High power high voltage bias-T for half wave resonators and radio frequency quadrupole couplers.

High power high voltage bias-T units capable of delivering up to 100 kW CW RF power at 176 MHz and up to 4 kV DC were developed at the Soreq Nuclear Research Center for the Soreq Applied Research Accelerator Facility linac. Two separate bias-T units with different requirements were designed for the radio frequency quadrupole couplers and the half wave resonator couplers. The purpose of this bias-T is to prevent multipacting phenomena by application of a high voltage DC bias to inner conductors of RF couplers. Underlying design principles, indigenous development, and successful off-line and on-line tests results are presented.

Complication and local recurrence rate after endoscopic resection of large high-risk colorectal adenomas of ≥3 cm in size.

PURPOSE: Endoscopic resection is a widely used technique for treatment of large colorectal adenomas, but few data are available including only lesions larger than ≥2 cm. The aim of this study is to evaluate the complication and recurrence rate after endoscopic resection of high-risk colorectal adenomas ≥3 cm in size. METHODS: Retrospective analysis of a prospectively maintained database of patients undergoing polypectomy of large colorectal polyps of ≥3 cm. RESULTS: In 341 patients, 360 colorectal adenomas with a mean size of 3.9 cm were resected endoscopically. In 25 patients, a complication including 22 delayed bleedings (6.5%) and three perforations (0.9%) occurred. Single-variate analysis showed an increasing risk of complications for larger adenomas (3.9 vs. 4.6 cm; p ≤ 0.05). Two hundred twelve patients with 224 adenomas had undergone at least one documented follow-up endoscopy with a medium follow-up period of 16 months. In 95 resected lesions (42.4%), a residual adenoma occurred in the first follow-up colonoscopy (n = 88, 92.6%) or a recurrent adenoma occurred after at least one negative follow-up colonoscopy (n = 7, 7.4%). In multivariate analysis, risk factors were lesion size, sessile growth pattern, and the performing endoscopist. The complication and recurrence rate correlated inversely between endoscopists. CONCLUSIONS: The present study is the largest study showing complication and recurrence rates after colorectal polypectomy of advanced colorectal adenomas of ≥3 cm in size. Polyp size was identified as the most important risk factor for complications. For the first time, this study shows that the complication rate after colorectal polypectomy of large adenomas is correlated inversely with the residual and/or recurrence rate.

Polymorphisms in the STAT6 gene and their association with carcass traits in feedlot cattle.

Identification of the genes and polymorphisms underlying quantitative traits, and understanding how these genes and polymorphisms affect economic traits, are important for successful marker-assisted selection and more efficient management strategies in commercial cattle populations. Signal transducer and activator of transcription 6 (STAT6) gene is tightly connected to IL-4 and IL-13 signalling and plays a key role in T(H)2 polarization of the immune system. In addition, STAT6 acts as a mediator of leptin signalling and has been associated with body weight regulation. The objective of this study was to determine if SNPs within the bovine STAT6 gene are associated with economically important traits in feedlot cattle. The approach consisted of resequencing STAT6 using a panel of DNA from unrelated animals of different beef breeds. Specifically, 16 kb of STAT6 was resequenced in 47 animals and the process revealed 39 SNPs. From the 39 SNPs, a panel of 15 tag SNPs was genotyped in 1500 beef cattle samples with phenotypes to perform a marker-trait association analysis. Among the 15 tag SNPs, five and six were polymorphic in Bos taurus and Bos indicus respectively. An association analysis was performed between the 15 tag SNPs and 14 performance and production traits. SNP ss115492459:C > A, ss115492461:A > G and ss115492458:G > C were significantly associated with back fat, calculated yield grade, cutability, hot carcass weight, dry matter intake, days on feed, back fat rate and average daily gain. These three SNPs were present in all Bos taurus beef breeds examined. Our results provide evidence that polymorphisms in STAT6 are associated with carcass and growth efficiency traits, and may be used for marker-assisted selection and management in feedlot cattle.

Inexpensive detector for terahertz imaging.

Glow discharge plasma, derived from direct-current gas breakdown, is investigated in order to realize an inexpensive terahertz (THz) room-temperature detector. Preliminary results for THz radiation show that glow discharge indicator lamps as room-temperature detectors yield good responsivity and noise-equivalent power. Development of a focal plane array (FPA) using such devices as detectors is advantageous since the cost of a glow discharge detector is approximately $0.2-$0.5 per lamp, and the FPA images will be diffraction limited. The detection mechanism of the glow discharge detector is found to be the enhanced diffusion current, which causes the glow discharge detector bias current to decrease when exposed to THz radiation.

Mast cell density and IL-8 expression in nonlesional and lesional psoriatic skin.

BACKGROUND: An important cellular aberration at sites of psoriatic inflammation is an increase in the number of dermal mast cells. Being multifactorial immune effector cells, it is believed that mast cells play an essential role in perpetuating the inflammatory process of psoriasis. However, factors responsible for the infiltration and accumulation of mast cells in psoriatic lesions are largely unknown. Recent studies have demonstrated that Interleukin-8 (IL-8) exerts strong chemotactic effects on mast cells in vitro. Overexpression of IL-8 has also been reported in psoriatic lesions. In this study, we have found a correlation between the expression of IL-8 and dermal mast cell density in lesional psoriatic skin as compared to nonlesional psoriatic skin. METHODS: Four-mm punch biopsies were taken from 14 psoriatic patients and eight healthy volunteers. Using immunohistochemical techniques, 8 microm sections of lesional psoriatic, nonlesional psoriatic, and normal control samples were evaluated for dermal mast cell density and the density of IL-8 expressing keratinocytes. RESULTS: It was found that dermal mast cell density in lesional psoriatic, nonlesional psoriatic, and normal skin was 105.4 +/- 71.2, 42.3 +/- 30.1, and 47.5 +/- 32.5 mast cells/mm(2), respectively. IL-8+ keratinocyte density in lesional psoriatic, non lesional psoriatic, and normal skin was 171.5 +/- 67.1, 25.4 +/- 14.9 and 20.6 +/- 8.7 IL-8+ Keratinocytes/mm(2), respectively. CONCLUSIONS: The results of this study suggest that increased levels of IL-8 in the keratinocytes of psoriatic plaques play a contributing role in the migration of mast cells to lesion sites.

Effect of nerve growth factor on endothelial cell biology: proliferation and adherence molecule expression on human dermal microvascular endothelial cells.

In addition to its effect on the central nervous system, nerve growth factor (NGF) appears to play a key role in the initiation and maintenance of inflammation in many organs. NGF degranulates mast cells, recruits inflammatory cellular infiltrates and activates T cells. Extravascular migration of leukocytes is initially controlled by the interaction of cell surface adhesion molecules of leukocytes and endothelial cells. A marked upregulation of NGF in keratinocytes is also observed in conditions characterized by angiogenesis such as psoriasis and wound healing. In this study we investigated the role of NGF in inflammation by studying its effects on endothelial cell proliferation and intracellular adhesion molecule expression by endothelial cells. The effect of NGF on human dermal microvascular endothelial cell (HDMEC) proliferation was measured using the hexosaminidase assay. ICAM-1 expression on HDMEC was measured by ELISA. The function of ICAM-1 was assessed by adherence of peripheral blood mononuclear cells (PBMC) to HDMEC using 51Cr-labeled PBMC. There was a significant increase in proliferation of HDMEC stimulated with NGF as compared to unstimulated HDMEC (P < 0.001). NGF-neutralizing antibody decreased the mitogenic effect of NGF significantly (P < 0.05). NGF also increased ICAM expression on HDMEC as compared to unstimulated HDMEC (P < 0.05). NGF-neutralizing antibody decreased ICAM expression on NGF-stimulated HDMEC (P < 0.05). The percentage of PBMC adherence was higher in NGF-stimulated HDMEC (P < 0.001). Anti-ICAM antibody decreased PBMC adherence. In the study reported here, the role of NGF in two important aspects of inflammation, i.e. angiogenesis and inflammatory cell recruitment at the site of inflammation, was investigated.

Cellular localization of fractalkine at sites of inflammation: antigen-presenting cells in psoriasis express high levels of fractalkine.

BACKGROUND: Chemokines play a key role in cell trafficking at sites of inflammation. The fractalkine CX3C chemokine is unique in several aspects. Fractalkine is expressed on activated endothelial cells and exists in two forms, either membrane anchored or in a soluble form. The soluble form is a potent chemotactic agent for T cells/monocytes and the anchored form functions as an adhesion molecule. In view of these specific functions fractalkine is capable of controlling the key regulatory mechanisms of cell trafficking at sites of inflammation. OBJECTIVES: Little is known about the significance of this important molecule in inflammatory diseases. We undertook this study to elucidate the role of fractalkine in inflammatory diseases of the skin. METHODS: We used a polyclonal antifractalkine antibody (immunoperoxidase and immunofluorescence stainings) in cryosections obtained from tissues of normal skin and that of selected cutaneous inflammatory diseases (psoriasis, lichen planus, eczema). RESULTS: Increased expression of fractalkine was observed in the dermal blood vessels of lichen planus, eczema and psoriasis tissues. The most striking finding was that the dermal dendrocytes in the papillary dermis of psoriasis tissues expressed high levels of fractalkine. Compared with 186.64 +/- 51.69 fractalkine positive dermal dendrocytes per mm2 of the upper dermis of psoriatic tissue, the number of positive cells in lichen planus, eczema, and normal skin were 17.29 +/- 12.50, 12.50 +/- 6.75 and 5.93 +/- 3.53, respectively. We also performed double label immunofluorescence staining with nerve growth factor receptor (NGF-R) antibody and fractalkine antibody. NGF-R-positive terminal cutaneous nerves were in close contact with the fractalkine-positive dermal dendrocytes in psoriatic lesions. CONCLUSIONS: The results of this study confirm that fractalkine is upregulated at sites of inflammation. Thus, it is likely that this molecule plays a key part in cell trafficking. An increased expression of fractalkine at the dermal papillae provides a plausible explanation for the migration and accumulation of T cells at these sites in psoriasis. Earlier studies have reported an increased number of dermal dendrocytes in psoriatic tissue; however, the functional role of these cells in the pathogenesis of psoriasis is largely unknown. Expression of fractalkine on the surface of dermal dendrocytes suggests an active role for these cells in localization and activation of lesional T cells.

Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation.

Elucidation of the molecular and cellular mechanisms responsible for the pathogenesis of psoriasis had been significantly handicapped due to lack of an ideal animal model. To overcome this hurdle several investigators have developed a number of animal models for psoriasis. Recent establishment of the SCID-human skin chimeras with transplanted psoriasis plaques has opened new vistas to study the molecular complexities involved in psoriasis. This model also offers a unique opportunity to investigate various key biological events such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. The SCID mouse model will be of immense help to target the cellular and molecular events associated with these pathogenic processes and develop novel drugs for psoriasis and other inflammatory diseases. In this article we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.

Role of nerve growth factor in RANTES expression by keratinocytes.

A role of neurogenic inflammation induced by the neuropeptides and nerve growth factor (NGF) has been attributed to the pathogenesis of several cutaneous disorders such as psoriasis, wound healing and eczematous dermatitis. The underlying mechanisms of the inflammatory process induced by NGF are not clearly established. This study explored whether NGF influences the inflammatory process by inducing chemokines. The effects of NGF were investigated on induction of 2 important chemokines, interleukin-8 and RANTES, which are known to be upregulated in the keratinocytes of various inflammatory conditions. NGF significantly increased RANTES production by the keratinocytes (p < 0.001, 2-tailed Student's t-test). Induction of RANTES expression in the keratinocytes by NGF provides further insight regarding the role of NGF-NGF receptor system in cutaneous inflammatory conditions.

Is psoriasis a T-cell disease?

The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

Risk assessment for possible carcinogens: a critical look.

Our overall understanding of mechanisms of toxicology in relation to human disease, with prevention of disease as a major objective, depends in part on the development of an adequate number of ways to assess risks, both short term and long term. Despite the cost, the long duration of the test, and some pitfalls, the long-term animal tests remain, to date, the only reliable assay for possible carcinogens. Recent work has concentrated increasingly on the development of short-term tests to replace the long-term tests. Such a development would be most welcome from several points of view. To date, a variety of approaches have been or are being used. These include (1) activation to an alkylating agent with DNA as the most important target, generating possible mutations in DNA and DNA damage with or without repair, (2) induction of cell proliferation, at least a few cycles, with DNA synthesis as the major target, again favoring mutations, and (3) decrease in cell-to-cell communication (gap-junctional intercellular communication) as a supposed test for promotion. None of these proposed assays are reliable indices for possible carcinogenic effects of chemicals or other agents; the scientific basis for this negative conclusion is discussed.

Resilience factors associated with adaptation to HIV disease.

This study examines the hardiness dimensions of commitment, challenge, and control as resilience factors in adaptation among persons with symptomatic HIV disease and AIDS. Two hundred participants completed self-report questionnaires measuring hardiness, psychological distress, quality of life, and core personal beliefs. A series of standard multiple regression analyses revealed that high hardiness was significantly related to 1) lower psychological distress levels; 2) higher perceived quality of life in physical health, mental health, and overall functioning domains; 3) more positive personal beliefs regarding the benevolence of the world and people, self-worth, and randomness of life events; and 4) lowered belief in controllability of life events. Commitment was the hardiness factor that most frequently made a unique contribution to predicting adaptation in the regression models. Implications of these findings for understanding HIV-related adaptation and for clinical mental health intervention are considered. Future directions in HIV-related adaptation research are suggested.

The resistance phenotype in the development and treatment of cancer.

Phenotypic resistance, acquired early in carcinogenesis, has an established role in the pathogenesis of cancer in well-characterised experimental systems, and possibly also has a role in the origin of human cancer. It has been suggested that sunlight, an established risk factor for human skin carcinogenesis, is able to induce rare altered cells resistant to toxicity and to favour their clonal expansion via toxic effects exerted on normal keratinocytes. Other major risk factors for human neoplasia, including smoking and ageing, may also act partly through imposition of a constrained growth environment in the target organ to favour the emergence of altered resistant cells. Strategies aimed at counteracting this constrained environment could be effective in attenuating the force that sustains clonal expansion of altered cells.

Childhood psoriasis.

Psoriasis is a common skin disease in infants, children, and adolescents. A review of the clinical, epidemiologic, genetic, and therapeutic aspects of childhood psoriasis is presented. Population studies indicate that the first signs of psoriatic lesions occur in the pediatric age group, birth to 18 years of age, and that both genetic and environmental factors interact to precipitate the development of psoriasis. Koebner reactions are the result of external or internal triggering factors, such as physical injury to the skin, low humidity, and certain drugs. The most frequently observed variant to psoriasis is the plaque type, followed by guttate psoriasis, and juvenile psoriatic arthritis. Pustular psoriasis and erythrodermic psoriasis are rare forms of the disease, but are seen in children from infancy to adolescence. The scalp is the most frequently affected site of involvement in pediatric psoriasis, followed by the appearance of lesions on the extensor surfaces of the extremities, trunk, and nails. Although not common in adult psoriasis, the face and ears are often involved. Topical medications such as corticosteroids, calcipotriol, coal tar preparations, anthralin formulations, and ultraviolet B are recommended in monotherapy or in combination therapy, whereas psoralen plus ultraviolet A, methotrexate, and retinoids should only be administered in crisis situations. The treatment objectives in childhood psoriasis are to preserve skin surfaces, to afford physical relief from the disease, and to employ treatments that do not endanger the health or future development of the child.

Search for the psoriasis susceptibility gene: the Newfoundland Study.

The authors review early pioneering research on the genetics of psoriasis and recently published independent and collaborative investigations searching for the psoriasis susceptibility genes. We describe the research design and current plans for a joint pursuit between the Psoriasis Research Institute, the Memorial University of Newfoundland, and Chiroscience R&D, Inc., for susceptibility genes. A unique study sample from Newfoundland, drawn from affected and unaffected members of multiplex families and relatives, provides a nearly homogeneous isolated population. Families reflect English, Scottish, and Irish ancestry, and have been in residence in Newfoundland for over 300 years. The prevalence of psoriasis is estimated to be 2 to 3%. Familial psoriasis occurs in over 85% of families, with at least one affected member. The experimental strategy using linkage analysis and linkage disequilibrium analysis of the collected tissue bank are discussed, emphasizing prospects for the future outcome of the research findings.