System level design of the ITER bolometer port plug cameras.

The ITER bolometer diagnostic is planned to have 550 lines of sight (LOS) distributed all over the vessel. 240 channels are provided by cameras mounted in two upper ports and in one equatorial port. This paper describes the current status of the system level design of the port cameras and the solutions proposed on how to implement all required camera components while meeting a multitude of competing requirements. Sensor holders, support structures, and different apertures depending on the camera type (pinhole or collimator), cable connectors, ceramic track plates, and many mineral insulated cables have to be integrated within a restricted space envelope to guarantee functionality. The design of the internal electrical interfaces and the external mechanical mountings will be described as well. Using the example of an upper port camera with 60 LOS, the assembly of the camera components is explained and two currently discussed architecture options for the remote handling maintenance scheme in the hot cell are compared.

Recent findings on the pathogenesis of bronchial asthma.

In the first part of this series of papers (Székely and Pataki, 102) the pathogenesis of asthma was approached as a pathological antigen-antibody complex induced vago-vagal axon reflex. In the next part (103) the contribution of individual hormonal predisposition, the environmental and the most frequent allergizing factors have been reviewed. In the first section of this last (third) part of the review the genetic factors contributing to the asthma are surveyed. In this field a great progress has been made during the last decade, a lot of genes have been pinpointed which contribute to the heredity of the disease. In the second section of this last paper on the etiology of asthma an attempt is made to summarize the previously reviewed data and some new ones. Actually a new hypothesis is proposed that beyond the multitude of genetic, environmental and hormonal factors the underlying biochemical mechanism is simple: the disequilibrium of two functionally opposing second messenger systems in the airways: the Ca i ++ liberating PLC-PKC cascade and the Ca i ++ level reducing cAMP mediated one with preponderance of the former.

Recent findings on the pathogenesis of bronchial asthma. Part II. The role of hormonal predisposition, environmental influences and conditioning leading to bronchial asthma.

In this second part of the review on the pathogenesis of asthma the hormonal factors and adverse external events are shortly reviewed which skew the balance of Th1 vs. Th2 CD4+ lymphocytes towards the latter ones and this way increase the probability of atopic diseases. Among other the role of transplacental priming, insulin, insulin-like and other growth factors, lack of the usual microbial infections in the early childhood (the so-called hygiene hypothesis), gender, diminished testosterone production, gastroesophageal reflux, adverse effects during pregnancy are discussed. A separate chapter deals with the role of central nervous system in the etiology and finally the most common allergizing and airway tissue damaging agents are listed in tabulated form.

Recent findings on the pathogenesis of bronchial asthma. Part I. Asthma as a neurohumoral disorder, a pathological vago-vagal axon reflex.

The novel data on the pathogenesis of asthma are summarized in this three-part review. Its immunological background is well established but it is more than an immunological disorder. Multiple lines indicate that both peripheral and central neural mechanisms are also involved in the pathogenesis of asthma. In the present first part of the review asthma is described as vago-vagal axon reflex brought about by multiple positive feed-back mechanisms, receptor upregulation, wind-up, phenotypic switch and formation of a pathological conditioned reflex. In the coming second part the main dispositional (mostly hormonal) and external contributing factors are reviewed, while the third part deals with the role of inheritance, i.e., with gene alleles leading to enhanced production of mediators of asthma.

Long-term zoledronic acid treatment increases bone structure and mechanical strength of long bones of ovariectomized adult rats.

Zoledronic acid (ZOL) is a highly potent heterocyclic bisphosphonate which has been shown to inhibit bone resorption in short-term experiments in young growing animals. In this investigation we have evaluated the effects of a 1-year administration to mature, ovariectomized (OVX) rats as a model for postmenopausal osteoporosis in order to elucidate (1) the temporal changes in urinary biochemical markers of bone turnover and femoral bone mineral density (BMD), (2) to measure changes of static and dynamic histomorphometric parameters and mechanical strength, and (3) to assess the preventive effects of chronic treatment with ZOL on these parameters. In urine, deoxypyridinoline increased after OVX and was significantly reduced by ZOL administration, indicative of a reduced bone collagen turnover. These changes were accompanied by alterations of tibial cancellous bone: trabecular bone volume and parameters of bone architecture were significantly augmented by ZOL and bone formation rates fell as a consequence of suppressed bone turnover, but were still measurable. No signs of "frozen bone" or osteomalacia could be detected. BMD of the whole femurs rose in sham-operated control animals (SHAM) during the entire experimental period, whereas in OVX animals, BMD plateaued after 32 weeks at a lower level. ZOL at a low dose (0.3 mg/kg/week s.c.) did not alter whole femur BMD, but at higher doses (1.5 and 7.5 mg/kg/week s.c.) BMD increased to the level of the SHAM group. A distinct pattern was noted for the distal quarter of the femur, a region rich in cancellous bone: BMD initially increased in all treatment groups except the OVX group, and at a later stage fell again at a comparable rate irrespective of treatment. Mechanical stability, as assessed by a 3-point bending test, was significantly increased by all doses of ZOL and exceeded OVX and sham-operated controls. The effects on mechanical properties were observed at a low dose which did not measurably increase femoral BMD after 1-year treatment. Multiregression analysis revealed a significant positive correlation between maximum load and BMD, and a significant negative correlation of maximum load with labeled perimeter, a marker of bone formation and turnover. No significant correlation was found with urinary deoxypyridinoline, a marker of bone resorption. The data show that mechanical testing detects improvements of functional bone quality following low dose bisphosphonate treatment which are not identified by standard DXA measurements of BMD.

Differential modulation of the GYKI 53784-induced inhibition of AMPA currents by various AMPA-positive modulators in cerebellar Purkinje cells.

The effects of various (S)-alpha-amino-3-hydroxy-5-methyl-4-izoxazole-propionate (AMPA) receptor modulators on AMPA-induced whole-cell currents were compared in isolated rat cerebellar Purkinje cells. The positive modulators, aniracetam, cyclothiazide, 1-(1, 3-benzodioxol-5-ylcarbonyl)-piperidine (1-BCP), and 1-(quinoxaline-6-ylcarbonyl)-piperidine (BDP-12), dose-dependently potentiated the steady-state component of AMPA currents. The negative modulator, (-)1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine (GYKI 53784), dose-dependently suppressed AMPA responses. Its concentration-response curve was shifted to the right in a parallel fashion by all positive modulators, indicating a competitive type of interaction. However, the relative potencies of the positive modulators were different with regard to the enhancement of AMPA responses and the reversal of GYKI 53784-induced inhibition, respectively. It is supposed that positive modulators act at multiple allosteric sites and that they interact with GYKI 53784 at only one of these sites.

Local expression of tumor necrosis factor alpha in an experimental model of acute osteomyelitis in rats.

The inflammatory response associated with Staphylococcus aureus osteomyelitis results in extensive bone damage characterized by apparent increases in bone resorption and formation. These results suggest an increased local release of agents capable of modulating bone remodelling. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine proposed to play an important role both in normal bone remodelling and in bone diseases; however, its potential role in osteomyelitis is unclear. This study evaluated changes in bone TNF levels during infection, using a rat model of acute osteomyelitis due to S. aureus. Following direct tibial infection, bacterial counts in bone were persistently high (approximately 6 log10 CFU/g of bone over 63 days) and bone weights increased. TNF activity was undetectable in uninfected bone (<0.01 ng/g of bone) but dramatically higher in infected bone (up to 5.2 +/- 3.5 ng/g of bone). Although TNF-alpha mRNA was weakly detected in uninfected bone, osteomyelitis was associated with up to 37-fold increases in expression of both the 1.6- and 2.4-kb transcripts. Both TNF activity and mRNA transcript levels remained elevated throughout the course of infection. TNF-alpha mRNA detected by in situ hybridization was present in osteoblasts as well as in populations of marrow cells and/or inflammatory infiltrate cells. Histopathology of infected bone indicated extensive bone resorption and adjacent areas of formation that were associated with cells expressing TNF-alpha mRNA. These data suggest that the elevated TNF levels induced by experimental infection may be directly related to changes in the histology of bone during osteomyelitis.

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment.

To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 microg/kg) or pamidronate (3.7-370 microg/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure.

Characterization of the cerebroprotective efficacy of the competitive NMDA receptor antagonist CGP40116 in a rat model of focal cerebral ischemia: an in vivo magnetic resonance imaging study.

The cerebroprotective properties of the competitive NMDA antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) were evaluated in a rat model of focal cerebral ischemia. CGP 40116 (5-40 mg/kg i.v.) was injected immediately following permanent occlusion of the left middle cerebral artery (MCA). MK 801 (1 or 3 mg/kg i.v.), D-CPPene (20 mg/kg i.v.), and CGS 19755 (40 mg/kg i.v.) were used for comparison. Lesion volume was assessed using in vivo magnetic resonance imaging, which in initial experiments with parallel histological determinations proved to be an accurate method for the measurement of brain infarction and the determination of a cerebroprotective drug effect. CGP 40116 dose-dependently reduced the volume of cortical infarction, with an ED50 of 11 mg/kg i.v. and a maximal effect equivalent to a 62% reduction in cortical edema volume. Its cerebroprotective efficacy was thus comparable to that of MK 801. The rank order of potency for the NMDA antagonists was MK 801 > CGP 40116 approximately D-CPPene > CGS 19755. Neuroprotection by CGP 40116 was still apparent when treatment was started 30 min after MCA occlusion. It is concluded that CGP 40116 is an effective cerebroprotectant with potential clinical utility for amelioration of focal cerebral ischemic damage.

Quantitative radiographic diagnosis of osteo-arthritis of the knee-joint in the C57BL mouse.

Comparative histopathological and radiographic investigations in the C57BL mouse model of spontaneous osteo-arthritis of the knee-joint indicate that there is a relation between quantitative radiographic diagnosis and semiquantitative histopathological diagnosis. Statistical analysis based on a set of quantitative radiographic parameters of the mouse knee-joint shows that the greater part of the radiographic information reflecting the histopathological degree of the osteo-arthritis is contained in the projection areas of the lateral and medial meniscus: progression of the osteo-arthritic process is accompanied with enlargement of the menisci. On the basis of these observations, a radiography score for the osteo-arthritis has been constructed, which consists of a weighted sum of the - suitably transformed - projection areas of the lateral and medial meniscus. In addition to the size of the menisci, the width of the joint space is also a useful quantitative parameter of osteo-arthritis of the mouse knee-joint.

Spontaneous osteo-arthritis of the knee-joint in C57BL mice receiving chronic oral treatment with NSAID's or prednisone.

In a statistically planned study based on quantitative radiography, treatment for 25-26 weeks with the 2 NSAIDs, diclofenac sodium, or indomethacin (both 0.5 and 1.5 mg/kg p.o. daily), or prednisone (6 mg/kg p.o.) had no influence on the progression of spontaneous osteo-arthritis of the knee-joint of the C57BL mouse, by comparison with placebo-treated controls.

Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466.

The effects of GYKI 52466, a new 2,3-benzodiazepine with muscle relaxant and anticonvulsant properties, were investigated and compared to those of midazolam in electrophysiological experiments. The effects of the drugs on the reflex potentials evoked by afferent nerve stimulation and recorded from the spinal roots in unanesthetized spinal cats were studied. GYKI 52466 exerted a strong inhibitory effect on the monosynaptic as well as the polysynaptic ventral root reflexes, while the dorsal root responses decreased slightly. In contrast, midazolam markedly enhanced the dorsal root responses, did not modify the monosynaptic reflex and partially inhibited the polysynaptic reflex. The spontaneous firing of cerebellar Purkinje cells was depressed by midazolam, but not by GYKI 52466. These results suggest strongly that, contrary to the classical 1,4-benzodiazepines, potentiation of the GABA-A receptor-mediated inhibition does not play a significant role in the pharmacological actions of GYKI 52466.

Arthritis induced by continuous infusion of hr-interleukin-1 alpha into the rabbit knee-joint.

Continuous infusion of 200 ng/day hrIL-1 alpha for 14 days into knee-joints of rabbits leads to a severe arthritis of low aggressivity. This arthritis shows simultaneously characteristics of acute (serous and fibrinous exudation, polymorph infiltration, etc.) as well as chronic (synovial cell proliferation and fibrosis, pannus formation, cartilage and bone erosion, etc.) inflammation. The arthritis was associated with a distinct loss of metachromasia of the articular cartilage. These results indicate that IL-1 might play an important role in the induction and maintenance of arthritis.

Induction of erosive arthritis in mice after passive transfer of anti-type II collagen antibodies.

The passive transfer of concentrated immunoglobulins or affinity-purified anti-collagen antibodies from sera of mice with type II collagen-induced arthritis can induce erosive arthritis in recipient animals. In both cases, the incidence of arthritis was over 60% and the inflammation persisted for at least two weeks. Radiography revealed bone destruction and apposition of a newly formed material while histologic examination showed cartilage and bone degradation, accompanied with synovitis and periarthritis. Inflammatory infiltrates were composed of polymorphonuclear leucocytes and lymphocytes, and were associated with a proliferation of connective tissue cells.

Qualitative radiographic diagnosis of osteo-arthritis of the knee joint in the C57BL mouse.

Experiments were performed to assess the diagnostic value of radiography in osteo-arthritis (OA) of the knee joint in C57Bl mice. Comparative histological and radiographic examination of knee joints from 96 animals showed that if the classical diagnostic criteria (narrowing of the joint space, sclerosis of the subchondral bone, deformation of the joint epiphyses) are applied, OA is not readily detectable by radiography. If these criteria are extended to include radiographic changes in the menisci (enlargement, deformation, increased and/or heterogeneous density), the frequency of detection is much improved. However, except in the severest forms of OA, radiography does not afford a satisfactory means of distinguishing between various degrees of severity. The qualitatively evaluated data nevertheless do suggest that quantitative radiographic diagnosis of OA of the murine knee joint may be useful, both for improving the detection rate and for discriminating various degrees of OA.

Arthritis in MRL/LPR mice and in collagen II sensitized DBA-1 mice and their use in pharmacology.

For assessment of anti-arthritic drugs, we used mice of the autoimmune MRL/lpr strain and DBA-1 mice sensitized with collagen type II. Our studies showed that in these two mouse arthritis models, unlike the classical rat adjuvant arthritis, the nonsteroidal antiinflammatory compounds tested were either ineffective or minimally affected a chosen number of humoral parameters and the incidence and severity of arthritis. Interestingly, both arthritis models showed a distinct pharmacological pattern in response to the slow-acting anti-rheumatic drugs, whereas steroids and cyclophosphamide inhibited both arthritic processes. Therefore, these two mouse models are useful for studying the immunopathological events operating in chronic inflammation and could potentially serve the characterization of new antirheumatic drugs.

Serum amyloid P component and autoimmune parameters in the assessment of arthritis activity in MRL/lpr/lpr mice.

The concentration of immunoglobulins, anti-ssDNA, anti-dsDNA, anti-TNP antibodies, IgM rheumatoid factor, C3, immune complexes and serum amyloid P component (SAP), in the serum were measured in 68 male and female MRL/lpr/lpr mice, a strain affected with a systemic autoimmune disease. The degree of lymphoproliferation was assessed by the spleen weight. Spontaneous secretion of immunoglobulins and anti dsDNA antibodies were measured in spleen cell cultures. All mice presented age related increases or decreases (C3) in the level of measured parameters. Inflammatory lesions were detected, by light microscopy in the joints of all mice. There was a significant correlation, in both sexes between the serum level of SAP and the severity of the polyarthritis, as assessed by light microscopy. In female mice the levels of anti-dsDNA antibodies, immunoglobulins, either measured in serum or in the spleen compartment, and circulating immune complexes also showed correlation with the activity of the arthritis, but neither of these variables correlated as closely with arthritis scores as did serum SAP.