using only economic indicators) was applied to other industrialized countries. In Canada, the United States, the United Kingdom, and Sweden, the simple version of the economic change model could be successfully applied only if the analysis was begun before World War II; for analysis beginning in the postwar era, the more sophisticated economic change model, including behavioral and environmental risk factors, was required. In France, West Germany, Italy, and Spain, by contrast, some success was achieved using the simple economic change model.

The seasonal profiles of free and conjugated abscisic acid (ABA) in seed, pod wall, and leaf tissue were determined using field‐grown control and depodded ‘Clay’ soybean (Glycine max(L.) Merr.) plants. Total seed ABA was initially high (13.0 /µg/g fresh weight) but decreased to 0.4 µg/g at maturity. The pod wall contained much less ABA than did seeds (ca. 0.5 µg/g). Pod wall ABA level was constant during development except for a twofold increase during final pod maturation. Leaves also contained much less ABA (< 1 µg/g) than did seeds. Upper canopy leaves contained more ABA than did lower canopy leaves. Depodding had no consistent effect on leaf ABA levels. Water stress caused an increase in ABA content in leaf tissue with no effect on pod wall tissue, while senescence increased ABA content hi pod walls with little effect on leaf tissue.

ABSTRACT: The effect of breast-feeding on the development of lymphocyte responsiveness in infants has been studied. Peripheral blood mononuclear cells from 15 breast- and 15 bottle-fed infants were obtained sequentially between 6 days and 9 months of age. A number of agents were used to stimulate the cells in vitro and the resulting proliferative responses were compared between the two feeding groups. A hanging drop microculture system using serum-free medium, enabled spontaneous proliferation and proliferative responses to several stimuli (T and B cell mitogens, allogeneic lymphocytes, and antigen) to be studied at a range of cell concentrations and days of culture. Significant age-related differences were found between the responses of cells from the two feeding groups. Spontaneous proliferation and proliferative responses to the T cell mitogen phytohaemagglutinin and the antigen tetanus toxoid were significantly greater in the breast-fed group at the two earliest ages studied (6 days and 6 wk). Responses to mitogens which predominantly affect B cells, such as pokeweed mitogen and Staphylococcus aureus (Cowan), were similar in both feeding groups at this age. In contrast, from 3 to 9 months of age, responses of cells from bottle-fed infants were significantly greater to all stimuli than responses from breast-fed infants. One possible explanation for the higher level of proliferation by cells from newborn breast-fed infants, is that these infants may absorb the cell-growth factors and lymphokines known to be present in human colostrum and milk. These factors may stimulate T cells and/or their precursors in vivo. The subsequent greater responsiveness of peripheral blood mononuclear cells from the bottle-fed group at 3 to 9 months of age appears to be due to a higher level of antigenic stimulation in vivo in this group. This could result from the greater intake of cow milk proteins or from the absence of the passive protective effect of the antimicrobial components in human milk.

Objective: The purpose of this study is to investigate the effects of lung volume reduction surgery on pulmonary compliance, airway flow, and helium lung volumes in an elastase-induced emphysema animal model. Methods: A 15,000-unit bolus of elastase was aerosolized through an endotracheal tube in 14 New Zealand White rabbits to induce emphysema. Stapled lung volume reduction of bilateral upper and middle lobes was performed through a midline sternotomy at 4 weeks after induction of emphysema. Lung functions were measured at baseline before induction of emphysema, preoperatively at 4 weeks, and 1 week postoperatively. Results: Compliance increased after induction of emphysema and decreased in response to lung volume reduction surgery. Functional residual capacity decreased after lung volume reduction surgery in proportion to the amount of excised lung tissue. Expired flows suggested improvement in response to lung volume reduction surgery. Histologic examination confirmed presence of diffuse heterogeneous emphysema in each animal at necropsy. Conclusions: The decreased compliance and increased airway flow after volume reduction surgery in this model parallels findings in human studies and suggests that similar mechanisms of increased elastic recoil and airway support contribute to improvement. (J Thorac Cardiovasc Surg 1998;115:328-35)