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Summary We present a seismic history matching workflow where 4D seismic data is assimilated in the pressure and saturation domain, using the results of a previously computed Bayesian 4D seismic inversion. The inversion provides an estimation to the changes in pressure and saturation and also their related uncertainties. This uncertainty estimation is assimilated into the history matching workflow in a weighting approach, by penalizing the seismic inversion maps with respect to the Bayesian inversion uncertainties. We show that the proposed penalization method leads to a focused assimilation of the trustworthy seismic information, which may prove crucial when assimilating seismic data in the pressure and saturation domain. The workflow is applied to a real data case to assess and update global reservoir connectivity in a North Sea reservoir.

BackgroundGiant cell arteritis (GCA) has the tendency to relapse once treatment is tapered or stopped. Such relapses represent a potential threat to GCA patients as they can lead to severe symptoms and organ damage.ObjectivesTo assess the frequency and type of relapses in patients with GCAMethodsThe Real-Life Treatment and Safety (REATS)-GCA cohort has been established by extracting the data on clinical presentation, inflammatory markers, imaging, comorbidities, treatments and serious adverse events of GCA patients from 6 specialized centres in Germany. We undertook descriptive and survival analyses (Kaplan-Meier), and compared baseline characteristics of participants with vs. without relapse. Ethical approval for the cohort was obtained.ResultsWe included 395 patients with a mean age of 71 years, including 264 (66.8 %) females and 129 (32.7%) males. Diagnosis of GCA was supported by temporal artery ultrasound in 37%, 18F-FDG-PET/CT in 29%, temporal artery biopsy in 14% of patients and by MRI or clinically in the remaining patients. 31% of patients presented with an isolated cranial manifestation and 18% with isolated extracranial manifestations. Most common presenting symptoms were headache (57%), fatigue (55%), weight loss (42%) and polymyalgia (38%) (Table 1). The most common comorbidities at the time of study inclusion were arterial hypertension (68%), followed by osteoporosis (26%). Within a median total follow-up duration of 22.2 (11.7-40.6) months, 97 of the 395 patients relapsed including 15 patients who relapsed more than once. The median (IQR) time to first relapse was 12.5 (7.1-21.8) months. Median relapse-free survival was 7.8 years with a relapse risk of 12% (CI, 9 to 15%) at 1 year and 38% (CI, 30 to 45%) at 5 years (Figure 1). Most common symptoms at relapse were headache (35%), polymyalgia (23%), fatigue (19%) and night sweats (12%) (Table 1). Three patients relapsed with sudden loss of vision. Among the 114 relapses observed, 94 (83%) occurred under prednisolone treatment with a median dose of 7.0 mg/day (IQR 4.0-12.5). 26 (23%) occurred under methotrexate and 14 (12%) under tocilizumab treatment. Comparing the baseline characteristics that were documented in this study, we did not find a statistically significant difference in relapsing versus non-relapsing GCA patients.Table 1.Symptom at disease onsetN=395 (%)Symptom at relapseN=97 (%)Headache216 (54.7)Headache35 (30.7)Fatigue208 (52.7)Polymyalgia (PMR)23 (20.2)Weight loss159 (40.3)Fatigue19 (16.7)Polymyalgia (PMR)144 (36.5)Vision impairment13 (11.4)Night sweats140 (35.4)Night sweats12 (10.5)Headache in the temple area125 (31.6)Headache in the temple area12 (10.5)Jaw pain121 (30.6)Jaw pain11 (9.6)Vision impairment118 (29.9)Morning stiffness7 (6.1)Morning stiffness89 (22.5)Weight loss7 (6.1)Fever80 (20.3)Claudication upper limb6 (5.3)Swelling temporal arteries77 (19.5)Arthralgia6 (5.3)Vision loss57 (14.4)Claudication lower limb5 (4.4)Scalp tenderness38 (9.6)Vision loss3 (2.6)Claudication upper limb38 (9.6)Arthritis3 (2.6)Claudication lower limb34 (8.6)Scalp tenderness2 (1.8)Arthralgia28 (7.1)Fever2 (1.8)Arthritis3 (0.8)Swelling temporal arteries2 (1.8)Figure 1.ConclusionAbout one fourth of GCA patients relapsed and the overwhelming majority of relapses occurred before patients were able to stop glucocorticoids. The leading symptoms at relapse are headache and fatigue, while loss of vision is rare (0.76%). Baseline characteristics seem to be poorly informative about the risk of relapse, therefore regular monitoring of GCA patients is necessary.AcknowledgementsThis research was financially supported by Roche Pharma Ag and Chugai Pharma Europe Ltd.Disclosure of InterestsVerena Schönau Speakers bureau: Novartis, Janssen, Grant/research support from: Roche, Chugai, Giulia Corte: None declared, Sebastian Ott: None declared, Koray Tascilar: None declared, Fabian Hartmann: None declared, Bernhard Manger: None declared, Bernhard Hellmich: None declared, Alexander Pfeil: None declared, Peter Oelzner: None declared, Wolfgang A. Schmidt: None declared, Andreas Krause: None declared, Marc Schmalzing: None declared, Matthias Fröhlich: None declared, Michael Gernert: None declared, Nils Venhoff: None declared, Jörg Henes: None declared, Jürgen Rech Speakers bureau: Abbvie, Biogen, BMS, Chugai, GSK, Lilly, MSD; Novartis, Roche, Sanofi, Sobi, UCB,, Consultant of: Biogen, BMS, Chugai, GSK, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, UCB, Grant/research support from: Sobi, Novartis, Georg Schett: None declared

BackgroundRheumatoid arthritis (RA) requires early diagnosis and tight surveillance of disease activity. Patient self-sampling of blood for the analysis of autoantibodies and inflammation markers could facilitate the identification of patients at-risk for RA and improve tight disease monitoring [1].ObjectivesA randomized, controlled trial to evaluate the feasibility, acceptability and accuracy of an upper arm self-sampling device (UA) and finger prick-test (FP) to measure capillary blood from RA patients for C-reactive protein (CRP) levels and the presence of IgM rheumatoid factor (RF IgM) and anti-cyclic citrullinated protein antibodies (anti-CCP IgG).Methods50 RA patients were randomly assigned in a 1:1 ratio to self-collection of capillary blood via UA or FP. Venous blood sampling (VBS) was performed as gold standard in both groups to assess the concordance of CRP levels as well as RF IgM and CCP IgG. General acceptability and pain during sampling were measured and compared between UA, FP and VBS. The number of attempts for successful sampling, requests for assistance, volume and duration of sample collection were also assessed.Results49/50 (98%) patients were able to successfully collect capillary blood. Overall agreement between capillary and venous analyses for CRP (0.992), CCP IgG (0.984) and RF IgM (0.994) were good. In both groups 4/25 (16%) needed a second attempt and 8/25 (32%) in the UA and 7/25 (28%) in the FP group requested assistance. Mean pain scores for capillary self-sampling (1.7/10 ± 1.1 (UA) and 1.9/10 ± 1.9 (FP)) were lower on a numeric rating scale compared to venous blood collection (UA: 2.8/10 ± 1.7; FP: 2.1 ± 2.0). UA patients were more likely to promote the use of capillary blood sampling (net promoter score: +28% vs. -20% for FP) and were more willing to perform blood collection at home (60%) vs. 32% for FP).ConclusionThis study shows that self-sampling is accurate, feasible and well accepted among patients. The implementation could allow tight remote monitoring of disease activity as well as identifying patients at-risk for RA and potentially other rheumatic diseases.References:[1]Knitza J, Knevel R, Raza K, Bruce T, Eimer E, Gehring I, et al. Toward Earlier Diagnosis Using Combined eHealth Tools in Rheumatology: The Joint Pain Assessment Scoring Tool (JPAST) Project. JMIR Mhealth Uhealth. 2020;8:e17507.AcknowledgementsWe thank all patients for their participation in this study. This study is part of the PhD thesis of the first author JK (AGEIS, Université Grenoble Alpes, Grenoble, France). We thank Josefine Born and Deniz Krämer for their help recruiting patients.Disclosure of InterestsJohannes Knitza Grant/research support from: Thermo Fisher Scientific, Novartis, Koray Tascilar: None declared, Nicolas Vuillerme: None declared, Ekaterina Vogt Employee of: Thermo Fisher Scientific, Paul Matusewicz Employee of: Thermo Fisher Scientific, Giulia Corte: None declared, Louis Schuster: None declared, Timothée Aubourg: None declared, Gerlinde Bendzuck: None declared, Marianne Korinth: None declared, Corinna Elling-Audersch: None declared, Arnd Kleyer: None declared, Sebastian Boeltz: None declared, Axel Hueber: None declared, Gerhard Krönke: None declared, Georg Schett: None declared, David Simon: None declared

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focussed international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF. Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel. 509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of Krebs von den Lungen-6 and viral testing, while high-resolution computed tomography, brain natriuretic peptide and D-dimer are generally applied. High-dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%). Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed. Copyright © ERS 2020

Background Cathepsin D is the proteolytic enzyme most frequently implicated as a prognostic factor in primary breast cancer. In the present study we evaluated by means of an immunoradiometric assay the tumor content of this protease in primary breast cancer, its relationship with tumor-related clinical and pathological parameters, and its prognostic significance in a large series of breast cancer patients. Method The study comprised 1033 women with histologically established invasive breast cancer. Cathepsin D was measured in cytosol samples by means of an immunoradiometric assay to determine the total amount of cathepsin D (52 kDa, 48 kDa and 34 kDa). Evaluation of relapse-free survival and cause-specific survival was performed in the group of 1003 patients without evidence of metastasis at the time of initial diagnosis. The median follow-up of the patients who were free of recurrence was 54 months. Results Cathepsin D levels showed a wide range among the studied tumors (n=1033; median (range) 41 (0.9–2504) pmol/mg protein). Statistical analysis showed that the median cathepsin D levels were considerably higher in large tumors (T2–4) than in smaller ones (T1) (p=0.017), as well as in node-positive than in node-negative tumors (p=0.004). Cathepsin D levels were also higher in ductal tumors than in the other histological types (p=0.001), as well as in moderately or poorly differentiated tumors (p59 pmol/mg protein) were notably associated with a shorter cause-specific survival in the whole group of patients with breast cancer, as well as in the subgroup of node-positive patients (pConclusions This study suggests that elevated intratumoral cathepsin D levels may identify a subset of node-positive breast cancer patients showing a high probability of earlier death.

Altered EGFR activity is a causal factor for human tumor development, including malignant pleural mesotheliomas. The aim of the present study was the evaluation of the effects of Gefitinib on EGF-induced mesothelioma cell proliferation and the intracellular mechanisms involved. Cell proliferation, DNA synthesis and apoptosis were measured by MTT, thymidine incorporation and FACS analysis; EGFR, ERK1/2 and Akt expression and phosphorylation by Western blot, whereas receptor sites were analyzed by binding studies. Gefitinib inhibited EGF-induced proliferation in two mesothelioma cell lines, derived from pleural effusion (IST-Mes2) or tumor biopsy (ZL55). The treatment with Gefitinib induced cell cycle arrest in both cell lines, while apoptosis was observed only for high concentrations and prolonged drug exposure. EGF-dependent mesothelioma cell proliferation was mediated by EGFR and ERK1/2 phosphorylation, while Akt was not affected. Gefitinib inhibited both EGFR and ERK1/2 activation, being maximal at drug concentrations that induce cytostatic effects, suggesting that the proapoptotic activity of Gefitinib is independent from EGFR inhibition. Gefitinib treatment increased EGFR Bmax, possibly through membrane stabilization of inactive receptor dimers that we show to be induced by the drug also in the absence of EGF. EGFR activation of ERK1/2 represents a key pathway for pleural mesothelioma cell proliferation. Low concentrations of Gefitinib cause mesothelioma cell cycle arrest through the blockade of EGFR activity while high concentrations induce apoptosis. Finally, we propose that the formation of inactive EGFR dimers may contribute to the antitumoral activity of Gefitinib.

CD44s (standard isoform) is a cell adhesion molecule belonging to the family of the hyaluronan-binding proteins. The CD44 family has been found to be overexpressed in epithelial tumors, where they are generally in relationship with tumor growth and metastasic properties. The aim of this work was to evaluate the membranous CD44s content in colorectal cancer and in healthy surrounding mucosa, its possible relationship with clinicopathological parameters, and its potential prognostic significance.Membranous CD44s levels were measured by an immunoenzymatic assay in tumors and surrounding mucosa samples from 72 patients with resectable colorectal carcinomas. The patients were followed for a mean time period of 30 months.There was a wide variability of CD44s levels in tumor-surrounding mucosal samples (26.6-727 ng/mg protein) as well as in tumors (28.5-381 ng/mg protein). Tumor samples showed significantly higher CD44s levels (median: 99.1 ng/mg protein) than surrounding mucosal samples (81 ng/mg protein) (p=0.03). In the same way, CD44s levels in tumors as well as in surrounding mucosal samples were significantly higher in high S-phase tumors than in low S-phase tumors (p=0.001 for both). There was no significant relationship between tumor CD44s levels and patient's outcome. However, high levels of the glycoprotein in nonneoplastic surrounding mucosa were significantly (p=0.018) associated with a poor overall patient survival.CD44s may play a role in the tumorogenesis of colorectal carcinomas. In addition, CD44s levels in tumor-surrounding mucosa may provide, in concert with some clinicopathological parameters, important information about prognostic evaluation of patients with resectable colorectal carcinomas.

L’utilisation des nouvelles technologies chez le sujet âge en situation de dependance constitue desormais un axe pertinent de la prise en charge en complement de l’aide humaine. L’analyse des besoins des personnes âgees doit s’accompagner d’une evaluation de la propension individuelle a l’utilisation de ces nouvelles aides techniques pour compenser les differentes situations d’incapacites. La place des differentes technologies est discutee a travers l’identification de groupes cibles en termes de perte d’autonomie et de dependance. Le developpement des nouvelles technologies et leur prescription impliquent un accompagnement des professionnels du soin qui doivent participer largement aux efforts de recherche pour ameliorer leur acceptabilite tout en veillant a respecter les principes ethiques fondamentaux en matiere de respect de l’autonomie et de bientraitance.

Most of the tests, questionnaires, and neuropsychological batteries for the assessment of dementia have been translated and adapted for use in the Hispanic population without having normative data, which results in a high number of false positives when age and educational level are not considered. The Short Cognitive Performance Test (SKT) is a psychometric instrument evaluating memory and attention deficits that has been developed and standardized in Germany (Erzigkeit, 1989a, 1989b). The objective of this study was to adapt the SKT, to establish normative criteria that take into consideration age and educational level, and to establish its concurrent validity in comparison to other neuropsychological tests: Brief Neuropsychological Evaluation for Spanish-Speaking Subjects (Ostrosky-Solís et al., 1994), the Mini-Mental State Examination (Folstein et al., 1975), and the Blessed Functional Scale (Blessed et al., 1968) in 238 neurologically intact subjects and 97 subjects with mild to moderate dementia. The SKT showed adequate sensitivity (80.5%) and specificity (80.3%) in subjects with medium and high educational level; however, the sensitivity and specificity diminished (75% and 56.7%) in subjects with no education or low educational level. The adapted and validated version of the SKT in the Mexican population has been shown to be a psychometric instrument that in subjects with medium educational level can detect cognitive alterations and is able to determine the severity of deterioration; however, in subjects with low educational level and severe dementia, the SKT cannot be usefully administered.

Sir, A 76-year-old female patient suffering from long-term arterial hypertension had a nephrotic syndrome in 1997, being diagnosed of membranous glomerulonephritis clinically and with biopsy. She was resistant to steroids and azathioprine. Then, her treatment was changed to Mycophenolate Mofetil. In 2005, she had anuria, abdominal discomfort and acral edema. Serologic studies were negative. Hemodyalisis, besides steroids and cyclofosphamide treatment were started. Her renal function was worsening and a new biopsy showed a crescentic glomerulonephritis with epithelial crescents, severe tubulointerstitial changes and focal tubular hyperplasia. IF studies were identical to the previous biopsy and consistent with membranous glomerulonephritis (granular peripheral glomerular deposits of Ig G, C3 and C1q). EM is not available. CT scan and MRI displayed multiple renal cysts suggesting ACDK with a 2.5 cm solid nodule and a total right nephrectomy was performed. The removed kidney (Fig. 1) had multiple cysts, numerous minute nodules and a tangreen 2.5 cm mass. Studied by routine methods and immunohistochemistry (cytogenetics and EM are not available), a crescentic GN with many obsolescent glomeruli was found (Fig. 2). There were prominent tubulointerstitial changes: severe tubular atrophy, frequent tubular hyperplasia and oncocytic changes, sometimes papillary; Virchows Arch (2007) 450:365–367 DOI 10.1007/s00428-006-0324-0

Besides their regulatory role in embryogenesis, homeobox (HOX) genes are expressed in a specific manner in hematopoietic cell lineages, implying a role in the molecular regulation of hematopoiesis. Some HOX C cluster genes are found to be expressed in lymphoid cells of mice and humans. Their function and expression in normal hematopoiesis are still largely unknown. We have studied the mRNA expression of HOXC4, HOXC5, and HOXC6 in several stages of lymphocyte maturation by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNA in situ hybridization (RISH). We examined CD34+/CD38low and CD34+/CD38high cells obtained from normal donor bone marrow (BM), a panel of 19 lymphoid cell lines, several types of leukemias and non-Hodgkin's lymphomas (NHL), and lymphocytes isolated from tonsillar tissue and peripheral blood (PB). HOXC4 and HOXC6 were found to be expressed during maturation in B- and T-lymphoid cells. The expression of each gene was found to be initiated at different cell maturation stages. HOXC4 transcripts were present in CD34+/CD38low cells, which are thought to comprise stem cells and noncommitted progenitor cells, and in subsequent stages to terminally maturated lymphoid cells. HOXC6 expression is initiated in equivalents of prothymocyte and pre-pre-B cell stage and remains present in mature cells. However, HOXC5 is only expressed in neoplastic cell lines and in neoplastic cells of NHL, but not in CD34+ BM cells, nor in resting or activated lymphoid cells isolated from tonsil, PB, or in leukemia cells. In cell lines, weak expression of HOXC5 is initiated in equivalents of pre-B cell and common thymocyte stage and is continuously expressed in mature cell lines. Semi-quantitative RT-PCR showed that expression levels of HOXC5 were much lower than those of HOXC4 and HOXC6; furthermore an increase of expression of HOXC4, HOXC5, and HOXC6 during lymphoid cell differentiation was demonstrated. Thus, mainly mature lymphoid cell lines and neoplastic cells of NHL do express HOXC5, in contrast to the lack of expression in normal lymphoid cells and leukemias. These findings suggest involvement of HOXC5 in lymphomagenesis.

Besides their regulatory role in embryogenesis, homeobox (HOX) genes are expressed in a specific manner in hematopoietic cell lineages, implying a role in the molecular regulation of hematopoiesis. Some HOX C cluster genes are found to be expressed in lymphoid cells of mice and humans. Their function and expression in normal hematopoiesis are still largely unknown. We have studied the mRNA expression of HOXC4, HOXC5, and HOXC6 in several stages of lymphocyte maturation by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNA in situ hybridization (RISH). We examined CD34+/CD38low and CD34+/CD38high cells obtained from normal donor bone marrow (BM), a panel of 19 lymphoid cell lines, several types of leukemias and non-Hodgkin's lymphomas (NHL), and lymphocytes isolated from tonsillar tissue and peripheral blood (PB). HOXC4 and HOXC6 were found to be expressed during maturation in B- and T-lymphoid cells. The expression of each gene was found to be initiated at different cell maturation stages. HOXC4 transcripts were present in CD34+/CD38low cells, which are thought to comprise stem cells and noncommitted progenitor cells, and in subsequent stages to terminally maturated lymphoid cells. HOXC6 expression is initiated in equivalents of prothymocyte and pre-pre-B cell stage and remains present in mature cells. However, HOXC5 is only expressed in neoplastic cell lines and in neoplastic cells of NHL, but not in CD34+ BM cells, nor in resting or activated lymphoid cells isolated from tonsil, PB, or in leukemia cells. In cell lines, weak expression of HOXC5 is initiated in equivalents of pre-B cell and common thymocyte stage and is continuously expressed in mature cell lines. Semi-quantitative RT-PCR showed that expression levels of HOXC5 were much lower than those of HOXC4 and HOXC6; furthermore an increase of expression of HOXC4, HOXC5, and HOXC6 during lymphoid cell differentiation was demonstrated. Thus, mainly mature lymphoid cell lines and neoplastic cells of NHL do express HOXC5, in contrast to the lack of expression in normal lymphoid cells and leukemias. These findings suggest involvement of HOXC5 in lymphomagenesis.

Presently, a large effort is being made worldwide to increase the sustainability of industrial development, while preserving not only the quality of the environment but also that of animal and human life. In this work, sea urchin early developmental stages were used as a model to test the effects of the organophosphate pesticide (diazinon) on the regulation of gene expression by immunohistochemical localization of the human regulatory protein against the human OTX2. Egg exposure to diazinon did not affect fertilization; however, at concentrations 10(-5)-10(-6) M, it did cause developmental anomalies, among which was the dose-dependent alteration of the intracellular distribution of a regulatory protein that is immunologically related to the human OTX2. The severe anomalies and developmental delay observed after treatment at 10(-5) M concentration are indicators of systemic toxicity, while the results after treatment at 10(-6) M suggest a specific action of the neurotoxic compound. In this second case, exposure to diazinon caused partial delivery of the protein into the nuclei, a defective translocation that particularly affected the blastula and gastrula stages. Therefore, the possibility that neurotoxic agents such as organophosphates may damage embryonic development is taken into account. Specifically, the compounds are known to alter cytoplasmic dynamics, which play a crucial role in regulating the distribution of intracellular structures and molecules, as well as transcription factors. Speculatively, basing our assumptions on Fura2 experiments, we submit the hypothesis that this effect may be due to altered calcium dynamics, which in turn alter cytoskeleton dynamics: the asters, in fact, appear strongly positive to the OTX2 immunoreaction, in both control and exposed samples. Coimmunoprecipitation experiments seem to supply evidence to the hypothesis.

To determine whether the expression of collagenase-3 (MMP-13) in biopsies from patients with inflammatory bowel disease is correlated with histological inflammation parameters.Fifty-nine patients with inflammatory bowel disease were included in the study. The control group comprised 20 patients free of inflammatory disease and ten patients with acute diverticulitis. MMP-13 expression was determined by immunohistochemical staining and the specimens were assigned a histological inflammation score.It was found that 62.8% of patients with ulcerative colitis (UC) and 54.1% of patients with Crohn's disease (CD) showed MMP-13-positive immunostaining in biopsies from affected areas. MMP-13-positive staining was more intense in ulcerated colonic mucosa. A positive and significant correlation was found between MMP-13 expression and the histological inflammation scores in mucosal samples from patients with CD (r = 0.74, p0.0001) or UC (r = 0.62, p0.0001). However, no MMP-13-positive immunostaining was found in either the biopsy specimens of the control group or those biopsies taken from patients with UC or CD in microscopically confirmed non-affected areas of the colonic mucosa. Similarly, colonic mucosa samples of the 10 patients with acute diverticulitis did not show immunostaining for MMP-13.Our findings demonstrating the absence of MMP-13 expression in non-inflamed colonic mucosa or in acute diverticulitis, as well as a positive correlation between elevated MMP-13 expression and histological criteria of inflammation in patients with inflammatory bowel diseases (CD and UC) suggest a role of the protease in the pathogenesis of these latter processes.

Amniotic fluid embolism is an obstetric complication that can present during pregnancy or labor and is associated with high rates of morbidity and mortality. The incidence is low but the mortality rates for both mother and fetus are high. A 34-year-old woman in the 41st week of gestation was admitted for induction of labor. While still in the labor room, she complained of pruritus around the mouth and tongue. Tonic-clonic convulsions, hypotension, and loss of consciousness followed. Cardiopulmonary resuscitation maneuvers were started and an immediate cesarean section under general anesthesia was performed to deliver a live infant boy. The Apgar score at 5 minutes was 8. The mother was transferred for recovery to the intensive care unit (ICU), where rapid cardiocirculatory and pulmonary decline continued. After 2 episodes of electromechanical dissociation, exitus occurred 2 hours after ICU admission. The autopsy confirmed the diagnosis of amniotic fluid embolism. Keratin squames were found in the capillaries of both lungs and polymorphonuclear cells and proteinaceous material were observed in alveoli. Mechanical obstruction is not the only cause of amniotic fluid embolism. Circulating substances that affect myocardial contractility and coagulation are also implicated and the cause may even be an allergic reaction. The usual signs are acute respiratory failure, cardiovascular collapse, and occasionally convulsions and coagulopathy. Cardiac arrest occurs in 80% of the cases. Treatment is symptomatic to provide life-sustaining measures in response to the clinical picture as it develops.

BackgroundMatrix metalloproteases (MMPs), enzymes with the ability to degrade the extracellular matrix, play an important role in tissue invasion by cutaneous malignant melanoma (CMM). One specific MMP, collagenase-3 (MMP-13), is thought to have a key function in the activation of MMP.AimsTo evaluate the expression of MMP-13 in CMM and assess its possible relationship to clinical and pathological parameters.MethodsMMP-13 expression was analyzed in 51 paraffin-embedded tumor samples from patients with invasive CMM, ten samples from in situ melanomas, and in eight samples from benign lesions (three dermal melanocytic nevi, three compound melanocytic nevi and two atypical melanocytic nevi) using immunohistochemical techniques. The median follow-up period in patients with invasive CMM was 50 months.ResultsBenign lesions were consistently negative for MMP-13, whereas three of the ten in situ melanomas (30%) and 23 of the 51 invasive CMMs (45%) showed positive immunostaining for MMP-13. The percentage of MMP-13-positive tumors correlated significantly and positively with the mitotic index (p=0.002) in invasive CMM. However, our results did not show any significant association between tumoral MMP-13 expression and relapse-free survival in patients with invasive CMM.ConclusionsMMP-13 appears to be a factor associated with tumor aggressiveness in CMM. It seems to eliminate an important barrier not only against tumoral invasion but also against proliferation.

PIASx belongs to the PIAS protein family, the members of which modulate activities of several transcription factors and act as E3 ligases in the sumoylation pathway. The PIASx gene is highly expressed in testis, suggesting a role in spermatogenesis. To investigate the function of PIASx in vivo, we have disrupted the PIASx gene in mice. Interestingly, the knockout mice were viable and fertile. Despite the normal fertility, the testis weight of the mutant animals was reduced and their number of apoptotic testicular cells was increased. Also, the sperm count of mutant mice tended to be reduced, but the quality of their sperm cells was normal. No significant changes were observed in the serum levels of LH and FSH or in the intratesticular testosterone concentration between the knockout animals and their wild-type littermates. Compensatory increases in other PIAS protein mRNAs were not observed in the knockout mice. These results imply that PIASx is required quantitatively rather than qualitatively for normal spermatogenesis.

Background The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA in MCF-7 breast cancer cells and is also expressed by colorectal carcinomas. The objective of this work was to evaluate the cytosolic TFF1 content in colorectal carcinomas, its possible relationship with estrogen and progesterone receptors as well as with clinicopathological tumor parameters, and its potential prognostic significance. Methods Cytosolic TFF1 levels were examined by immunoradiometric assay in 178 patients with resectable colorectal cancer. The mean follow-up period was 32 months. Results There was a wide variability of cytosolic TFF1 levels in tumor-surrounding mucosa samples (0.09-42.5 ng/mg protein) as well as in tumors (0.01-270 ng/mg protein). Comparison of paired mucosa and carcinoma samples showed significantly higher TFF1 levels in tumors (mean: 17.1 ng/mg protein) than in mucosa samples (10 ng/mg protein) (p=0.027). TFF1 levels were significantly higher in mucosa samples surrounding distal colon and rectal tumors (p=0.0001) and in tumor samples obtained from older patients (p=0.007). However, there were no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, tumor location, stage, histological grade, ploidy, S-phase, or tumor estrogen and progesterone receptors. In addition, there was no significant relationship between tumor TFF1 levels and disease outcome. Conclusions TFF1 may play an as yet undetermined role in the tumorigenesis of colorectal carcinomas. However, cytosolic levels of TFF1 do not seem to have any prognostic significance in colorectal carcinomas.

Objetivos: investigar en una población de pacientes de nuestro ámbito clínico con cáncer colorrectal la distribución de sus edades, posibles diferencias en cuanto a los síntomas de presentación, características clínico-biológicas de sus tumores, diferencias en el tratamiento y en el pronóstico. Emplazamiento: Hospital de Jove de Gijón y el Hospital de referencia, Central de Asturias de Oviedo durante el periodo 1975-1999. Material y métodos: se realizó un estudio retrospectivo entre los meses de julio de 2001 a enero de 2002 que incluyo 473 pacientes del ámbito urbano y rural, diagnosticados de cáncer colorrectal. En todos se realizó el diagnóstico histológico de adenocarcinoma colorrectal. Se investigaron las características clásicas de los pacientes y de sus tumores así como su contenido de ADN, fase S, tipo de tratamiento y pronóstico de la enfermedad. Resultados: la edad media de los pacientes fue de 67,5 años (intervalo: 25-90 años). La década de mayor presentación fue la de los 70 años (33,2%) seguida de los 60 (32,6%) y la incidencia más baja correspondió a los

Aims We analyzed the tPA content in primary gastric carcinomas and surrounding mucosa in order to assess the relationship between tPA content, clinicopathological tumor characteristics, and estrogen and progesterone receptor content. We evaluated the prognostic value of this serine protease in gastric cancer patients. Patients and methods 122 resected gastric neoplasms and 95 adjacent mucosa samples were studied. The tPA content was measured in cytosol by an ELISA method. Cytosolic ER and PgR were measured with a solid phase enzyme immunoassay. Results Cytosolic tPA levels in neoplastic tissues (median 1.0 ng/mg prot) were significantly lower (p=0.002) than those found in paired mucosa samples (median 2.3 ng/mg prot). There was no significant association between tPA levels and clinicopathological parameters or PgR content, but tPA levels were significantly correlated with ER content. The intermediate-tPA-content group, corresponding to samples with between 0.3 and 1.70 ng/mg protein, proved to have a significantly high risk of relapse. Conclusions We found a wide variability in tPA levels in gastric carcinoma and adjacent mucosa samples, with significantly decreased levels in tumors and a significantly positive relationship between tPA levels and ER status. There was a non-monotonic relationship between tPA levels and prognosis in patients with gastric cancer.

Objetivo: analizar la importancia de la edad como factor pronóstico en el cáncer de mama, lo cual podría tener importantes implicaciones en el tratamiento y manejo clínico de las pacientes. Material y métodos: estudio retrospectivo de 769 pacientes intervenidas quirúrgicamente por cáncer de mama (1983-1999). El tiempo medio de seguimiento fue de 34,4 meses. Se realizaron estudios bioquímicos para la determinación de receptores de estrógenos y progesterona, contenido de ADN y fase S. Resultados: la edad media de las 769 pacientes fue de 59 años, y la década de mayor presentación del cáncer de mama fue la de los 50 años (26,5%). Encontramos una asociación estadísticamente significativa entre la edad de las pacientes y el tamaño tumoral (p

A 65 year-old man, right-handed, without any family history of left handiness, suddenly developed a left homonymous hemianopia and incapacity for reading. Neurological and neuropsychological examinations showed the presence of a profound alexia with preservation of writing to dictation and spontaneously. He was unable to read what he had written. He could spell the words letter by letter but he was unable to read the complete word. MRI showed an extensive infarct in the territory of the right posterior cerebral artery. The infarct extended anteriously to the right thalamus and to the medial temporal fifth or fusiform gyrus. The splenius was spared. Brain SPECT disclosed the area of the infarct and an extensive area of decreased cerebral perfusion over the right parietal and temporal areas.Alexia without agraphia has been reported in right-handed patients with left occipital lesions and in right occipital regions in left-handed patients but rarely if ever in right occipital lesions in right-handed patients.

Introduction Les troubles du comportement chez les dements sont frequents. L’agitation, l’agressivite et la deambulation sont difficiles a gerer et source de stress pour l’equipe soignante et l’entourage. Ces complications sont plus frequentes le soir avec le “sundowning” et la nuit avec l’inversion du cycle veille sommeil ou les parasomnies. L’apparition d’un etat confusionnel aigu sur un syndrome dementiel peut reveler la presence d’une pathologie sous-jacente ou bien un trouble metabolique. Le reperage de ces troubles par une meilleure analyse de l’activite nocturne peut aider a la gestion des patients et eviter l’abus des psychotropes. Materiel/methode Nous presentons le cas d’un homme de 79 ans suivi par actimetrie d’environnement avecle systeme GARDIEN® qui comporte 8 capteurs infra rouges installes dans une chambre d’hospitalisation. Le systeme reconnait la presence du personnel dans la chambre et cette activite n’est pas prise en compte.Ce patient qui etait connu pour une demence mixte et un diabete insulino requerant est arrive confus et agressif aux urgences avant d’etre hospitalise en geriatrie. Les donnees des transmissions infirmieres ont ete comparees avec celles obtenus par le systeme GARDIEN® par un expert independant. Resultat Nous avons enregistre 75 nuits sur une periode de 4 mois. La moyenne d’activite entre minuit et 6 h etait de 17.9 minutes et entre 21 et 6 h de 35 minutes ce qui est eleve en comparaison au groupe de reference. Le patient a presente des pics d’hyperactivite nocturne a plusieurs reprise qui ne correspondent pas toujours aux rapports des soignants. Le systeme apparait performant pour identifier une hyperactivite en lien avec une alteration metabolique (hyper ou hypoglycemie). L’actimetrie revele egalement un pattern de stabilisation comportemental chez ce patient dont le MMSE au depart de 11/30 est passe a 21/30 apres 23 jours suggerant le controle de l’etat confusionnel et psycho-comportemental. Conclusion La chambre actimetrique au sein des unites cognitivo- comportementales peut etre utile pour la surveillance des troubles du comportement surtout nocturne et reveler des pathologies intercurrentes chez le patient dement.

Recently it has been described in the literature a subpopulation of PBC patients with negative AMA that might represent patients with ANA positive autoimmune cholangitis. We review 25 cases of PBC (23 females) with AMA negative. Our aim was to determine the frequency of ANA(+) in this group. We studied serum transaminases, total bilirubin, AMA and ANA by indirect immunofluorescence considering positive dilutions of 1:40. All patients had elevated alkaline phosphatase (641 +/- 389 U/l). Total bilirubin was below 2.5 in 59%. Thirteen patients had esophageal varices. The histologic stage was I-II in eleven and III-IV in 14 cases. Fourteen patients (56%) has ANA(+) (dilution 1:40), 44% had lower dilutions. We confirm the presence of a subpopulation of PBC AMA negative, ANA positive patients and the observations of different and diverse immune alterations in PBC patients.

Our objective was to evaluate prospectively, objectively and in a systematic way the evaluation of patients with Ulcerative Colitis (UC) with moderate activity. We studied 14 outpatients, who were evaluated for an experimental therapeutic protocol. The activity of the disease was established using clinical, endoscopic and histologic parameters. The Kappa Index (K) was used for statistical analysis. The average number of bowel movements was 4/day; rectal bleeding and urgency were found in 100%, diarrhea in 78% and abdominal pain in 64%. The severity of rectal bleeding and urgency was graded II or III in 92% and 78% respectively. The correlation between endoscopy and histology (K = 0.55), and between clinical and endoscopy (K = 0.45) was moderate. There was no correlation between clinical and histological parameters.the variability of symptoms impairs the clinical evaluation as the unique method to determine the activity of UC and to take therapeutical decisions is necessary to perform a endoscopic/histology correlation.

Embryo development is controlled by a successive series of genes that provide each cell in the growing embryo with precise position information. Knowledge of these genes is known most completely from Drosophila, where a simple initial pattern generated by maternal effect genes is gradually segmented by the sequential transient expression of three successive series of genes: the gap genes, the pair-rule genes, and the segment polarity genes. Superimposing their action on the preexisting segments, these homeotic genes cause unique and often very distinctive patterns of differentiation for different segments. In humans, about 40 homeotic genes have been identified and are grouped into four clusters on chromosomes 2, 7, 12, and 17, whose organization reflects their spatial and temporal expression. Several homeotic genes have been found expressed not only in embryonic tissues, but also in adult tissues, most notably in the hematopoietic lineage, and also in tumors, especially leukemia, teratocarcinoma, and neuroblastoma, wherein their expression pattern is modified in a complex manner by retinoic acid. The target genes of the transcription factors encoded by the homeotic genes are largely unknown, but recent reports indicate that they may regulate the expression of adhesion molecules on the membrane and the production of components of the extracellular matrix. Abnormal expression of these genes can therefore affect not only cell proliferation, but also the spread of cells to aberrant locations.

Introduction and clinical case A 65 year-old man, right-handed, without any family history of left handiness, suddenly developed a left homonymous hemianopia and incapacity for reading. Neurological and neuropsychological examinations showed the presence of a profound alexia with preservation of writing to dictation and spontaneously. He was unable to read what he had written. He could spell the words letter by letter but he was unable to read the complete word. MRI showed an extensive infarct in the territory of the right posterior cerebral artery. The infarct extended anteriously to the right thalamus and to the medial temporal fifth or fusiform gyrus. The splenius was spared. Brain SPECT disclosed the area of the infarct and an extensive area of decreased cerebral perfusion over the right parietal and temporal areas. Conclusion Alexia without agraphia has been reported in right-handed patients with left occipital lesions and in right occipital regions in left-handed patients but rarely if ever in right occipital lesions in right-handed patients.

The tissue distribution and the ontogeny of DC-1 antigens have been investigated and compared with those of HLA-DR antigens. Indirect immunofluorescence (IIF) staining of surgically removed normal tissues from adults with the monoclonal antibody (MoAb) BT3.4 has detected DC-1 antigens in tissues of various embryologic origin. The tissue distribution of DC-1 antigens is more restricted than that of HLA-DR antigens, as the former are not detected in duodenal epithelium, colon mucosa, and ductal mammary gland epithelium. In fetuses up to 26 weeks of age, DC-1 antigens were detected only on cortical and medullary thymic dendritic cells with an anatomic distribution similar to that of reticuloepithelial cells and in endothelial cells of the small intestine. At this stage of intrauterine life, HLA-DR antigens have already reached their full tissue distribution. The tissue distribution and the ontogeny of DC-1 antigens resemble those of their murine counterparts, i.e., the I-A antigens.

The volatility of two fungicidal seed dressings, Panogen 15 B liquid and Panogen PX powder, containing methyl mercuric dicyandiamide in equivalent amounts at the dosage used, was compared with that of triple distilled mercury. Tests were made in the absence and presence of cleaned Manitou wheat of 12.0% and 17.1% moisture content. The Panogen formulations were compared at the recommended and twice the recommended rate at different dosages, storage periods and storage temperatures. The Hg content of air samples was determined by the Corte-Monkman method, capable of determining 0.4 ng of Hg, which in a 1-L air sample is equivalent to 0.049 ppb (v/v). The volatility of the interstitial air expressed as mug of Hg vapor/m3 air depended on temperature, wheat moisture content and storage duration and ranged from 150 to 2,240 for metallic Hg, 21 to 350 for Panogen 15 B, and 31 to 380 for PX. In the absence of wheat the volatility of 15 B was greatest (395) at -17.5 degees C and least (75) at 4.5 degrees C, but increased rapidly thereafter with increased temperature. Volatility of metallic Hg after application to wheat of 12.0% and 17.1% moisture content was not significantly reduced after four days storage, but that of Panogen 15 B and PX was reduced considerably, particularly at the higher moisture level. Thus, volatility of mercurial seed dressings cannot be predicted from Hg content alone. Reduction of volatility through possible irreversible chemical bonding of Hg with seed components is suggested for more detailed investigation.

We have studied the surface antigen pattern, enzymatic phenotype, and functional capacity of peripheral blood lymphocytes from a patient with Sézary syndrome (SS). The majority of these cells formed E rosettes but lacked the Fc(mu) receptor. The neoplastic cells were reactive with pan-T cell (OKT3)- and helper T cell (OKT4)-subset monoclonal antibodies; however, they lacked the 5/9 antigen, which identifies a more restricted subset of helper T cells. Most SS cells also reacted with PTF 29.12, a monoclonal antibody which recognizes DR determinants. Only 35% of the cells expressed single, focal accumulations of alpha-naphthyl-acid esterase activity, which is a characteristic of T.M cells, but 85% of them showed this focal staining pattern with acid phosphatase or beta-glucuronidase. Mononuclear cells from the SS patient showed poor or no proliferative response to phytohemagglutinin, pokeweed mitogen, concanavalin A, purified protein derivative, Candida, and allogeneic cells and lacked both helper and suppressor activity for pokeweed mitogen driven production of IgM and IgG immunoglobulins by normal B cells, but they were able to stimulate a marked proliferative response in mixed-lymphocyte culture. The defective expression of enzymatic and surface membrane characteristics, together with the lack of some T-cell functions, suggests that the patient cells may be immature T.M lymphocytes.