Continuous wave terahertz systems exploiting 1.5 microm telecom technologies.

A fiber-assembled CW THz System operating at 1.5 microm is presented. High speed telecom photodiodes integrated with planar THz antennas serve as THz emitters with power up to 10 microW. Photoconductive antennas based on LT InGaAs/InAlAs multi-layer structures allow coherent detection. The system operates in a wide frequency range of 0.1 -1.6 THz.

Phagocytosis of Candida albicans enhances malignant behavior of murine tumor cells.

Murine tumor cells were induced to phagocytize either Candida albicans or group A streptococcal cells. The presence of microbial particles within the tumor cell cytoplasm had no effect on in vitro tumor cell growth. However, when Candida albicans-infected tumor cells were injected into syngeneic mice, they formed tumors that grew faster, invaded the surrounding normal tissue more rapidly and metastasized more rapidly than control tumor cells. Tumor cells infected with group A streptococcal particles did not grow faster or show increased malignant behavior. These data indicate that the in vivo behavior of malignant tumor cells can be modulated by microbial particles, which are often present in the microenvironment of the growing tumor.

Evidence for role of hydroxyl radical in complement and neutrophil-dependent tissue injury.

Using our recently described model of acute lung injury in rats after systemic activation of complement by cobra venom factor (CVF), we demonstrated that pretreatment of animals with human milk apolactoferrin (in its native or derivatized form), but not iron-saturated lactoferrin, provides significant protection against complement- and neutrophil-mediated lung injury. The synthetic iron chelator deferoxamine mesylate also affords protection from lung injury. The protective effects of apolactoferrin are not related to a blocking of CVF-induced complement activation. We also demonstrated that infusion of ionic iron, especially Fe3+, greatly potentiates lung vascular injury after systemic complement activation. Finally, protection from lung injury occurs in animals pretreated with the potent scavenger of hydroxyl radicals (OH.), dimethyl sulfoxide. Based on transmission electron microscopy, CVF-treated rats show leukoaggregates and endothelial cell destruction in interstitial pulmonary capillaries, along with intraalveolar hemorrhage and fibrin deposition. In animals protected with apolactoferrin, deferoxamine mesylate, or dimethyl sulfoxide, the morphological studies reveal leukoaggregates but no endothelial cell damage, hemorrhage, or fibrin deposition. These data support the concept that tissue injury that is complement and neutrophil dependent may be related to generation of OH. derived from H2O2 after leukocytic activation.

Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites.

Intravascular activation of the complement system with cobra venom factor results in acute lung injury, which has been quantitated by increases in lung vascular permeability. Cobra venom factor preparations devoid of phospholipase A2 activity retain full lung-damaging capacity. The lung injury is associated with the preceding appearance of chemotactic activity in the serum coincident with the development of a profound neutropenia. The chemotactic activity is immunochemically related to human C5a. Morphologic studies have revealed discontinuities in the endothelial cell lining of lung alveolar capillaries, damage and/or destruction of endothelial cells in these areas, plugging of pulmonary capillaries with neutrophils that are in direct contact with vascular basement membrane, the presence of fibrin in alveolar spaces and in areas adjacent to damaged endothelial cells, and intraalveolar hemorrhage. Lung injury is dramatically attenuated in animals that have been previously neutrophil depleted. Teh intravenous injection of superoxide dismutase or catalase also provides significant protection from the pulmonary damage. Very little protection from the pulmonary damage. Very little protection is afforded by pretreatment of rats with antihistamine. These studies suggest that intravascular activation of the complement system leads to neutrophil aggregation and activation, intrapulmonary capillary sequestration of neutrophils, and vascular injury, which may be related to production of toxic oxygen metabolites by complement-activated neutrophils.

Systemic complement activation, lung injury, and products of lipid peroxidation.

Previously we have demonstrated that systemic activation of the complement system after intravenous injection of cobra venom factor (CVF) results in acute lung injury as reflected by increases in the vascular permeability of the lung as well as by morphologic evidence of damage to lung vascular endothelial cells. In using the vascular permeability of the lung as the reference, the current studies show a quantitative correlation between lung injury and the appearance in plasma of lipid peroxidation products (conjugated dienes) as well as increased concentrations of lactic dehydrogenase (LDH) and one of its isoenzymes (LDH-4). After injection of CVF, extracts of lungs also showed elevated levels of conjugated dienes, whereas no elevations were found in extracts of liver, kidney, and spleen. There was no evidence in CVF-injected rats of renal or hepatic injury as reflected by the lack of development of proteinuria and the failure to detect increased serum levels of liver-related enzymes. Other peroxidation products identified in plasma of CVF-injected rats involved hydroperoxides and fluorescent compounds with features of Schiff bases. Not surprisingly, malondialdehyde was not found to be a reliable plasma indicator of lipid peroxidation associated with oxygen radical-mediated lung vascular injury. In using a model of oxygen radical-independent lung injury induced by oleic acid, although large amounts of LDH and LDH-4 were found in the plasma, no increases in plasma levels of conjugated dienes were detected. In CVF-injected animals treated with interventions protective against lung injury (neutrophil depletion, catalase, hydroxyl radical scavengers, or iron chelators), there were striking reductions in the plasma levels of conjugated dienes, hydroperoxides, and fluorochromic products. Morphometric analysis of lung sections revealed that the protective interventions did not interfere with the accumulation of neutrophils in lung interstitial capillaries after systemic activation of complement. In vitro studies with phorbol-stimulated neutrophils failed to demonstrate appearance of conjugated dienes, suggesting that the dienes appearing in plasma of CVF-injected animals are not the result of autotoxic changes in neutrophils. The data presented in this paper suggest that acute lung injury mediated by oxygen radicals derived from phagocytic cells can be monitored by the appearance in plasma of products of lipid peroxidation.

Suppression of immune complex vasculitis in rats by prostaglandin.

Immune complex-induced vascular damage can be markedly suppressed by treatment of rats with either prostaglandin (PG)E1 or its stable derivative, 15-(S)-15-methyl PGE1, but not with PGF2 alpha. In addition, PGD2 and PGE2 also show suppressive effects. The PGE1 derivative is considerably more effective than PGE1 and shows potent anti-inflammatory activity even after oral administration. Suppression of the vasculitis reaction is reflected by a greatly diminished increase in vasopermeability, indicating little or no vascular damage. In suppressed animals, the infiltration of neutrophils is greatly reduced, and those leukocytes that have appeared at tissue sites fail to show phagocytic uptake of immune complexes. In suppressed animals, the skin sites nevertheless show deposits of immune complexes and C3 fixation in vascular walls. Neutrophils harvested from the blood of rats treated with PGE1 show depressed responsiveness in chemotaxis and in enzyme secretion after incubation with chemotactic peptide. These studies indicate that certain PG have potent anti-inflammatory activity, which may be related to their effects on leukocytes.

A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus.

Glucosylceramide (GlcCer) and related glycosphingolipids have been implicated as causal elements in both the growth of cells and in the regulation of hormonal signaling. We therefore studied whether the renal hypertrophy induced by diabetes was associated with enhanced synthesis of glycosphingolipids. 16 d after the induction of diabetes, increases in renal size and concentration of glucocerebroside and ganglioside GM3 were observed paralleling an increase in UDP-Glc concentration. GlcCer synthase and beta-glucosidase-specific activities were no different between control and diabetic kidneys. The apparent Km of the GlcCer synthase with respect to UDP-Glc was 250 microM and was unchanged in the diabetic kidneys. The observed concentrations of UDP-Glc were 149 and 237 microM in control and diabetic kidneys, respectively. The UDP-Glc level is thus rate limiting with regard to GlcCer synthesis. To determine whether the changes in glycolipid content were functionally significant, diabetic and control groups were treated with the GlcCer synthase inhibitor, D-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1- propanol, 2 wk after the induction of diabetes. Kidney weights in the diabetic rats treated with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol were no different than the control groups. Morphometric analysis of glomerular volumes paralleled changes in renal growth. Glycosphingolipid formation may therefore represent a significant pathway for glucose utilization in early diabetic nephropathy.

Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein.

The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. One of the striking consequences of liver injury is the associated pulmonary dysfunction that may be related to the release of hepatic-derived cytokines. We have previously employed an animal model of hepatic ischemia/reperfusion injury, and demonstrated that this injury causes the production and release of hepatic-derived TNF, which mediates a neutrophil-dependent pulmonary microvascular injury. In this study, we have extended these previous observations to assess whether an interrelationship between TNF and the neutrophil chemoattractant/activating factor, epithelial neutrophil activating protein-78 (ENA-78), exists that may be accountable for the pathology of lung injury found in this model. In the context of hepatic ischemia/reperfusion injury, we demonstrated the following alterations in lung pathophysiology: (a) an increase in pulmonary microvascular permeability, lung neutrophil sequestration, and production of pulmonary-derived ENA-78; (b) passive immunization with neutralizing TNF antiserum resulted in a significant suppression of pulmonary-derived ENA-78; and (c) passive immunization with neutralizing ENA-78 antiserum resulted in a significant attenuation of pulmonary neutrophil sequestration and microvascular permeability similar to our previous studies with anti-TNF. These findings support the notion that pulmonary ENA-78 produced in response to hepatic-derived TNF is an important mediator of lung injury.

Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat.

We have examined the role of intrapulmonary TNF in a rat model of acute immune complex-triggered alveolitis. Intratracheal instillation of IgG anti-bovine serum albumin (anti-BSA) followed by intravenous infusion of BSA results in acute alveolitis. Over the 4-h course of evolving lung injury, a 10-fold increase in TNF activity occurred in bronchoalveolar lavage (BAL) fluid. Immunohistochemical analysis of lung sections and BAL cells revealed that alveolar macrophages are the chief source of TNF. Antibodies that specifically neutralize rat TNF activity were raised in rabbits immunized with recombinant mouse TNF alpha. When administered into the lungs with anti-BSA, anti-TNF resulted in a marked reduction (up to 61%) in lung injury. Intratracheal instillation of exogenous TNF alone, or in combination with anti-BSA, resulted in an increase in lung injury compared to controls. Morphometric analysis and measurements of myeloperoxidase activities in whole lung extracts from rats treated with anti-TNF revealed a marked reduction in neutrophils compared to positive controls. The anti-TNF antibody preparation did not inhibit in vitro complement activation or diminish neutrophil chemotactic activity present in activated rat serum. These data indicate that intrapulmonary TNF activity is required for the full development of acute immune complex-triggered alveolitis, that alveolar macrophages are the primary source of this cytokine, and that TNF participates in the pathogenesis of immune complex alveolitis through a mechanism involving neutrophil recruitment.

Area-differentiated modelling of P-fluxes in heterogeneous macroscale river basins.

A model (MEPhos) for the calculation of the total phosphorus output from diffuse sources by drainage, wash-off, groundwater outflow, soil erosion and rainwater sewers as well as from point sources is presented. The model is based on a pathway- and area-differentiated emissions approach and calculates mean long-term P-inputs to surface waters. Phosphotopes are used for spatial discretization and modelling of diffuse P-inputs. Based on the modelling results "hot spots" for high P-loads can be localized and a management option for the input reduction to surface waters can be proposed which are adapted to site properties. The applicability of the model is demonstrated for two macroscale river basins in Germany (- 13,000 km(2) each) with contrasting natural conditions and land use patterns.

The influence of diffuse pollution on groundwater content patterns for the groundwater bodies of Germany.

Commissioned by Germany's Working Group of the Federal States on Water Problems (LAWA) the authors developed a procedure to define natural groundwater conditions from groundwater monitoring data. The distribution pattern of a specific groundwater parameter observed by a number of groundwater monitoring stations within a petrographically comparable groundwater typology is reproduced by two statistical distribution functions, representing the "natural" and "influenced" component. The range of natural groundwater concentrations is characterized by confidence intervals of the distribution function of the natural component. The applicability of the approach was established for 17 hydrochemical different groundwater typologies occurring throughout Germany. Based on groundwater monitoring data from ca. 26,000 groundwater-monitoring stations, 40 different hydrochemical parameters were evaluated for each groundwater typology. For all investigated parameters the range of natural groundwater concentrations has been identified. According to the requirements of the EC Water Framework Directive (article 17) (WFD) this study is a basis for the German position to propose criteria for assessing a reference state for a "good groundwater chemical status".

Water fluxes and diffuse nitrate pollution at river basin scale: coupling of agro-economic models and hydrological approaches.

An integrated model system has been developed to estimate the impact of nitrogen reduction measures on the nitrogen load in groundwater and in river catchment areas. The focus lies on an area-wide, regionally differentiated, consistent link-up between the indicator "nitrogen balance surplus" and nitrogen charges into surface waters. As a starting point of the analysis actual nitrogen surpluses in the soil were quantified using the agro-economic RAUMIS-model, which considers the most important N-inputs to the soil and N-removals from the soil through crop harvest. The most important pathways for diffuse nitrogen inputs into river systems are modelled with the water balance model GROWA. Additionally, the time-dependent nitrogen degradation along the nitrogen pathways in soil and groundwater are modelled using the WEKU-model. The two selected river basins in Germany cover a variety of landscape units with different hydrological, hydrogeological and socio-economic characteristics. The results indicate a wide range of annual nitrogen surpluses for the rural areas between than 10 kg N ha(-1) x a(-1) and 200 kg N ha(-1) x a(-1) or more, depending on the type and intensity of farming. The level of nitrogen inputs into the surface waters is reduced because of degradation processes during transport in soil and groundwater. Policy impact analyses for a nitrogen tax and a limitation of the livestock density stress the importance of regionally adjusted measures.

Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents.

Dendritic cells (DCs) can efficiently acquire foreign antigen(s) from apoptotic cells and induce MHC class I-restricted, antigen-specific CTLs. An accumulation of DCs within solid tumor masses in situ has been associated indirectly with a more favorable prognosis. Therefore, DCs may offer an efficient means for triggering immune responses within tumors, particularly in those masses containing significant apoptosis. We examined whether delivery of DCs could, alone, impact on the progressive growth of a tumor with a relatively high apoptotic index. We detected significant early apoptosis within the mass of a s.c. growing murine MT-901 breast carcinoma. DCs could efficiently engulf MT-901 tumor apoptotic cells in vitro. Intratumoral injections of syngeneic but not allogeneic DCs resulted in significant inhibition of MT-901 tumor growth. Histological examination of the tumor revealed intense mononuclear cell infiltration during and after DC injections. Tumor growth inhibition was relatively radiosensitive and dependent on host-derived CD8+ T cells. The baseline level of tumor apoptosis could be increased substantially by tumor necrosis factor alpha administration, leading to a greater DC-mediated antitumor effect. The antitumor effect could also be enhanced by first pulsing DCs with the foreign helper protein, keyhole limpet hemocyanin, prior to intratumoral delivery and combining it with the systemic administration of interleukin 2. Splenocytes from treated animals showed heightened levels of specific CTL activity and production of cytokines. The level of in situ tumor apoptosis appears to play a critical role in DC-mediated antitumor effects. The potential implication of these findings in DC-based tumor therapy strategies is discussed.

C-C chemokine-induced eosinophil chemotaxis during allergic airway inflammation.

The production of eosinophil-specific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA) -mediated allergic responses to examine the role of specific C-C chemokines [macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemoattractant protein-1 (MCP-1)] in eosinophil recruitment. We have previously identified a role for MIP-1alpha in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIP-1alpha and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48-96 h after allergen (SEA) challenge. Utilizing whole-lung homogenates from allergen-challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8-h lung homogenates and peak activity with samples from 24-h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen-challenged mice were preincubated in vitro with antibodies specific for MIP-1alpha, RANTES, or MCP-1, a significant reduction in eosinophil chemotaxis was observed with only MIP-1alpha and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP-1alpha are major eosinophil chemotactic factors produced during allergic airway responses.

Management of regional German river catchments (REGFLUD) impact of nitrogen reduction measures on the nitrogen load in the River Ems and the River Rhine.

The REGFLUD-project, commissioned by Germany's Federal Research Ministry (BMBF), addresses the problem of reducing diffuse pollution from agricultural production. The objective of the project is the development and application of multi-criteria scientific methods, which are able to predict diffuse pollution in river basins subject to economic feasibility and social acceptability. The selected river basins (Ems and Rhine basins) cover a variety of landscape units with different hydrological, hydrogeological and socio-economic characteristics. This paper focuses on the analysis of the effects of certain policy measures to reduce diffuse pollution by nitrogen. For this purpose a model system consisting of an agricultural sector model, a water balance model and a residence time/denitrification model was developed and applied. First results indicate a wide range of annual nitrogen surpluses for the rural areas between less than 10 kg N/ha up to 200 kg N/ha or more depending on the type and intensity of farming. Compared to the level of nitrogen surpluses the level of nitrogen inputs into the surface waters is relatively moderate because of degradation processes during transport in soil and groundwater. Policy impact analysis for a nitrogen tax and a limitation of the livestock density stress the importance of regionally tailored measures.

A procedure to define natural groundwater conditions of groundwater bodies in Germany.

Commissioned by Germany's Working Group of the Federal States on Water Problems (LAWA) the authors developed a procedure to define natural groundwater conditions from groundwater monitoring data. The distribution pattern of a specific groundwater parameter observed by a number of groundwater monitoring stations within a petrographically comparable groundwater typology is reproduced by two statistical distribution functions, representing the "natural" and "influenced" components. The range of natural groundwater concentrations is characterized by confidence intervals of the distribution function of the natural component. The applicability of the approach was established for four hydrochemically different groundwater typologies occurring throughout Germany. Based on groundwater monitoring data from 7920 groundwater monitoring stations, 15 different hydrochemical parameters were evaluated for each groundwater typology. For all investigated parameters the range of natural groundwater concentrations has been identified. According to the requirements of the EC Water Framework Directive (article 17) (WFD) this study is a basis for the German position to propose criteria for assessing a reference state for a "good groundwater chemical status".

Improvement in symptoms of depression and in an index of life stressors accompany treatment of severe hypertriglyceridemia.

In 14 men and nine women referred because of severe primary hypertriglyceridemia, our specific aim in a 54-week single-blind treatment (Rx) period was to determine whether triglyceride (TG) lowering with a Type V diet and Lopid would lead to improvement in symptoms of depression, improvement in an index of life stressors, change in locus of control index, and improved cognition, as serially tested by Beck (BDI), Hassles (HAS) and HAS intensity indices, Locus of Control index, and the Folstein Mini-Mental status exam. On Rx, median TG fell 47%, total cholesterol (TC) fell 15%, and HDLC rose 19% (all p < or = 0.001). BDI fell at all nine Rx visits (p < or = 0.001), a major reduction in a test of depressive symptoms. The HAS score also fell at all nine visits (p < or = 0.05 - < or = 0.001). Comparing pre-Rx baseline BDI vs BDI at 30 and 54 weeks on Rx, there was a major shift towards absence or amelioration of depressive symptoms (chi 2= 5.9, p = 0.016). On Rx, the greater the percent reduction in TG, the greater the percent fall in BDI (r = 0.47, p < or = 0.05); the greater the percent reduction in TC, the greater the percent fall in HAS (r = 0.41, p < or = 0.05). Improvement in the BDI and HAS accompanied treatment of severe hypertriglyceridemia, possibly by virtue of improved cerebral perfusion and oxygenation. There may be a reversible causal relationship between high TG and symptoms of depression.

Spontaneous dyskinesia in subjects with schizophrenia spectrum personality.

OBJECTIVE: The study of spontaneous dyskinesia in schizophrenia is confounded by the widespread use of neuroleptics. The authors hypothesized that spontaneous dyskinesia would be present in subjects with schizophrenia spectrum personality (schizoid, paranoid, or schizotypal). They also tested the hypothesis that dyskinetic-like movements would increase after repeated dextroamphetamine challenge to the dopaminergic system. METHOD: Dyskinetic-like movements were assessed in 34 spectrum subjects and 22 normal subjects; nine subjects from each group were administered both placebo and repeated dextroamphetamine challenges. RESULTS: Spectrum subjects had more dyskinetic-like movements than normal subjects. Spontaneous dyskinesia was present in 12% of the spectrum subjects but was not seen in the normal subjects. Subjects with schizotypal personality had more dyskinetic-like movements than subjects with schizoid personality or normal subjects. Dyskinesia was present in 24% of the schizotypal subjects but not in the other groups. Dyskinetic movement scores correlated with positive symptom scores. With repeated amphetamine challenge, normal subjects showed a pattern of behavioral sensitization (an increase in dyskinetic-like movements), but spectrum subjects showed an abnormal response (fewer dyskinetic-like movements). CONCLUSIONS: Dyskinesia and dyskinetic-like movements are more common in subjects with schizophrenia spectrum personality (primarily schizotypal) than in normal subjects and are related to positive symptoms. A failure of normal behavioral sensitization mechanisms after dextroamphetamine challenge is seen in subjects with schizophrenia spectrum personality.

Impact of headache education program in the workplace.

We evaluated the impact of a headache education program in a workplace setting. A 45-minute standardized educational program was delivered to 492 participants at eight companies. Participants completed questionnaires regarding their headaches and headache management techniques, the Short Form (SF)-36, and the Headache Disability Inventory (HDI) before and 1 month after the presentation. The intervention significantly improved health-related quality of life, decreased headache-related disability, and promoted the use of self-management techniques.

Survey of migraineurs referred to headache specialists: care, satisfaction, and outcomes.

The authors report a survey of 281 migraineurs recently referred to headache specialists by primary care physicians. Compared with care before referral, specialists spent substantially more time with patients and were more likely to ask patients to take a prophylactic drug and to keep a headache diary, to discuss migraine triggers, and to prescribe 5-hydroxytryptamine1B/1D agonists (triptans). After referral, patients reported improved satisfaction with care and significant decreases in frequency, duration, and severity of attacks.