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Individuals can exhibit differences in metabolism caused by the interplay of genetic background, nutritional input, microbiota, and other environmental factors(1–4). It is difficult to connect differences in metabolism to genomic variation and derive underlying molecular mechanisms in humans due to differences in diet and lifestyle, among others. Here, we introduce the nematode Caenorhabditis elegans as a model to study inter-individual variation in metabolism. By comparing three wild strains and the commonly used N2 laboratory strain, we find differences in the abundances of both known and previously undescribed metabolites. Novel metabolites include conjugates between 3-hydroxypropionate (3HP) and several amino acids (3HP-AAs) that are much higher in abundance in one of the wild strains. 3HP is an intermediate in the propionate shunt pathway, which is activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed(5). We demonstrate that increased 3HP-AA accumulation is caused by genetic variation in HPHD-1, for which 3HP is a substrate. Our results suggest that 3HP-AA production represents a ‘shunt-within-a-shunt’ pathway to accommodate a reduction-of-function allele in hphd-1. This study provides a first step to developing metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity found in entire species.

SUMMARYIn humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Deletion of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the upregulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG, or by supplementing either vitamin B12 or the ketone body 3-hydroxybutyrate (3HB). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low, and in which a loss of dhgd-1 causes lethality by limiting ketone body production.HIGHLIGHTS-D-2-hydroxyglutarate is produced by HPHD-1 in the propionate shunt pathway-DHGD-1 recycles 2-hydroxyglutarate to sustain flux through the propionate shunt-dhgd-1 loss perturbs ketone body metabolism and causes embryonic lethality-3-Hydroxybutyrate, vitamin B12 or hphd-1 RNAi rescue dhgd-1 mutant lethality

Metabolic reactions form the basis of life to generate biomass, produce energy, and eliminate waste. Together, metabolic reactions function in the context of a highly interconnected metabolic network. Flux through this network needs to be adaptable depending on nutrient availability or metabolite buildup. Metabolic flux can be changed by different regulatory mechanisms, including the allosteric regulation of metabolic enzyme activity by small molecules and by changes in metabolic gene expression. For the transcriptional control of metabolic genes to happen accurately, the metabolic status of the system needs to be relayed to the regulators of gene expression, such as transcription factors. Allosteric regulation of metabolic enzymes can only be studied for individual proteins, whereas the transcriptional control of metabolism can increasingly be examined at a systems, or network level. Here, we discuss recent studies regarding the interplay between metabolic and gene regulatory networks using the nematode Caenorhabditis elegans. We discuss why C. elegans provides an elegant model system for studying the transcriptional regulation of metabolism and describe recent insights into its gene regulatory and metabolic networks. We then describe a recently discovered mechanism by which the buildup of a cellular metabolite can transcriptionally rewire metabolism. Finally, we discuss the future challenge of integrating large transcriptomic, proteomic, and metabolomic data sets to fully understand the transcriptional regulation of metabolic flux.

In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology and the response to therapeutic drugs. On March 15, 2020, a stay-at-home order was put into effect in the state of Massachusetts, USA, to flatten the curve of the spread of the novel SARS-CoV2 virus that causes COVID-19. For biomedical researchers in our state, this meant putting a hold on experiments for nine weeks until May 18, 2020. To keep the lab engaged and productive, and to enhance communication and collaboration, we embarked on an in-lab project that we all found important but that we never had the time for: the detailed annotation and drawing of C. elegans metabolic pathways. As a result, we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 66 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on our WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the unfortunate event of additional lockdowns, we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices.

In our group, we aim to understand metabolism in the nematode

Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. InCaenorhabditis elegans,low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requiresnhr-10and is referred to as ‘B12-mechanism-I’. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as ‘B12-mechanism-II’. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due to low dietary vitamin B12. B12-mechanism-II requiresnhr-114to activate Met/SAM cycle gene expression, the vitamin B12 transporter,pmp-5, and adjust influx and efflux of the cycle by activatingmsra-1and repressingcbs-1, respectively. Taken together, Met/SAM cycle activity is sensed and transcriptionally adjusted to be in a tight metabolic regime.

Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. In Caenorhabditis elegans, low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requires nhr-10 and is referred to as “B12-mechanism-I”. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as “B12-mechanism-II”. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due to low dietary vitamin B12. B12-mechanism-II requires nhr-114 to activate Met/SAM cycle gene expression, the vitamin B12 transporter, pmp-5, and adjust influx and efflux of the cycle by activating msra-1 and repressing cbs-1, respectively. Taken together, Met/SAM cycle activity is sensed and transcriptionally adjusted to be in a tight metabolic regime.

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level “suggestive of progressive supranuclear palsy” for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background: The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. Methods: We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. Results: Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. Conclusions: The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society. © 2019 International Parkinson and Movement Disorder Society

SUMMARY Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a “persistence detector” in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis., Graphical Abstract, In Brief Bulcha et al. discover a transcriptional persistence detector composed of a type 1 coherent feed-forward loop with an AND-logic gate that rewires propionate metabolism in C. elegans.

SUMMARY Vitamin B12 functions as a cofactor for methionine synthase to produce the anabolic methyl donor S-adenosylmethionine (SAM) and for methylmalonyl-CoA mutase to catabolize the short-chain fatty acid propionate. In the nematode Caenorhabditis elegans, maternally supplied vitamin B12 is required for the development of offspring. However, the mechanism for exporting vitamin B12 from the mother to the offspring is not yet known. Here, we use RNAi of more than 200 transporters with a vitamin B12-sensor transgene to identify the ABC transporter MRP-5 as a candidate vitamin B12 exporter. We show that the injection of vitamin B12 into the gonad of mrp-5 deficient mothers rescues embryonic lethality in the offspring. Altogether, our findings identify a maternal mechanism for the transit of an essential vitamin to support the development of the next generation., In Brief How dietary vitamin B12 is transported from the mother to developing offspring is unknown. Na et al. demonstrate that the ABC transporter MRP-5 (multidrug resistance protein 5) transports vitamin B12 from the intestine of C. elegans mothers to the offspring to promote embryonic viability and development

Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society

Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society

A wealth of physical interaction data between transcription factors (TFs) and DNA has been generated, but these interactions often do not have apparent regulatory consequences. Thus, equating physical interaction data with gene regulatory networks (GRNs) is problematic. Here, we comprehensively assay TF activity, rather than binding, to construct a network of gene regulatory interactions in the C. elegans intestine. By manually observing the in vivo tissue-specific knockdown of 921 TFs on a panel of 19 fluorescent transcriptional reporters, we identified a GRN of 411 interactions between 19 promoters and 177 TFs. This GRN shows only modest overlap with physical interactions, indicating that many regulatory interactions are indirect. We applied nested effects modeling to uncover information flow between TFs in the intestine that converges on a small set of physical TF-promoter interactions. We found numerous cell nonautonomous regulatory interactions, illustrating tissue-to-tissue communication. Altogether, our study illuminates the complexity of gene regulation in the context of a living animal.

Maintenance of consciousness importantly depends on systemic arterial blood pressure (BP) remaining above the lower pressure limit for cerebrovascular au- toregulation. This study evaluated the impact of age and baseline arterial blood pressure (BP) on the BP recorded at onset of syncope in otherwise healthy individu- als undergoing passive head-up tilt (HUT) testing for suspected vasovagal syncope. Since hypertension is thought to shift the lower autoregulation point to higher val- ues, and since older healthy patients tend to have higher BP than younger individu- als, we hypothesized that even among healthy individuals HUT-induced syncope would occur at higher BP in older compared with younger subjects. Three groups of otherwise healthy individuals who had positive HUT were identified: Group 1: !25 years, n ¼ 17; Group 2: 25e59 years, n ¼ 18; and Group 3: R60 years, n ¼ 7. As ex- pected, baseline arterial systolic blood pressure of patients R60 years (162G37 mmHg) was significantly higher than in the other two groups (Group 1: !25 years, 116G15 mmHg; Group 2: 25e59 years, 128G12 mmHg). Further, the R60 age group tolerated upright posture for a longer period before syncope than did younger patients. However, despite a trend for BP at syncope to increase with age, differences were small (Group 3: R60 years, 61G15 mmHg, Group 2: 25e59 years, 58G6 mmHg, and Group 1: 54G16 mmHg) and were not statistically

Maintenance of consciousness importantly depends on systemic arterial blood pressure (BP) remaining above the lower pressure limit for cerebrovascular autoregulation. This study evaluated the impact of age and baseline arterial blood pressure (BP) on the BP recorded at onset of syncope in otherwise healthy individuals undergoing passive head-up tilt (HUT) testing for suspected vasovagal syncope. Since hypertension is thought to shift the lower autoregulation point to higher values, and since older healthy patients tend to have higher BP than younger individuals, we hypothesized that even among healthy individuals HUT-induced syncope would occur at higher BP in older compared with younger subjects. Three groups of otherwise healthy individuals who had positive HUT were identified: Group 1:25 years, n=17; Group 2: 25-59 years, n=18; and Group 3:or =60 years, n=7. As expected, baseline arterial systolic blood pressure of patientsor =60 years (162+/-37 mmHg) was significantly higher than in the other two groups (Group 1:25 years, 116+/-15 mmHg; Group 2: 25-59 years, 128+/-12 mmHg). Further, theor =60 age group tolerated upright posture for a longer period before syncope than did younger patients. However, despite a trend for BP at syncope to increase with age, differences were small (Group 3:or =60 years, 61+/-15 mmHg, Group 2: 25-59 years, 58+/-6 mmHg, and Group 1: 54+/-16 mmHg) and were not statistically significant. Thus, in generally healthy individuals, age and baseline BP has only a minor effect on the lower limit of BP necessary for maintenance of consciousness. On the other hand, higher baseline BP provides older individuals a greater blood pressure 'reserve' for maintenance of consciousness compared with younger subjects.

To help clarify the possible usefulness of nuclear DNA content and S-phase fraction (SPF) as additional prognostic factors in node-positive breast cancer patients because there is increased interest in the development of new factors that might provide more detailed prognostic information.We performed a DNA and SPF analysis by flow cytometry using a multivariate statistical model on a group of 139 node-positive breast cancer patients with clearly defined inclusion and exclusion criteria.The percentage of aneuploidy increased with the number of involved nodes. Aneuploid tumors were more often found among grade 3 and among receptor-negative tumors. Univariate analysis showed a strong effect on recurrence-free survival (RFS) for the number of involved nodes (P.001) and for tumor size (P = .013). Grade 3 and receptor-negative tumors showed a nonsignificant trend toward increased risk. The relative risk of aneuploid tumors was 1.19 (95% confidence interval, 0.75-1.87). Multivariate analysis revealed only the number of involved nodes to be an independent prognostic factor (P = .002); ploidy showed no effect (P = .684). SPF did not show any significant effect on RFS, even in a univariate analysis.These results suggest that nuclear DNA content and SPF correlate with morphologic factors. Their routine clinical use, however, in node-positive breast cancer patients receiving adjuvant therapy seems to have no clinical relevance and therefore can be omitted.

Die vorzeitige Plazentalosung gehort zu den akuten Ereignissen in der Geburts hilfe. Sie ist definiert als partielle oder vollstandige Losung der regelrecht lokalisierten Plazenta vor der Geburt des Kindes. Dies fuhrt abhangig von der Grose der gelosten Plazentahaftflache zur akuten intrauterinen Asphyxie des Feten bis hin zum intrauterinen Fruchttod. Die klassischen Symptome wie Blutung und schmerzhafter Uterustonus treten stets akut auf, wahrend Hinweiszeichen, die sich aus dem Verlauf der Schwangerschaft ableiten lassen, fehlen. Assoziationen zur Gestose/Praeklampsie und zum vorzeitigen Blasensprung sind bekannt; im Einzelfall last sich das Risiko allerdings nicht vorhersagen [1, 3, 6, 9, 10, 20]. Neben der akuten Gefahrdung des Kindes ist stets auch eine Gefahrdung der Mutter gegeben. Durch das sich bildende retroplazentare Hamatom kann es zur Aktivierung des mutterlichen Gerinnungssystems kommen, so das sich eine disseminierte intravasale Koagulopathie (DIC) entwickelt [5, 14, 22]. Dies kann einerseits uber eine Verbrauchskoagulopathie zu unstillbaren Blutungen, andererseits zu Organnekrosen, z.B. zum Nierenversagen, fuhren.

A group of 241 nonpretreated breast carcinomas was studied for estrogen receptor (ER) and progesterone receptor (PR) content by both immunocytochemistry (ICC) and biochemical analysis (dextran-coated charcoal [DCC]). While the tumors were judged to be ER positive in 67.6% and PR positive in 65.6% by ICC, DCC analysis showed positive results in 77.6% for both ER and PR. There was only a moderate correlation between the semiquantitative results of ER and PR ICC and the corresponding values for DCC receptor determination. Among tumors shown to be steroid receptor positive by ICC, a majority showed a wide spectrum of staining intensity, from negative to intensely positive (type C staining pattern, ER 87.7%, PR 73.4%). Less frequently, carcinomas showing uniform, intense staining of all epithelial tumor cells were observed (type A staining pattern, ER 11.7%, PR 18.4%). Finally, only very few tumors had both clearly negative and distinctly positive cells (type B staining pattern, ER 0.6%, PR 8.2%). On analyzing the relationship between the expression of steroid receptors (ICC and DCC) and the prognostic factors axillary node status, tumor size, tumor histology, grade and patient age, only a significant correlation between patient age and ER (ICC, r = .46; DCC, r = .43), a weakly significant negative correlation between node involvement and ER, and a weakly significant negative correlation between tumor grade and ER (ICC only) as well as between tumor grade and PR were found. Among all patients, the recurrence-free interval was significantly longer in patients with ER- or PR-positive carcinomas (ICC and DCC).(ABSTRACT TRUNCATED AT 250 WORDS)

Anhedonic subjects, potentially at risk for psychopathology because of a deficient ability to experience pleasure, have demonstrated a large N200 component in the event-related brain potential (ERP). The present experiment attempted to determine the psychological significance of this finding in light of Naatanen's (1990) distinction between N2a and N2b subcomponents. Anhedonics were contrasted with controls and dysthymics, an at-risk group reporting depression. Across groups, N2a was larger when a tone mismatched a longer run of preceding identical tones. Thus, an involuntary mismatch process appears to be intact in both at-risk groups. However, the three groups produced distinct N2bs as a function of stimulus sequence. The N2b finding for anhedonics is consistent with Knight's (1984, 1992) model of early stimulus processing deficits in schizophrenia.

Die kontrollierten Studien der Gynecologic Oncology Group (GOG) haben gezeigt, das die Ausbreitung des Endometriumkarzinoms durch die praoperative Stadienein- tieilung nicht ausreichend erfasst wird (1). Zu den entscheidenden Prognosefaktoren des Endometriumkarzinoms zahlen neben dem histologischen Typ und Differenzie- rungsgradvor allem die Infiltrationstiefe ins Myometrium und die Ausbreitung auserhalb des Uterus. Das operative Vorgehen hat sich deshalb in den letzten Jahren trotz des zum Teil recht hohen Alters der Patientinnen allgemein durchgesetzt, so das seit 1988 auf Empfehlung der FIGO die Stadieneinteilung nicht mehr klinisch (praoperativ) sondern chirurgisch (pathologisch) erfolgen soll. Die Unterteilung im Stadium I richtet sich nicht mehr nach der Sondenlange bei der Abrasio sondern nach der Infiltrationstiefe ins Myometrium. Der wesentliche Unterschied ergibt sich im Stadium III, da jetzt alle primar okkulten Lymphknoten extrauterinen Ausbreitungen im kleinen Becken, den retroperitonealen Lymphknoten und in der Peritonealzytologie zum Stadium III gezahlt werden. Die Bestimmung der exakten Ausbreitung wird mit der Forderung nach einer ausgedehnteren Operation verknupft und fand nicht allgemeine Zustimmung (2). Die vorliegende Untersuchung soll die Unterschiede zwischen klinischem und postoperativem Stadium am Kollektiv einer Klinik dargestellt und die Schwierigkeiten aufzeigen, die sich bei einem Vergleich der Therapieergebnisse zwischen alter und neuer Klassifikation ergeben.

Das Auftreten eines Rezidivs verschlechtert die Prognose einer Patientin mit dem allgemein eher als gunstig eingeschatzten Endometriumkarzinom erheblich. Das Rezidiv kann entweder aufgrund unzureichender Therapie oder aufgrund besonderer Aggressivitat des Karzinom bei vermeintlich adaquater Therapie entstehen (1). In einer retrospektiven Analyse soll gezeigt werden, welche Parameter des Primatumors die Rezidivhaufigkeit beeinflussen und so den Grad der Malignitat widerspiegeln. Weiterhin soll der Einflus der adjuvanten Strahlentherapie auf die Rezidivhaufigkeit und die Lokalisation analysiert werden.

Mehr als 90% aller malignen Tumoren beim Menschen sind Karzinome, bei denen transformierte Zellen epithelialen Ursprungs unkontrolliert wachsen, die Basalmembran durchbrechen und ins Mesenchym eindringen. Von Bedeutung fur die molekularen Mechanismen dieser Vorgange ist das Zeil-Zeil-Adhasionsmolekul ARC-1/Uvomorulin. Es ist ein guter Indikator fur die Differenzierung und Invasi-vitat menschlicher Karzinomzellen in vitro.

In der UFK Freiburg wurden von 1973–1989 1404 Patientinnen wegen eines Mammakarzinoms behandelt. Die 5-J-ULZ aller Patientinnen lag bei 67%, die 10-J-ULZ bei 41,6%. Die mediane Beobachtungsdauer betragt derzeit 76 Monate.

Die unvollstandige oder vollstandige Losung der Plazenta von der Uteruswand vor der Geburt des Kindes kann sich nicht nur fur das Kind intrauterin, sondern auch fur die Mutter zu einem vital bedrohlichen Krankheitsbild entwickeln. Als mogliche Ursachen dieser Erkrankung, die uber die Bildung eines retroplazen-taren Hamatoms zur Gerinnungsstorung der Mutter fuhren kann, gelten die Gestose und Veranderungen an den Arteriolen des Endometriums. Doch sind hier noch viele Fragen offen. Die Diagnostik stutzte sich fruher allein auf die klinische Symptomatik: den schmerzhaften Uterus, die Blutung und die Veranderung der kindlichen Herztone. Darauf basierte die Einteilung dieses Krankheitsbildes in vier Schweregrade nach Page et al. 1954. Die Sonographie hat hier die diagnostischen Moglichkeiten entscheidend verbessert. Auch die Therapie hat sich in den vergangenen Jahren gewandelt: einerseits konnte die Perinatologie die Prognose der Fruhgeburten entscheidend verbessern, andererseits haben der Einsatz von Prostaglandinen und die gezielte Substitution von Gerinnungsfaktoren die moglichen mutterlichen Komplikationen reduziert. Um diese Vermutung zu uberprufen, wurden die an der UFK Freiburg in den Jahren 1968–1987 beobachteten Falle einer vorzeitigen Plazentalosung retrospektiv analysiert und die zwei Dezennien einander gegenubergestellt.

The edge plasma density versus plasma radius function of the MT-1 Tokamak plasma is measured by a new laser blow-off method. A thin film of sodium evaporated on a glass substrate is brown off by a Q-switched ruby laser pulse. The enhanced shortening of the pulse of neutrals was observed along the beam propagation toward the plasma center by measuring the resonance light intensity of atoms excited by the plasma electrons. The density of the plasma is calculated from the measured exponential time decay of the blow-off-light pulse without any further calibrating measurements.

Bile sequestrant resins are used to lower the levels of low-density lipoprotein cholesterol in plasma because this may ameliorate atherosclerosis. Yet the levels and compositions of all the lipoproteins may affect atherogenesis. We have previously shown alterations in very-low-density lipoprotein (VLDL) metabolism in response to one of these agents, colestipol HCl. Here we report the effects of colestipol on the composition of low-density and high-density lipoproteins (HDL). Eighteen subjects with type II hyperlipoproteinemia were studied during baseline, diet, and drug periods lasting 2–3 mo. Lipoprotein lipids and apolipoproteins A-I, A-II, and B were measured, and indices of lipoprotein composition were calculated. Colestipol produced significant changes in all lipoproteins. VLDL-triglyceride rose transiently, the magnitude and duration both correlated with pretreatment values (r = 0.84 and 0.76, respectively, both p < 0.001). Low-density (density 1.006–1.063) lipoprotein cholesterol fell below the dietary mean by 28%, but low-density triglyceride fell by only 13% and apolipoprotein B by 17%. Thus, low-density lipoprotein cholesterol/apolipoprotein B ratios decreased (1.9 versus 1.6, p < 0.005). Low-density and very-low-density cholesterol/apoprotein B ratios also decreased significantly. Thus, all the apolipoprotein-B-containing lipoproteins had less cholesterol relative to apolipoprotein B. High-density lipoprotein cholesterol remained unchanged, although transient increases in high-density lipoprotein triglyceride occurred. Apolipoprotein A-I levels remained constant (∼105 mg/dl), but A-II levels fell (from 55 to 45 mg/dl); therefore, A-IA-II ratios rose (2.0 versus 2.5, p < 0.001). Thus, alterations in the composition of both high-density and low-density lipoproteins occurred. Colestipol produced changes in lipoprotein composition that may have effects on atherogenesis independent of its effects on lowering plasma cholesterol. Further studies will be needed to determine whether or not these changes are beneficial.

SummaryA wealth of physical interaction data between transcription factors (TFs) and DNA has been generated, but these interactions often do not have apparent regulatory consequences. Therefore, equating physical interaction data with gene regulatory networks (GRNs) is problematic. Here, we comprehensively assay TF activity, rather than binding, to construct a network of gene regulatory interactions in the C. elegans intestine. By manually observing the in vivo tissue-specific knockdown of 921 TFs on a panel of fluorescent transcriptional reporters, we identified a GRN of 411 interactions between 19 promoters and 177 TFs. This GRN shows only a modest overlap with physical interactions, indicating that many regulatory interactions are indirect. We applied nested effects modeling to uncover the information flow between TFs in the intestine that converges on a small set of physical TF-promoter interactions. We found numerous cell non-autonomous regulatory interactions, illustrating tissue-to-tissue communication. Our study illuminates the complexity of gene regulation in the context of a living animal.

Pressure induced changes in optical pathlength are being utilized to realize a hydro -phone consisting of glass fibers in a Mach - Zehnder interferometric arrangement. In our expe-rimental setup we use single -mode fiber optical power dividers and a simple control systemthat maintains the polarization of both light signals so that interference with constantcontrast is obtained after superposition. We use a modified phase- tracking detection systemto maintain maximum interferometer sensitivity and show a design for a sensor -body withhigh acoustical sensitivity.IntroductionOptical fiber sensors1 are being worked on in research and development since the pastfew years now because they offer a number of advantages over existing techniques. The mainfeatures are an increased sensitivity, light weight, more freedom in geometric shape design,insensitivity against electromagnetic field disturbances including a perfect electric insu-lation of the point of measurement and applications in high temperature or aggressive envi-ronments. Besides there is the possibility to use optical signal and data processing meth

Tumorpatientinnen werden in der Regel mehrfach stationar und ambulant behandelt. Die Arztbriefe enthalten daher zu einem grosen Teil wiederkehrende Informationen. Durch den EDV-Einsatz erhofften wir uns eine effektivere Arbeitsbewaltigung in den Bereichen Arztbriefschreibung und Dokumentation.

A particular problem, of those arising in the economic development of estuary regions, concerns the maintenance and enlargement of navigation channels. The sediment transport plays an important role in connection with this problem. .Though the hydrodynamical processes are today, with the help of mathematical procedures, fairly exactly grasped, there is still insufficient knowledge about the related transport processes, the formation of ripples and dunes and of longterm periodical morphological changes. Nevertheless, the engineer wants information about sediment transport for his planning. A well-known aid is the movable bed hydraulic model, which has been technically developed to simulate the natural fluid-sediment interaction. Such models are not yet standard in hydraulic research institutes and. furthermore, they are not easy to handle. This is probably due to a lack of suitable similarity criteria for insuring valid experimental results. However, there exist recently developed somewhat compromised similarity relationships, which can be used for distorted movable bed tidal models. The experience gained with the movable bed. model Elbe I at the Bundesanstalt fur Wasserbau (BAW) in Hamburg provides an incentive for investigating special cases in other large tidal models of the German North-Sea coast. These models are presented in Fig. 1.

One of the characteristics of the North Sea between the British Isles, the Netherlands, Germany and Denmark is the occurrence of heave storm surges especially in autumn and winter with heights of about 4 m above spring highwater. Coastal areas and especially the estuaries of the tidal rivers are hit by these storm surge events. The mean tidal range at the German coast comes to about 3 m with relatively low daily and semimonthly inequalities of less than 0.5m. Within the framework of long-term developments of the navigation channels of the estuaries as well as of the storm surge protection works, physical model tests had to be carried out in order to predict the influences of such measures on the storm surge heights to be expected.

In der Universitats-Frauenklinik Freiburg wurden zwischen 1974 und 1986 703 Patientinnen wegen eines Mammakarzinoms primar behandelt.