Summary of major conclusions from the 4th IWGT, San Francisco, 9-10 September, 2005.
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Animals↗
Biomedical subjects
L Müller
Publications and source records attributed to L Müller.
The International Workshops on Genotoxicity Testing (IWGT): history and achievements.
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Animals↗
TCP34, a nuclear-encoded response regulator-like TPR protein of higher plant chloroplasts.
We describe the identification of a novel chloroplast protein, designated TCP34 (tetratricopeptide-containing chloroplast protein of 34 kDa) due to the presence of three tandemly arranged tetratricopeptide repeat (TPR) arrays. The presence of the genes encoding this protein only in the genomes of higher plants but not in photosynthetic cyanobacterial prokaryotes suggests that TCP34 evolved after the separation of the higher plant lineage. The in vitro translated precursor could be imported into intact spinach chloroplasts and the processed products showed stable association with thylakoid membranes. Using a specific polyclonal antiserum raised against TCP34, three protein variants were detected. Two forms, T(1) and T(2), were associated with the thylakoid membranes and one, S(1), was found released in the stroma. TCP34 protein was not present in etioplasts and appeared only in developing chloroplasts. The ratio of membrane-bound and soluble forms was maximal at the onset of photosynthesis. The high molecular mass thylakoid TCP34 variant was found in association with a transcriptionally active protein/DNA complex (TAC) from chloroplasts and recombinant TCP34 showed specific binding to Spinacia oleracea chloroplast DNA. Two TCP34 forms, T(1) and S(1), were found to be phosphorylated. An as yet unidentified phosphorelay signal may modulate its capability for plastid DNA binding through the phosphorylation state of the putative response regulator-like domain. Based on the structural properties and biochemical analyses, we discuss the putative regulatory function of TCP34 in plastid gene expression.
Amino Acid Sequence↗
Ultrasound assessment of detrusor thickness in children and young adults with myelomeningocele.
PURPOSE: We determine by ultrasonography the range of dT in carefully treated and followed children with myelomeningocele, and evaluate the role of such measurements for the understanding of bladder abnormalities in these patients. MATERIALS AND METHODS: We studied 66 children and young adults with MMC (34 males and 32 females, median age 8.1 years, range 1.1 to 20.1). Detrusor thickness was measured with a previously established ultrasonographic technique and the results were compared to those in normal children. The variation in detrusor thickness with degree of bladder dysfunction as well as with bladder wall trabeculation, kidney function and anticholinergic treatment was studied. RESULTS: The detrusor of the ventral wall was slightly thinner in children with MMC compared to normal. No significant variation in dT was found for different degrees of bladder dysfunction, bladder wall trabeculation, kidney function or anticholinergic treatment. Boys had thicker detrusor of the ventral wall than girls. CONCLUSIONS: Children with MMC, followed closely and treated according to international standards, do not acquire detrusor thickening as measured by ultrasonography. The detrusor thickness did not correlate with the degree of bladder dysfunction or renal function, or with anticholinergic treatment. Bladder wall trabeculation at VCU was not associated with bladder wall thickening on ultrasonography. We postulate that in a closely monitored and actively treated population of patients with MMC muscular hypertrophy and the development of connective tissue in the bladder wall is kept to a minimum.
Adolescent↗
Testing strategies in mutagenicity and genetic toxicology: an appraisal of the guidelines of the European Scientific Committee for Cosmetics and Non-Food Products for the evaluation of hair dyes.
The European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) guideline for testing of hair dyes for genotoxic/mutagenic/carcinogenic potential has been reviewed. The battery of six in vitro tests recommended therein differs substantially from the batteries of two or three in vitro tests recommended in other guidelines. Our evaluation of the chemical types used in hair dyes and comparison with other guidelines for testing a wide range of chemical substances, lead to the conclusion that potential genotoxic activity may effectively be determined by the application of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal changes. We conclude that highly effective screening for genotoxicity of hair dyes can be achieved by the use of three assays, namely the bacterial gene mutation assay, the mammalian cell gene mutation assay (mouse lymphoma tk assay preferred) and the in vitro micronucleus assay. These need to be combined with metabolic activation systems optimised for the individual chemical types. Recent published evidence [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggests that our recommended three tests will detect all known genotoxic carcinogens, and that increasing the number of in vitro assays further would merely reduce specificity (increase false positives). Of course there may be occasions when standard tests need to be modified to take account of special situations such as a specific pathway of biotransformation, but this should be considered as part of routine testing. It is clear that individual dyes and any other novel ingredients should be tested in this three-test battery. However, new products are formed on the scalp by reaction between the chemicals present in hair-dye formulations. Ideally, these should also be tested for genotoxicity, but at present such experiences are very limited. There is also the possibility that one component could mask the genotoxicity of another (e.g. by being more toxic), and so it is not practical at this time to recommend routine testing of complete hair-dye formulations as well. The most sensible approach would be to establish whether any reaction products within the hair-dye formulation penetrate the skin under normal conditions of use and test only those that penetrate at toxicologically relevant levels in the three-test in vitro battery. Recently published data [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggest the three-test battery will produce a significant number of false as well as real positives. Whilst we are aware of the desire to reduce animal experiments, determining the relevance of positive results in any of the three recommended in vitro assays will most likely have to be determined by use of in vivo assays. The bone marrow micronucleus test using routes of administration such as oral or intraperitoneal may be used where the objective is extended hazard identification. If negative results are obtained in this test, then a second in vivo test should be conducted. This could be an in vivo UDS in rat liver or a Comet assay in a relevant tissue. However, for hazard characterisation, tests using topical application with measurement of genotoxicity in the skin would be more appropriate. Such specific site-of-contact in vivo tests would minimise animal toxicity burden and invasiveness, and, especially for hair dyes, be more relevant to human routes of exposure, but there are not sufficient scientific data available to allow recommendations to be made. The generation of such data is encouraged.
Amines↗
Bevacizumab plus high-dose ifosfamide, etoposide and carboplatin (HD-ICE) as third-line salvage chemotherapy induced an unexpected dramatic response in highly platinum refractory germ-cell cancer.
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Antibodies, Monoclonal↗
Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986.
PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.
Adult↗
Herpes simplex virus type-1 amplicon vectors for vaccine generation in acute lymphoblastic leukemia.
For leukemia vaccine generation, high-efficiency gene transfer is required to express immunomodulatory molecules that stimulate potent antileukemic immune responses. In this context, herpes simplex virus type-1 (HSV-1)-derived vectors have proven to be a promising tool for genetic modification of lymphoblastic leukemia cells. Yet, vector-associated viral protein expression might inadvertently modulate vaccine efficacy facilitating both immune evasion and immune stimulation. To explore the issue of immune-stimulation versus immune-suppression in immature lymphoblastic leukemia cells, two types of HSV-1 amplicon vectors, helper virus-dependent and helper virus-free that express the immunomodulatory molecules CD70 and IL-2, were compared with regard to their vector-associated immunomodulatory potential. We first established that lymphoblastic cell lines and primary acute lymphoblastic leukemia (ALL) cells express HSV receptor genes. Lymphoblastic cell lines were transduced with high efficiency, and in primary ALL cells high gene transfer rates of 47+/-15 and 42+/-14% were obtained with helper virus-dependent and -free HSV-1 amplicon vectors, respectively. The efficacy of the two amplicon vectors to induce antineoplastic responses was assessed in a vaccine setting in mice with pre-existing highly malignant lymphoblastic disease. Treatment of mice with vaccine cells transgenically expressing CD70+IL2 significantly suppressed lymphoblastic cell proliferation and improved survival. Of note, when helper virus-dependent HSV-1 amplicon vectors were used for vaccine preparation, the high immunogenic potential of the vector itself, in the absence of transgenic CD70+IL2 expression, seemed to be sufficient to mediate protection comparable to the antineoplastic response achieved by expression of immunomodulatory molecules. Thus for vaccine generation in B lymphoblastic leukemia, the immunogenic potential of HSV-1 helper virus-dependent amplicon vectors does provide additional benefit to the high transduction efficiency of HSV-1-derived vectors.
Animals↗
A patient with insidious onset of exertional dyspnoea.
The case history is presented of a 42 year old woman with pulmonary artery occlusion due to tuberculous vasculitis that masqueraded as chronic pulmonary artery embolism and led to severe life threatening haemoptysis necessitating emergency pneumonectomy. It is concluded that obliterative tuberculous endarteritis of the pulmonary arteries should be considered in the differential diagnosis of any acquired obstruction of pulmonary arteries.
Adult↗
Hsp70 and Hsp90--a relay team for protein folding.
Molecular chaperones are a functionally defined set of proteins which assist the structure formation of proteins in vivo. Without certain protective mechanisms, such as binding nascent polypeptide chains by molecular chaperones, cellular protein concentrations would lead to misfolding and aggregation. In the mammalian system, the molecular chaperones Hsp70 and Hsp90 are involved in the folding and maturation of key regulatory proteins, like steroid hormone receptors, transcription factors, and kinases, some of which are involved in cancer progression. Hsp70 and Hsp90 form a multichaperone complex, in which both are connected by a third protein called Hop. The connection of and the interplay between the two chaperone machineries is of crucial importance for cell viability. This review provides a detailed view of the Hsp70 and Hsp90 machineries, their cofactors and their mode of regulation. It summarizes the current knowledge in the field, including the ATP-dependent regulation of the Hsp70/Hsp90 multichaperone cycle and elucidates the complex interplay and their synergistic interaction.
Adenosine Triphosphate↗
Acute respiratory diseases/influenza sentinel 2000/2001.
A sentinel surveillance system of the public health service for acute respiratory diseases (ARD), especially influenza, has been realized in the Free State of Saxony of Germany for 25 years. The epidemiological sentinel is based on weekly registration of morbidity and mathematical-statistical calculations. For a microbiological sentinel, a fast diagnosis by nucleic acid amplification techniques and improvements of sample management in connection with the rapid transmission of results have been introduced. In the present report, the ARD/influenza sentinel is demonstrated for the season 2000/2001. The sentinel system provides scientific and practical information for a prophylactic and therapeutic control program. Economic significance has been proved by verifiable numerical data derived from several epidemiological and microbiological investigations. The realized system has been considered superior to the influenza surveillance scheme of the Arbeitsgemeinschaft Influenza (AGI, Marburg, Germany) for all Germany and another system of a pharmaceutical company which is under construction.
Acute Disease↗
Use of the photo-micronucleus assay in Chinese hamster V79 cells to study photochemical genotoxicity.
Photochemical genotoxicity can be detected using appropriately adapted versions of most of the standard in vitro genotoxicity assays. The most sensitive approach to detect potentially photogenotoxic agents seems to be the investigation of DNA damage (DNA strand breakage, chromosomal aberrations, micronuclei) in mammalian cells in vitro. In a previous paper, we proposed the use of the micronucleus assay in Chinese hamster V79 cells for this purpose. This assay was found suitable to detect various photogenotoxic compounds with different photoactivation mechanisms. In order to extend the experimental experiences with this assay, we present here further data from a screening mode testing of 16 different potential photosensitizers. The photoclastogenic and photocytotoxic potential of the compounds was investigated concomitantly. So far, all substances detected in the photo-micronucleus assay as photogenotoxins also exhibited photocytotoxic properties but not vice versa. Among the compounds tested in the present study, tiaprofenic acid, 5-MOP, angelicin, nitrazepam, bendroflumethiazide, and dacarbazine were photogenotoxic and photocytotoxic. Further, 6-mercaptopurine, a metabolite of azathioprine was positive for both endpoints, whereas azathioprine was found negative. Azathioprine seems to be an example of a compound which lacks photo(geno)toxic properties in vitro but may be converted to a photosensitizer by enzymatical metabolization. With the results obtained in this study, the data base for the photo-micronucleus assay was extended to 35 compounds, which were tested using the same protocol and the same irradiation conditions. The photogenotoxicity results of all these compounds are summarized and discussed in correlation to their different photoactivation mechanisms, photocytotoxicity and photocarcinogenicity.
Animals↗
Biological monitoring of metals and organic substances in hazardous-waste incineration workers.
OBJECTIVES: To determine blood and urine concentrations of a number of metals and organic substances in workers at a hazardous-waste incinerator (HWI) 1 year after regular operations in the facility, and to compare these concentrations with the baseline levels. METHODS: The employees were divided into three groups according to their workplaces. Plasma analyses of hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs 28, 52, 101, 138, 153 and 180) and polychlorinated dibenzo- p-dioxins and dibenzofurans (PCDD/Fs), and urinary analyses of 2,4- and 2,5-dichlorophenol (DCP), 2,4,5- and 2,4,6-trichlorophenol (TCP), pentachlorophenol (PCP) and 1-hydroxypyrene (1-HP) were carried out. The blood concentrations of beryllium, manganese, mercury and lead, and the urine levels of cadmium, chromium, nickel and vanadium were also determined. RESULTS: The current plasma HCB, PCB and PCDD/F levels, and the urine levels of chlorophenols (CLPs) and 1-HP did not show significant differences between workplace groups or the baseline concentrations. Moreover, no significant differences between metal levels could be observed. DISCUSSION AND CONCLUSION: The lack of differences between the current levels of metals and organic substances and the respective baseline concentrations, together with the absence of differences depending on the workplace indicate that the potential exposure of HWI workers to the analyzed compounds was insignificant. According to these results, 1 year of potential exposure to the above metals and organic substances would not mean any specific health problem for the workers at the HWI.
Adult↗
PCDD/Fs and PCBs in airborne particulate matter of the greater Thessaloniki area, N. Greece.
Particle-bound polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) were monitored at two sites in northern Greece for an eight-month period in 1999. PCDD/F concentrations were close to the lower end of reported values worldwide. Excepting a few cases, the PCDD/Fs homologue profile was stable. The gaseous PCDD/F fractions calculated were found to account for a small percentage of the total concentrations (<2% for OCDD/Fs and HpCDD/Fs, while 30-35% for TCDFs). Particle-bound PCBs were also found at low concentrations which, however, were higher at the urban site. Calculations of the dry deposition of particulate PCDD/ Fs and PCBs gave mean values of 0.52 and 0.59 pg I-TEQ/m2/day of PCDD/Fs, while 242 and 74 pg/m2/day of sigmaPCBs for the urban and the semirural areas respectively. An anticorrelation of PCDD/F concentrations with ambient temperature was derived particularly for the lower chlorinated congeners. A weak association with winds of western and southern origin was also observed. Factor analysis and literature source profiles were employed to identify possible emission sources. It was appeared that the PCDD/F compositional pattern of TSP is influenced by mixed sources the most prominent being uncontrolled fires and car exhausts.
Air Movements↗
PCDD/F levels in the neighbourhood of a municipal solid waste incinerator after introduction of technical improvements in the facility.
In 1998 and 1999, the concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were determined in soil and herbage samples collected in the vicinity of an old municipal solid waste incinerator (MSWI) (S. Adrià del Besòs, Barcelona, Spain). Just after the 1999 collection, an adaptation to the EU legislation on pollutant emissions from the stack was carried out in this facility. The purpose of the present study was to determine the current concentrations of PCDD/Fs in soil and herbage samples collected in the neighbourhood of the MSWI and to compare these concentrations with those obtained in the 1998 and 1999 surveys. During the period 1998-1999, an increase of 31% (P>.05) was found in the median PCDD/F levels in soils, while a reduction of 40% (P>.05) was observed in the period 1999-2000. Similarly, in the period 1998-1999 an increase of 41% (P>.05) was found in the levels of PCDD/Fs in vegetation, while a 30% decrease (P<.05) was seen in the period 1999-2000. Although after introduction of the technical improvements in the MSWI a notable reduction in the levels of PCDD/Fs in soil and vegetation has been noted, the median decreases have not been as great as it could be expected according to the very pronounced reductions in PCDD/F emissions from the stack. It indicates that other emission sources of PCDD/Fs also have a notable impact on the area under direct influence of the MSWI.
Benzofurans↗
Open Facilities for Training in European Neurology (OFTEN): a European Board of Neurology initiative.
The European Board of Neurology has established Open Facilities for Training in European Neurology (OFTEN) by creating a databank of excellent or good neurological departments from 14 European countries willing to receive trainees from abroad (http://www.uems.be/neuro.htm). Further expansion of this databank with an increased number of participating departments and countries is planned. The databank should make it easier both to find a relevant department for training abroad and to obtain funding from various sources. No financial support is available in the program itself. The ultimate aim of this cross-European training is to improve neurological skill, knowledge and attitude. It will also promote European co-operation and harmonization in quality of care.
Databases, Factual↗
[Formation of portal venous collaterals after ligation of the portal vein for induction of liver regeneration].
PURPOSE: Unilateral occlusion of the portal vein induces contralateral lobar hypertrophy - in contrast to complete portal vein occlusion which will result in a cavernous transformation. The impact of the formation of collaterals in partial portal vein occlusion is not sufficiently known. The lobar-hypertrophy- phenomenon is in clinical use for several years to induce iatrogenic liver growth to enable extended resections. After portal vein ligation in patients prior to extended hepatic resections, we noticed a perfusion of the formerly occluded side on CT. Using the well-established mini pig model, we were interested whether portal collaterals are formed as cause of the reperfusion. Ex-situ angiograms of the liver were used for the depiction of collaterals. MATERIALS AND METHODS: Using a median laparotomy as access for preparation of the hepatoduodenal ligament, a proximal left portal vein ligation was performed in eight mini pigs under general anesthesia. The total arrest of the portal blood flow (except in segments VI and VII) was documented by duplex ultrasound. After 4 weeks, all pigs were sacrificed and the weight of the ligated liver segments and non-ligated liver segments was measured and compared to a sham group (n = 5). After insertion of a guiding sheath, an ex-situ DSA of the portal vein was acquired. RESULTS: Compared with the sham group, the liver weight increased by 60 % (23 - 99 %, std. dev. 30 %) in segments VI and VII. Atrophy of the ligated segments was signified by a weight loss of 10 % (standard deviation 15 %). The ex-situ angiograms revealed a uniform pattern of collaterals with subsequent complete total recanalization of the formerly occluded portal vein distal from the ligation. The collaterals reduced the portal venous flow rate. CONCLUSION: After portal vein ligation, uniform collateralization results in recanalization of the occluded portal vein. The extent of the collaterals exceeds the known cavernous transformation. The increase in liver volume is not restrained by the formation of collaterals.
Aged↗