[Partial response of solar urticaria to omalizumab therapy]. / Partielles Ansprechen einer Lichturtikaria auf Omalizumab.

The treatment of solar urticaria is regarded as difficult. In some cases good responses to the anti-IgE antibody omalizumab (Xolair®), approved for treatment of chronic spontaneous urticaria, have been reported. We report on a 50-year-old Caucasian woman who for the last 5 years has developed localized itching and stinging erythemas following exposure to sunlight accompanied sometimes by anaphylactic reactions. Oral antihistamines in three- to four-fold doses and a topical sun screen had been only partially effective in long-term use. Positive immediate-type reactions with whealing appeared in phototesting with low doses of UVB and UVA. Three weeks after s. c. injection of 300 mg omalizumab, the minimal urticarial dose (MUD) for UVB was increased at least 20-fold (from <0.001 to 0.02 J/cm2) and for UVA four-fold (from 0.1 to 0.4 J/cm2) and the patient reported no itching at the test area. On the other hand, MUD for UVA1 remained unchanged (5.0 J/cm2). The weekly urticarial activity score (UAS7) was reduced from 30 points before omalizumab administration to 14 points in weeks two and three. Overall, a partial response of solar urticaria to omalizumab therapy could be observed in the present case.

Upscaling the synthesis of biodegradable multiblock copolymers capable of a shape-memory effect.

Thermoplastic, phase-segregated multiblock copolymers (MBC) with shape-memory capability consisting of poly(ε-caprolactone) (PCL) switching segments and poly(p-dioxanone) (PDO) or poly(ω-pentadecalactone) (PPD) hard segments were prepared on a scale of several kilograms following a newly developed upscaling procedure. Dihydroxytelechelic poly(ether)esters were coupled by an aliphatic diisocyanate gaining products of sufficiently high molecular weights. The obtained biodegradable MBC exhibited good elastic properties and a shape-memory effect (SME) with a switching temperature (T (sw)) around body temperature. The yield of the synthesis could be improved and reaction time reduced, while mechanical and shape-memory properties were not affected. These multifunctional materials, which are now available in a larger scale have a high application potential as smart implant materials especially for minimally invasive surgery.

Induction of murine peritoneal gamma/delta T cells and their role in resistance to bacterial infection.

Previous studies have reported an association of gamma/delta T cells with microbial infection in both human lesions and murine infectious disease models. In this study we provide a comprehensive analysis of the conditions under which the induction of gamma/delta T cells occurs at a site of infection. We found a site-specific induction of gamma/delta T cells after the injection of Listeria monocytogenes in the peritoneal cavity of C3H mice. No changes were seen in the splenic or lymph node populations after these injections. Both the proportion and the absolute number of gamma/delta T cells increased in the peritoneal cavity. Additionally, when peritoneal T cells from Listeria-immune mice were restimulated in vitro, the induced gamma/delta T cells exhibited a greater expansion potential than the alpha/beta T cells. Neither the induced gamma/delta T cells nor those from normal mice expressed CD4 or CD8 on the cell surface. Thy-1 was expressed on only 29% of normal peritoneal gamma/delta T cells, but after intraperitoneal Listeria injection 65% of induced gamma/delta T cells expressed. Thy-1, Pgp-1 and CD45R expression on both normal and induced gamma/delta T cells was consistent with an activation phenotype. Significant increases in peritoneal gamma/delta T cells were not seen until 5-7 d after Listeria injection. The proportion of the CD3+ population expressing the gamma/delta T cell receptor remained elevated for 6-7 wk, while the absolute numbers of peritoneal gamma/delta T cells declined gradually over this time period, reflecting a decrease in both the number of lymphocytes and the percentage of these that were CD3+. Peak numbers of gamma/delta T cells were seen at day 10 with live microbes such as Listeria. A variety of microbes, toxins, mitogens, antigens, cytokines, and nonspecific inflammatory agents were evaluated for their ability to induce gamma/delta T cells in the peritoneal cavity. Both Gram-positive and Gram-negative bacteria as well as Mycobacteria were able to induce gamma/delta T cells that showed increased in vitro expansion potential. An exotoxin from a Gram-positive organism, listeriolysin-o, and the lipopolysaccharide (LPS) endotoxin from a Gram-negative organism were also effective. gamma/delta T cell responses to LPS were under lps gene control. Peak numbers of gamma/delta T cells were observed at day 3 after injection with exotoxins and endotoxins. Modifications that abrogated the virulence of a bacterial strain also eliminated the inductive effect for gamma/delta T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Intercellular interactions and cytokine responsiveness of peritoneal alpha/beta and gamma/delta T cells from Listeria-infected mice: synergistic effects of interleukin 1 and 7 on gamma/delta T cells.

Peritoneal gamma/delta T cells from Listeria-immune mice show an enhanced potential to expand when restimulated with antigens or mitogens in vitro (see companion paper [Skeen, M. J., and H. K. Ziegler. 1993. J. Exp. Med. 178:971]). When cocultured with peritoneal alpha/beta T cells, the gamma/delta T cell population expanded preferentially even when the in vitro stimulus was specific for the alpha/beta T cell population. Purified gamma/delta T cells did not respond to alpha/beta T cell-specific stimuli. If isolated T cell subsets were recombined in cell mixing experiments, the resulting proliferative response was greater than additive. Irradiated alpha/beta T cells could enhance the proliferation of responding gamma/delta T cells, but the effect was unidirectional; i.e., irradiated gamma/delta T cells did not stimulate responding gamma/delta T cells. This effect appeared to be cytokine mediated and did not require cell-cell contact. Both recombinant interleukin 2 (rIL-2) and rIL-7 could support the expansion of the gamma/delta T cells, while rIL-7 was only minimally stimulatory for the alpha/beta T cells. The magnitude of the response by gamma/delta T cells to rIL-7 exceeded the response to other in vitro stimuli, including immobilized anti-T cell receptor monoclonal antibody, and was 50-100-fold greater than the alpha/beta T cell response to IL-7. This unique sensitivity of gamma/delta T cells to IL-7 was strongly enhanced by the presence of accessory cells. These cells could be replaced by rIL-1, establishing a synergy for IL-1 and IL-7 as factors that could uniquely stimulate this gamma/delta T cell population. Isolated peritoneal gamma/delta T cells from Listeria-immune mice react to heat-killed Listeria preparations in the presence of macrophages accessory cells in a non-H-2-restricted manner. Considered collectively, these results suggest a potential mechanism by which gamma/delta T cells can predominate in epithelial tissues and at sites of infection.

[Is the experimental gold standard actually worth a mint for evidence-based early support systems?]. / Ist der experimentelle Goldstandard wirklich Gold wert für eine Evidenzbasierung der Praxis Früher Hilfen?

The article discusses the capacities of experimental impact research in the practice of early support systems or primary prevention. It criticizes the conception of evidence-based child and youth welfare services relying on results of such experimental research. In the final section, the potentials of an alternative form of impact research, such as process-mechanism research, are discussed with respect to professional practice in child and youth welfare.

Xylem-tapping mistletoes: water or nutrient parasites?

Most mistletoes parasitize higher plants by tapping the xylem (a conduction tissue) of their hosts. Field observations of diurnal gas exchange parameters and carbon isotope ratios in xylem-tapping mistletoes from three continents support the hypotheses that water use efficiency and carbon isotope composition are related and that mistletoes which are parasitic for water are also nutrient parasites, differing in their water use efficiency relative to that of their hosts on the basis of host nitrogen supply in the transpiration stream.

Successful transplantation of a human leukemia cell line into nude mice: conditions optimizing graft acceptance.

Conditions were determined for successful subcutaneous tumor development of MOLT-4 human T-cell leukemia cells in BALB/c nude (nu/nu) female mice. MOLT-4 cells injected alone at one site resulted in tumors in none of 21 mice, whereas MOLT-4 cells injected with X-irradiated human fibrosarcoma cells (HT-1080) at another site resulted in tumors in 5 of 21 mice. When X-irradiated three times with 200 rad over a 3-week period and then inoculated with MOLT-4 cells and X-irradiated HT-1080 cells, 19 of 25 mice developed tumors, which indicated that a combination of X-irradiation of the recipients and inoculation of an admixture of the leukemia cells with X-irradiated fibrosarcoma cells markedly increases tumor incidence. The cells growing in the tumors had the characteristics of MOLT-4, as assessed by marker studies and histology.

Protein-catalyzed phospholipid exchange in bilayer vesicles determined by flow cytometry and electron microscopy.

The protein-induced lipid transfer between phosphatidylcholine vesicles was investigated. Measurements of the degree of polarization at single vesicles were made by flow cytometry using diphenylhexatriene as the optical probe. Vesicles differing in phase transition temperature could be distinguished by their degree of polarization at a temperature where one population was in the fluid (T greater than Tt) and the other one in the quasi-crystalline (T less than Tt) state. Besides vesicles containing exchange lipids we also observed fractions of unaffected vesicles. The lipid exchange was visualized directly by freeze-fracture electron microscopy. The characteristic 'ripple' structure of phosphatidylcholine vesicles disappeared upon exchange with lipid in the fluid state.

Reduction of clinically manifest colorectal cancer by endoscopic screening: empirical evaluation and comparison of screening at various ages.

Endoscopic screening (sigmoidoscopy, colonoscopy) with removal of precancerous lesions can prevent a large proportion of colorectal cancers (CRCs). However, there is lack of data regarding optimal age, time intervals and numbers of screening examinations. We developed and applied modified techniques of epidemiological analysis to evaluate the impact of various endoscopy-based screening strategies on prevention of clinically manifest CRCs between the ages of 50 and 79 in a population-based case-control study (294 cases, 254 controls) conducted in Saarland, Germany. We found a strong potential for reduction of CRC occurrence even with a single screening endoscopy. The optimal age for a single screening endoscopy appears to be around 55 (estimated potential for prevention of cases between the ages of 55 and 79 in case of 100% compliance: 77% (95% confidence interval (CI) 46-90%)). A single screening endoscopy at age 50 would have a lower impact due to failure to prevent CRC at higher ages. Similarly, screening at ages 60 or older would have a lower impact because it would fail to prevent CRC at lower ages. Repeated offers of screening examinations could provide substantial additional benefit with the levels of compliance to be expected in practice, but they would have to be weighed against the increased risks and costs.

Changes in peritoneal myeloid populations and their proinflammatory cytokine expression during infection with Listeria monocytogenes are altered in the absence of gamma/delta T cells.

Evidence that gamma/delta T cells play a broad, immunoregulatory role has been accumulating steadily. We show here that myeloid cells are disregulated after peritoneal infection with Listeria monocytogenes in mice lacking gamma/delta T cells. Inflammatory populations of neutrophils and monocytes recruited to the site of infection remained longer. Intracellular cytokine analysis showed that frequencies of myeloid cells producing interleukin-12 and tumor necrosis factor alpha were higher and remained elevated longer after infection in mice genetically deficient in gamma/delta T cells. In vivo dye-tracking studies indicated that the majority of inflammatory monocytes differentiated into resident tissue macrophages in situ. In vitro experiments confirmed that monocytes harvested from mice lacking gamma/delta T cells were defective in their maturation process. This evidence suggests that gamma/delta T cells promote differentiation in the monocyte/macrophage lineage. These cells are important for bactericidal activity, inflammatory cytokine production, clearance of inflammatory neutrophils, and ultimately, antigen presentation to T cells. Regulation of monocyte/macrophage differentiation may underlie a broad segment of the phenotypic alterations that have been reported in mice lacking gamma/delta T cells.

Interferon-gamma and interleukin-10 have cross-regulatory roles in modulating the class I and class II MHC-mediated presentation of epitopes of Listeria monocytogenes by infected macrophages.

IFN-gamma is an important cytokine in resistance to infection with Listeria monocytogenes, and interleukin 10 is known to exacerbate infection with Listeria and other intracellular pathogens. We examined the effects of these cytokines on antigen presentation by macrophages infected with live Listeria. Listeriolysin O, a hemolysin secreted by Listeria, is an immunodominant antigen presented by both class I and class II MHC on infected cells. Thioglycollate-elicited macrophages were pretreated with exogenous IFN-gamma, IL-10, or both cytokines overnight, infected with bacteria, and then fixed. Epitope-specific, MHC-restricted, T cell hybridomas were then added to detect the presentation of the class I or class II ligand. We found that IFN-gamma enhanced the presentation of both the class I and class II epitopes and IL-10 strongly inhibited the presentation of both ligands. The degree of inhibition of presentation caused by IL-10 was dose dependent. IL-10 was also able to inhibit the presentation of exogenously added class II-binding peptide but had a less dramatic effect on the presentation of the added class I-binding polypeptide epitope. Flow cytometric analysis of expression of class I and class II on treated macrophages demonstrated that the inhibitory effect of IL-10 on antigen presentation was not due to significant downregulation of MHC expression. This loss of antigen presentation was also not due to downregulation of the costimulatory molecule, B7-2. We have found that IFN-gamma and IL-10 have opposing immunoregulatory effects on the presentation of antigens derived from an intracellular pathogen and that the class I vs. class II-mediated presentation of antigens is differentially regulated by IL-10.

The role of gamma/delta T cells in immunity to infection and regulation of inflammation.

The role of gamma/delta T cells in immunity to bacterial infection and control of inflammation is discussed. Special emphasis is placed on the use of murine models in which various aspects of immune function can be monitored in the absence of gamma/delta T cells. Issues discussed include the response to and control of cytokine production by gamma/delta T cells. Especially relevant is the apparent paradox that gamma/delta T cells play both pro-inflammatory and antiinflammatory roles in response to infection.

Estimating completeness of cancer registration in Saarland/Germany with capture-recapture methods.

Completeness of population-based cancer registration has been most commonly quantified by indirect measures, such as the death certificate only index or the mortality/incidence ratio. A major disadvantage of these measures is their strong dependence on the case fatality rate. Capture-recapture methodology offers an approach to estimate completeness directly which does not share this limitation. In this paper, a three-sources modelling approach is employed to derive estimates of completeness for the population-based cancer registry of Saarland. Overall, completeness is found to be high: estimates for all types of cancer range from 95.5 to 96.9% for calendar years 1970, 1975, 1980 and 1985. There is some variation with age (consistently high levels above age 30 years, a minimum of 87.7% in age group 15-29 years) and between cancer sites. Among the most common cancer sites, estimates of completeness are highest for gastrointestinal cancers (97.2%) and breast cancer (97.1%), while lower estimates of completeness are derived for cancers of the female genital organs (92.5%), the urinary tract (91.8%) and the prostate (91.0%). Although capture-recapture estimates are sensitive to the underlying assumptions about dependence between sources, careful application is encouraged to supplement traditional methods for evaluating completeness of cancer registration.

Magnitude and time trends of the life-time risk of developing cancer in Saarland, Germany.

The probability of developing cancer within defined age-intervals or during life-time was assessed for the population of Saarland, Germany in 1970-1972 and 1980-1985 based on life-tables and age-specific cancer incidence rates. As a result of increasing life expectancy and, for some forms of cancer, increasing age-specific incidence rates, the probability at birth of eventually developing a malignant neoplasm (ICD-9 140-208) increased from 24.12% in 1970-1972 to 32.35% in 1980-1985 in men, and from 24.76 to 29.72%, respectively, in women. Comparable calculations are presented and discussed for all of the most common malignancies in women and men. The relation to common measures of descriptive epidemiology, mainly the cumulative rate and the cumulative risk, is numerically illustrated.

Second primary neoplasms following breast cancer in Saarland, Germany, 1968-1987.

A statewide cohort study on the occurrence of second primary neoplasms was conducted among 9678 women first diagnosed with breast cancer in Saarland, Germany between 1968 and 1987. A total number of 409 second primary neoplasms was observed compared to 328 cases that would have been expected based on the incidence rates of the general population (standardised incidence ratio, SIR = 1.25). This elevation in incidence of second neoplasms was primarily due to increased occurrence of cancer of the opposite breast (SIR = 2.48), which was most pronounced for patients below the age of 50 (SIR = 4.20) and within the first 5 years after diagnosis (SIR = 2.91). There was a moderate elevation in incidence of malignant tumours of the ovaries (SIR = 1.46), while the incidence of most other malignancies was lower than in the general population. Our results, which are in agreement with previous findings from Northern Europe, the U.S.A. and Japan provide valuable background information for aetiological research, as well as for surveillance of breast cancer patients.

Age-specific detriments to quality of life among breast cancer patients one year after diagnosis.

The aim of our study was to identify any differences in the quality of life (QOL) of breast cancer survivors one year after diagnosis when the acute treatment effects should not longer be apparent. QOL was assessed in a population-based cohort of 387 women with breast cancer from Saarland (Germany) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLC30). Functional and symptom QOL-scores were compared with published reference data from the general population. Breast cancer survivors and women from the general population reported similar scores of global health/QOL. However, major deficits among women with breast cancer were found, for emotional, social, role and cognitive functioning. Age-specific comparisons between breast cancer patients and the reference population revealed that these deficits are predominantly found in younger age groups. The overall QOL of life of breast cancer survivors one year after diagnosis is comparable to women from the general population. However, some differences exist that seem to predominantly affect younger women who show a poorer QOL in certain domains.

Combining a name algorithm with a capture-recapture method to retrieve cases of Turkish descent from a German population-based cancer registry.

An increasing proportion of the 2 million Turkish residents in Germany is reaching the age in which cancer becomes a common health problem. However, data on cancer incidence and survival among Turkish residents are lacking due to incomplete reporting of nationality in German cancer registries. In the population-based cancer registry of the Saarland, retrieval by reported nationality yielded only 38% (95% confidence interval (CI): 31-45%) of the estimated number of Turkish cases in the registry; furthermore, nationality information was found to be inaccurate, and completeness dependent on the vital status of cases. A newly developed algorithm based on family names retrieved 85% (95% CI: 79-90%) of Turkish cases. Combining the two sources in a capture-recapture approach yielded 91% (95% CI: 86-94%) of the estimated total number of Turkish cases. Hence, the name-based algorithm provides a new and attractive tool for valid registry-based cancer research among Turks in Germany.

5-HT1A receptors are not involved in clozapine's lack of cataleptogenic potential.

Clozapine and 8-OH-DPAT antagonized haloperidol-induced catalepsy in rats (ED50 10 and 0.1 mg/kg s.c., respectively). Whereas the selective 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg s.c.) completely antagonized the inhibitory effect of 8-OH-DPAT, clozapine's effect was not affected. On the other hand, clozapine and 8-OH-DPAT inhibited ultrasonic vocalization in rats (ED50 0.7 and 0.03 mg/kg s.c., respectively), which effects were antagonized by WAY 100635. The lack of catalepsy of clozapine, therefore, cannot be addressed primarily to clozapine's agonistic activity at 5-HT1A receptors.

Macrophages as targets for inhibition by cyclosporine.

In order to understand the mechanism of immunosuppression by cyclosporine, its effects on macrophage-mediated antigen-specific T cell activation (IL-2 production) were studied in vitro. While cyclosporine (CsA) present during the macrophage-T cell coculture inhibited antigen presentation effectively, pretreatment (2 hr) of macrophages with the drug also caused marked inhibition regardless of the antigen concentration and order of drug/antigen addition. Pretreatment of T cells caused only modest inhibition. With macrophage pretreatment, the structural analog cyclosporine-G had the same inhibitory activity as cyclosporine (cyclosporine-A), whereas dihydro-cyclosporine-D and cyclosporine-H were inactive. Cyclosporine demonstrated saturable binding to macrophages suggesting the existence of CsA-binding sites. A 50% inhibition of IL-2 production was achieved with 10(-6) M CsA and 60-70% of the binding sites were occupied at this concentration. CsA-treated macrophages did not release inhibitory material and the drug did not appear to be transferred from the macrophages to the T cells during the coculture. Although antigen-specific T cells could bind to drug-treated macrophages, they did not produce IL-2. Collectively, these results suggest that CsA has a direct effect on macrophages that subsequently interferes with IL-2 production at a stage following T cell antigen recognition.

Enhanced immunogenicity of SIV Gag DNA vaccines encoding chimeric proteins containing a C-terminal segment of Listeriolysin O.

We investigated the potential of the C-terminal 59-amino acid segment of Listeriolysin O (LLO) in enhancing immune responses against the SIV Gag antigen in the context of DNA immunization. Genes with codons optimized for mammalian expression were synthesized for the SIVmac239 Gag, a secreted SIV Gag protein with the tissue plasminogen antigen (tPA) signal fused to its N-terminus (tPA/Gag), as well as their corresponding chimeric proteins Gag/LLO and tPA/Gag/LLO containing the C-terminal 59 amino acids of LLO. Analysis of immune responses to these DNA constructs in a Balb/c mouse model showed that the Gag/LLO construct induced higher levels of both CD4 and CD8 T cell responses against SIV Gag, whereas the tPA/Gag construct induced higher levels of CD4 T cell responses. Moreover, immunization with the tPA/Gag/LLO construct further enhanced both CD4 and CD8 T cell responses. DNA constructs encoding secreted Gag proteins (tPA/Gag and tPA/Gag/LLO) were also more effective in eliciting antibody responses against SIV Gag. Our results demonstrate that the C-terminal segment of LLO can be effectively employed to enhance both cellular and humoral immune responses in the context of a DNA vaccine.