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Paramos, unique and biodiverse ecosystems found solely in the high mountain regions of the tropics, are under threat. Despite their crucial role as primary water sources and significant carbon repositories in Colombia, they are deteriorating rapidly and garner less attention than other vulnerable ecosystems like the Amazon rainforest. Their fertile soil and unique climate make them prime locations for agriculture and cattle grazing, often coinciding with economically critical deposits such as coal which has led to a steady decline in paramo area. Anthropic impact was evaluated using multispectral images from Landsat and Sentinel over 37 years, on the Guerrero and Rabanal paramos in central Colombia which have experienced rapid expansion of mining and agriculture. Our analysis revealed that since 1984, the Rabanal and Guerrero paramos have lost 47.96% and 59.96% of their native vegetation respectively, replaced primarily by crops, pastures, and planted forests. We detected alterations in the spectral signatures of native vegetation near coal coking ovens, indicating a deterioration of paramo health and potential impact on ecosystem services. Consequently, human activity is reducing the extent of paramos and their efficiency as water sources and carbon sinks, potentially leading to severe regional and even global consequences., (© 2024. The Author(s).)

Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro . In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D-CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D-CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity., Competing Interests: Authors CR, EP, PK, HR, LF, RB, MG, CR, DS, EW, NS, EQ, and J-BM were employed by the company Transgene SA. MD, SS, CH, and PF were employed by the company Randox Laboratories Ltd., (Copyright © 2023 Remy, Pintado, Dunlop, Schön, Kleinpeter, Rozanes, Fend, Brandely, Geist, Suhner, Winter, Silvestre, Huguet, Fitzgerald, Quéméneur and Marchand.)

Despite compelling evidence that stress or stress-related hormones influence fear memory consolidation processes, the understanding of molecular mechanisms underlying the effects of stress is still fragmentary. The release of corticosterone in response to pre-learning stress exposure has been demonstrated to modulate positively or negatively memory encoding and/or consolidation according to many variables such as stress intensity, the emotional valence of the learned material or the interval between stressful episode and learning experience. Here, we report that contextual but not cued fear memory consolidation was selectively impaired in male mice exposed to a 50 min-period of restraint stress just before the unpaired fear conditioning session. In addition to behavioral impairment, acute stress down-regulated activated/phosphorylated ERK1/2 (pERK1/2) in dorsal hippocampal area CA1 in mice sacrificed 60 min and 9 h after unpaired conditioning. In lateral amygdala, although acute stress by itself increased the level of pERK1/2 it nevertheless blocked the peak of pERK1/2 that was normally observed 15 min after unpaired conditioning. To examine whether stress-induced corticosterone overflow was responsible of these detrimental effects, the corticosterone synthesis inhibitor, metyrapone, was administered 30 min before stress exposure. Metyrapone abrogated the stress-induced contextual fear memory deficits but did not alleviate the effects of stress on pERK1/2 and its downstream target phosphorylated CREB (pCREB) in hippocampus CA1 and lateral amygdala. Collectively, our observations suggest that consolidation of hippocampus-dependent memory and the associated signaling pathway are particularly sensitive to stress. However, behavioral normalization by preventive metyrapone treatment was not accompanied by renormalization of the canonical signaling pathway. A new avenue would be to consider surrogate mechanisms involving proper metyrapone influence on both nongenomic and genomic actions of glucocorticoid receptors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3 - 6 . Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29 , a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31 , which has weaker potency and increased permeability.

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.

Infectious diseases are among the greatest threats to global health in the 21st century, and one critical concern is due to antibiotic resistance developed by an increasing number of bacterial strains. New resistance mechanisms are emerging with many infections becoming more and more difficult if not impossible to treat. This growing phenomenon not only is associated with increased mortality but also with longer hospital stays and higher medical costs. For these reasons, there is an urgent need to find new antibiotics targeting pathogenic microorganisms such as ESKAPEE bacteria. Most of currently approved antibiotics are derived from microorganisms, but higher fungi could constitute an alternative and remarkable reservoir of anti-infectious compounds. For instance, pleuromutilins constitute the first class of antibiotics derived from mushrooms. However, macromycetes still represent a largely unexplored source. Publications reporting the antibacterial potential of mushroom extracts are emerging, but few purified compounds have been evaluated for their bioactivity on pathogenic bacterial strains. Therefore, the aim of this review is to compile up-to-date data about natural products isolated from fruiting body fungi, which significantly inhibit the growth of ESKAPEE pathogenic bacteria. When available, data regarding modes of action and cytotoxicity, mandatory when considering a possible drug development, have been discussed in order to highlight the most promising compounds., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

DNA-encoded small molecule libraries (DELs) have enabled discovery of novel inhibitors for many distinct protein targets of therapeutic value. We demonstrate a new approach applying machine learning to DEL selection data by identifying active molecules from large libraries of commercial and easily synthesizable compounds. We train models using only DEL selection data and apply automated or automatable filters to the predictions. We perform a large prospective study (∼2000 compounds) across three diverse protein targets: sEH (a hydrolase), ERα (a nuclear receptor), and c-KIT (a kinase). The approach is effective, with an overall hit rate of ∼30% at 30 μM and discovery of potent compounds (IC 50 < 10 nM) for every target. The system makes useful predictions even for molecules dissimilar to the original DEL, and the compounds identified are diverse, predominantly drug-like, and different from known ligands. This work demonstrates a powerful new approach to hit-finding.

Large tropical river dam projects are expected to accelerate over the forthcoming decades to satisfy growing demand for energy, irrigation and flood control. When tropical rivers are dammed the immediate impacts are relatively well studied, but the long-term (decades-centuries) consequences of impoundment remain poorly known. We combined historical records of water quality, river flow and climate with a multi-proxy (macrofossils, diatoms, biomarkers and trace elements) palaeoecological approach to reconstruct the limnological evolution of a shallow basin in Gatun Lake (Panama Canal, Panama) and assess the effects of multiple linked factors (river damming, forest flooding, deforestation, invasive species, pollution and hydro-climate) on the study area. Results show that a century after dam construction, species invasion, deforestation and salt intrusions have forced a gradual change in the study basin from a swamp-type environment towards a more saline lake-governed system of benthic-littoral production likely associated with the expansion of macrophyte stands. Hydrology still remains the most important long-term (decades) structural factor stimulating salinity intrusions, primary productivity, deposition of minerals, and reduction of water transparency during wet periods. During dry periods, physical-chemical conditions are in turn linked to clear water and aerobic conditions while nutrients shift to available forms for the aquatic biota in the detrital-rich reductive sediments. Our study suggests that to preserve the natural riverine system functioning of this area of the Panama Canal, management activities must address long-term ecosystem structural drivers such as river flow, runoff patterns and physical-chemical conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

High-resolution paleoclimate data on stable isotopes in a stalagmite were coupled to glycerol dialkyl glycerol tetraethers (GDGTs). The Indian Summer Monsoon (ISM) transitioned from limited rainfall during the Last Glacial Maximum (LGM) to intense precipitation during early Holocene (22 to 6 ka). This was associated with changes in stalagmite growth, abundance of branched (br) and isoprenoid (iso) GDGTs, as well as δ 18 O, δ 13 C, Sr/Ca and GDGT-derived signals providing both temperature and moisture information. The reconstructed mean annual air temperature (MAAT) of the most modern stalagmite sample at ~19 °C, matches the surface and cave MAAT, but was ~4 °C lower during LGM. Warming at the end of LGM occurred before ISM strengthened and indicate 6 ka lag consistent with sea surface temperature records. The isotope records during the Younger Dryas show rapid progressions to dry conditions and weak monsoons, but these shifts are not coupled to TEX 86 . Moreover, change to wetter and stronger ISM, along with warmer Holocene conditions are not continuous indicating a decoupling of local temperatures from ISM.

Archaeal tetraether membrane lipids span the whole membrane width and present two C 40 isoprenoid chains bound by two glycerol groups (or one glycerol and calditol). These lipids confer stability and maintain the membrane fluidity in mesophile to extremophile environments, making them very attractive for biotechnological applications. The isoprenoid lipid composition in archaeal membranes varies with temperature, which has placed these lipids in the focus of paleo-climatological studies for over a decade. Non-hydroxylated isoprenoid archaeal lipids are typically used as paleo-thermometry proxies, but recently identified hydroxylated (OH) derivatives have also been proposed as temperature proxies. The relative abundance of hydroxylated lipids increases at lower temperatures, but the physiological function of the OH moiety remains unknown. Here we present molecular dynamics simulations of membranes formed by the acyclic glycerol-dialkyl-glycerol-tetraether caldarchaeol (GDGT-0), the most widespread archaeal core lipid, and its mono-hydroxylated variant (OH-GDGT-0) to better understand the physico-chemical properties conferred to the membrane by this additional moiety. The molecular dynamics simulations indicate that the additional OH group forms hydrogen bonds mainly with the sugar moieties of neighbouring lipids and with water molecules, effectively increasing the size of the polar headgroups. The hydroxylation also introduces local disorder that propagates along the entire alkyl chains, resulting in a slightly more fluid membrane. These changes would help to maintain trans-membrane transport in cold environments, explaining why the relative abundance of hydroxylated Archaea lipids increases at lower temperatures. The in silico approach aids to understand the underlying physiological mechanisms behind the hydroxylated lipid based paleo-thermometer recently proposed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To assess the prevalence of vitreoretinal interface abnormalities in a general population of healthy adults ≥45 years of age., Design: Cross-sectional study carried out at 17 ophthalmology services throughout Spain., Participants: Between September 2015 and March 2016, all consecutive healthy persons aged ≥45 years who were accompanying patients to ophthalmology services were invited to take part in the study. Exclusion criteria were known retinal disease, uveitis, history of ocular trauma or previous intraocular surgery (including cataract surgery and intravitreal injections), severe myopia (>-6 dioptres), and poor ocular media transparency., Methods: Spectral-domain OCT or swept-source OCT was performed on all participants. Diseases of the vitreomacular interface were classified according to the OCT-based anatomic classification system of the International Vitreomacular Traction Study Group. All pathologic and borderline images as well as doubtful cases were evaluated blindly in a central reading center., Main Outcome Measures: Prevalence of vitreomacular interface abnormalities (vitreomacular traction epiretinal membrane, lamellar hole)., Results: The study included 2257 participants with a mean age of 59.5 years (range 45-90), and a total of 4490 eyes (right eyes 2242, left eyes 2248). Vitreoretinal interface abnormalities were detected in 70 eyes, with a prevalence of 1.6%. Vitreomacular adhesion was observed in 1317 eyes (29.3%). Results of spectral-domain OCT or swept-source OCT examination were unrevealing in 3103 eyes. Vitreoretinal interface abnormalities were found in 61 participants, with a prevalence in the study population of 2.7%. Vitreomacular traction was observed in 14 participants (0.6%), epiretinal membrane in 44 (1.9%), and lamellar macular hole in 3 (0.1%). The prevalence of both vitreomacular traction and epiretinal membrane increased significantly with age. The presence of vitreoretinal interface abnormalities was unrelated to concomitant diabetes mellitus or hypertension., Conclusions: An important percentage of healthy participants from the general population ≥45 years of age showed vitreoretinal interface abnormalities. Screening with OCT is advisable at any first routine consultation or preoperative assessment, particularly in older participants., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The infection caused by the zoonotic opportunistic pathogen Mycobacterium avium subsp. hominissuis (Mah) was reported for the first time in a pet ferret. Both owners were HIV-positive. Euthanasia of the pet was recommended due to medical reasons and as a preventive action. Disseminated and open tuberculosis lesions were observed in the gastrointestinal and respiratory systems of the ferret. Ecographic and radiographic surveys showed a severe generalized lymphadenopathy, strong thickening of the gastric wall and peritoneum layer. The histopathological findings revealed a disseminated, granulomatous, chronic inflammation affecting the gastrointestinal tract, lungs, lymphoid tissues (spleen, tonsils and lymph nodes) and liver. Ziehl-Neelsen staining displayed the presence of positive acid-fast bacilli within these granulomas. Bacteriology and sequencing of the isolates yielded Mah sequevar code 3. Ferrets can act as reservoirs of mycobacteria exposing their owners to the infection, which is of major concern in immunodeficient individuals, as those HIV-infected., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We have recently shown that post-extinction retraining of rats, with a shock intensity that is too weak to induce by itself significant fear acquisition, impairs the recall of fear extinction memory. Tetanic stimulation (TS) of the medial prefrontal cortex (mPFC), applied before or following this retraining, facilitates extinction recall. Here we investigated whether mPFC TS can also facilitate expression of fear extinction when rats are retrained with the same shock intensity as during the initial fear acquisition. Rats were implanted with stimulating electrodes in the mPFC and were trained to acquire freezing to a conditioning chamber, in which they had to enter freely. In Experiment 1, extinction of this response was followed by reconditioning and then another extinction training. Acquired freezing was extinguished successfully, while reacquired freezing, which was associated with increased chamber entry latencies, was resistant to subsequent extinction. Both reacquired freezing and increased chamber entry latencies were absent in rats that received post-reconditioning mPFC TS. In Experiment 2, post-conditioning mPFC TS had no effect on initially acquired freezing. In Experiment 3, rats were submitted to reconditioning without experiencing extinction training. In this condition, both reacquired freezing and increased chamber entry latencies were still present in rats that received post-reconditioning mPFC TS. These findings provide additional evidence for the fundamental role of the mPFC in maintaining expression of fear extinction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Lake Van in Turkey is the world's largest soda lake (607 km(3)). The lake's catchment area is estimated to be ∼12,500 km(2), and the terrestrial input is carried through eolian, riverine, snowmelt and anthropogenic paths. Extent and seasonality of the terrestrial inputs to the lake have not been studied, but it is essential to evaluate its environmental status and to assess the use of environmental proxies to estimate the lake's response to climate changes. This study aims to measure seasonal changes in terrestrial input of natural and anthropogenic origin as recorded by the fluxes of pollen and biomarkers of soil bacteria and vascular or higher plants, as well as petrogenic biomarkers in monthly resolved sediment traps from August 2006 to July 2007. Fluxes of pollen, soil and higher plant biomarkers seem to be related to precipitation and snowmelt in autumn and spring. In addition, dust storms, which are common during the summer months, may have resulted in long-distance transport. Anthropogenic biomarker fluxes indicate year-round petrogenic contamination although some mature biomarker fluxes are higher in summer and in late winter-spring. The relative changes between petrogenic markers indicate variations in the pollutant sources.

The degradation of organic carbon in subseafloor sediments on continental margins contributes to the largest reservoir of methane on Earth. Sediments in the Andaman Sea are composed of ~ 1% marine-derived organic carbon and biogenic methane is present. Our objective was to determine microbial abundance and diversity in sediments that transition the gas hydrate occurrence zone (GHOZ) in the Andaman Sea. Microscopic cell enumeration revealed that most sediment layers harbored relatively low microbial abundance (10(3)-10(5) cells cm(-3)). Archaea were never detected despite the use of both DNA- and lipid-based methods. Statistical analysis of terminal restriction fragment length polymorphisms revealed distinct microbial communities from above, within, and below the GHOZ, and GHOZ samples were correlated with a decrease in organic carbon. Primer-tagged pyrosequences of bacterial 16S rRNA genes showed that members of the phylum Firmicutes are predominant in all zones. Compared with other seafloor settings that contain biogenic methane, this deep subseafloor habitat has a unique microbial community and the low cell abundance detected can help to refine global subseafloor microbial abundance., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

There is great interest in the membrane lipids of archaea (glycerol dialkyl glycerol tetraethers [GDGTs]) as tracers of archaeal biomass because of their utility as paleoproxies and because of the biogeochemical importance of archaea. While core GDGTs (formed by hydrolysis of polar head groups of intact GDGTs after cell death) are appropriate for paleostudies, they have also been used to trace archaeal populations. Also, despite the small size (0.2 by 0.7 μm) of cultivated marine archaea, 0.7-μm glass-fiber filters (GFFs) are typically used to collect GDGTs from natural waters. We quantified both core and intact GDGTs in free-living (0.2- to 0.7-μm), suspended (0.7- to 60-μm), and aggregate (>60-μm) particle size fractions in Puget Sound (Washington State). On average, the free-living fraction contained 36% of total GDGTs, 90% of which were intact. The intermediate-size fraction contained 62% of GDGTs, and 29% of these were intact. The aggregate fraction contained 2% of the total GDGT pool, and 29% of these were intact. Our results demonstrate that intact GDGTs are largely in the free-living fraction. Because only intact GDGTs are present in living cells, protocols that target this size fraction and analyze the intact GDGT pool are necessary to track living populations in marine waters. Core GDGT enrichment in larger-size fractions indicates that archaeal biomass may quickly become attached or entrained in particles once the archaea are dead or dying. While the concentrations of the two pools were generally not correlated, the similar sizes of the core and intact GDGT pools suggest that core GDGTs are removed from the water column on timescales similar to those of cell replication, on timescales of days to weeks.

Dynamic modelling of hydrochemistry is a valuable tool to study and predict the recovery of surface waters from acidification, and to assess the effects of confounding factors (such as delayed soil response and changing climate) that cause hysteresis during reversal from acidification. The availability of soil data is often a limitation for the regional application of dynamic models. Here we present a method to upscale site-specific soil properties to a regional scale in order to circumvent that problem. The method proposed for upscaling relied on multiple regression models between soil properties and a suite of environmental variables used as predictors. Soil measurements were made during a field survey in 13 catchments in the Pyrenees (NW Spain). The environmental variables were derived from mapped or remotely sensed topographic, lithological, land-cover, and climatic information. Regression models were then used to model soil parameters, which were supplied as input for the biogeochemical model MAGIC (Model for Acidification of Groundwater In Catchments) in order to reconstruct the history of acidification in Pyrenean lakes and forecast the recovery under a scenario of reduced acid deposition. The resulting simulations were then compared with model runs using field measurements as input parameters. These comparisons showed that regional averages for the key water and soil chemistry variables were suitably reproduced when using the modelled parameters. Simulations of water chemistry at the catchment scale also showed good results, whereas simulated soil parameters reflected uncertainty in the initial modelled estimates.

Institutions should normally have an integrative influence. The family, for example, has the task of protecting and giving socio-emotional support to children, and schools should prepare young people for their future. Ideally the common goal of all of society's institutions is to secure the integration of youth and prevent or intervene against deviant behavior. But sometimes institutions provoke or even cause juvenile delinquency. The article discusses institutional influences and the role of the police in the criminal and violent situation in the favelas of Rio de Janeiro.Starting with an overview of the origins and the development of violence, crime, and drug trafficking in the favelas, the authors show how these slums arose. Their analysis examines the lack of a state presence with an integration policy to avoid social disintegration. Instead of social integration policy, there is a dual approach that both controls and produces violence. The article also presents the first results of a government attempt in 2000 to introduce a new police unit to stop the violence and improve the social opportunity structure of the residents of the favelas, especially young people.

The TEX86 is a recently proposed paleothermometer through which ancient seawater temperatures of up to 120 My ago can be reconstructed. It is based on the relative distribution of glycerol dibiphytanyl glycerol tetraethers as measured by high-performance liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry (HPLC/APCI-MS). The aim of this study was to examine and improve several analytical aspects in the determination of this important proxy in environmental matrices. Comparison of TEX86 analysis using single ion mode (SIM) and mass scanning (m/z 950 to 1450) detection, respectively, revealed that SIM is up to 2 orders of magnitude more sensitive and that the TEX86 can be determined with a reproducibility of +/-0.004 or +/-0.3 degrees C using this method. Comparison of TEX86 values obtained with two different HPLC/APCI-MS set-ups revealed no significant differences. In addition, analysis of TEX86 of extracts obtained by Soxhlet, ultrasonic, and accelerated high-pressure extraction techniques also showed no significant differences between the methods. Our results suggest that TEX86 analysis by HPLC/APCI-MS is robust and can be determined with analytical errors comparable to those of other temperature proxies.

Aim: The treatment of common bile duct stones has changed with the new therapeutic techniques, that have replaced the conventional therapy, represented by surgery. Anyway, they could cause some problems, that must be regarded. Therefore, we wish to confirm the importance of the conventional surgery in the management of patients with common bile duct stones., Methods: A total of 147 patients were operated for common bile duct stones (73 in emergency and 74 in election). The intraoperative cholangiography was carried out in 141 patients and a choledocoscopy in 130 patients. A drain of Kehr was positioned in 120 patients, a bilio-digestive anastomosis in 26 cases and in 1 case there was a direct suture of the common bile duct without drain. All patients were treated with a short-term antibioticotherapy, protracted to 5 days in the emergency cases. In the patients with the drain of Kehr there was a control cholangiography after 7 days from operation and it was removed after 25 days. The analysis of the results was done dividing the patients according to the age: <75 years old and >75 years old., Results: Nobody died during the operation. Complications were 17.4% in the patients >75 years old and 2,6% in the patients <75 years old. There were 2 death, in the postoperative period, for the group >75 years old. Cases operated in emergency were 68.1% of "old" patients and 37.2% of "young" patients. The postoperative period was 14.9+/-9.2 days for the "old" group and 10.9+/-5.2 days for the "young" group., Conclusions: The treatment of common bile duct stones is still a surgical treatment, particularly for "old" patients.

Duodenal cystic dystrophy due to ectopic pancreas deposit is an uncommon pathology. Diagnosis is made by modern imaging techniques, mainly endoscopic ultrasound which localizes precisely cysts in duodenal wall. The most frequent clinical symptoms are pain, duodenal obstruction, and weight loss. We report the case of a 40 year-old man with cystic dystrophy of the 2nd part of the duodenum, without chronic pancreatitis, treated by a conservative surgical procedure including segmental duodenal resection. This original approach is an alternative to the Whipple procedure.

Liver metastasis of carcinoid tumors from the digestive tract are rare entities, with characteristic symptoms and slow evolution. Symptomatic metastases may justify surgical resection. Herein, we report a series of nine patients, who underwent 14 hepatic resections (6 major and 8 minor), which was radically operated in 71%. The postoperative mortality was zero and the morbidity was 7%. Mean follow-up was 82 month (median 75 months) and global survival rate was 89%. Two patients are in complete remission. Our experience suggest that surgical hepatic resection, when feasible, is efficient and associated with prolonged survival despite a high recurrence rate.

Superficial lipomas are very common benign adipose tissue tumors. In contrast, deep-seated lipomas such as retroperitoneal lipomas, are extremely rare and have to be carefully distinguished from well-differentiated liposarcomas for appropriate treatment and follow-up. We report to, our knowledge, the first cytogenetic analysis of a retroperitoneal lipoma occurring in an adult, which showed a complex rearrangement interpreted as t(1;8)(q32;q22-q23) followed by a pericentric inversion of der(8). There was no detectable rearrangement of chromosome 12, and in particular no 12q14-q15 amplification. Because rearrangements of the 8q11-q13 region involving the PLAG1 gene have been described in lipoblastoma-another kind of benign adipose tumor--we used fluorescence in situ hybridization analysis to determine in the present case the chromosomal breakpoint on 8q was located between the ETO (8q22) and COX6C (8q22-q23) genes at a great distance from PLAG1. Karyotypic analysis of additional cases of retroperitoneal lipomas will be required to assess the significance of chromosome 1 and 8 rearrangements in a continuous effort to attain a better classification of adipose tissue tumors. Of great importance is the determination of such genetic markers as additional tools for the differential diagnosis between benign and malignant forms of adipose tumors, and to avoid erroneous diagnoses.

Unlabelled: Suicide gene therapy consists of transferring into tumor cells a viral or bacterial gene encoding for an enzyme which converts a non-toxic product into a lethal drug., Study Aim: To analyze the therapeutic potential of vaccination with tumor cells expressing the bacterial cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) treatment in a rat liver metastasis model., Material and Method: We used a rat colon carcinoma cell line which, after subcapsular or intraportal injection in syngenic animals, generates single or multiple experimental liver metastases, respectively. We have shown that introduction of a vector expressing the CD gene in this colon carcinoma cell line results in 5-FC sensitivity (PRObCD)., Results: Intrahepatic subcapsular injection of PRObCD tumor cells, followed by 5-FC treatment, induces total regression of a wild-type tumor pre-established in the contralateral liver lobe in 45% of animals with a 96% decrease in mean volume (p < 0.0001), demonstrating the existence of a distant bystander effect. This vaccination significantly increased the survival of rats with single (log-rank p < 0.0001) or multiple (log-rank p = 0.01) liver metastasis, Conclusions: These results suggest that suicide gene-modified tumor cells can act as potent therapeutic vaccines against liver metastasis from colon carcinoma.

We previously reported that the Ets1 transcription factor is expressed in endothelial cells during angiogenesis both in normal and pathological development. We analyse here the effects of the stable expression of an Ets transdominant negative mutant (Ets1-DB), consisting in an Ets1 protein lacking its transactivation domain. A retrovirus containing the Ets1-DB sequence fused to an IRES-Neo sequence was designed and used to infect brain capillary (IBE) and aorta (MAE) mouse endothelial cell lines. Cells expressing this Ets1 mutant were examined for proliferation, migration and adhesion. Consistent changes were observed on cell morphology, with increased spreading and modifications in the organization of the cytoskeleton, and increased cell adhesion. We investigated the ability of endothelial cells to organise into capillary-like structures using three-dimensional gels. On Matrigel, all endothelial cell lines formed a cord-like network within 24 h, with an increased ability of Ets1-DB cells to spread on this substrate. In long term cultures, IBE cells expressing Ets1-DB showed a higher capacity to form branched structures; this effect was potentiated by FGF2. These results demonstrate a role of the Ets transcription factors in the regulation of the adhesive and morphogenetic properties of endothelial cells.

Giant diverticulum of the colon is a rare complication of the colonic diverticulosis. It generally involves the sigmoid colon. In the chronic form, without symptoms or with only a few non-specific symptoms, an abdominal mass is frequently palpable. A plain abdominal radiogram, showing a gas-filled cyst, can suggest the diagnosis. If needed, an abdominal CT scan is appropriate and seems to be more accurate than a barium enema. The treatment of choice is a segmental resection of the colon involving the giant diverticulum, followed by a direct anastomosis. Despite the old age of these patients, both postoperative morbidity and mortality are low and justify such a radical approach. The acute clinical presentation (about 20%) is generally due to a peritonitis by perforation of the giant diverticulum and requires an emergency colectomy.

Adrenal medullary hyperplasia is often misdiagnosed. The clinical features may resemble those of pheochromocytoma, with paroxysmal hypertension and elevated urinary catecholamine and metanephrine levels. Pathologic study shows diffuse or nodular adrenal medullary hyperplasia, determined by morphometric analysis: increased adrenal gland weight, increased relative medullary volume, increased relative medullary weight, decreased cortico-medullary ratio. Adrenal medullary hyperplasia may be primary or sporadic, but is often associated with multiple endocrine neoplasia (MEN) type II.

The chicken proto-oncogene c-rel encodes a transcription factor of the Rel/NF-kappa B family. We have previously shown that c-rel mRNAs accumulate in different types of apoptotic cells of the chick embryo, especially in mesenchymal cells within the four cell death areas of the limb bud: the anterior and posterior necrotic zones, the opaque patch and the interdigital necrotic zones. This study aimed to further establish the involvement of c-Rel in apoptosis of the developing limb by investigating its expression in the talpid3 mutant which was originally shown to be defective in apoptosis. However, our preliminary examinations highlighted the apparent presence of apoptotic cells in talpid3 embryos. Hence, we performed a systematic study of the occurrence of apoptosis in mutant and control embryos by the TUNEL method. The results revealed that apoptosis does occur in talpid3 embryos but with altered spatial and temporal patterns. This suggests that the talpid3 mutation does not affect a gene involved in apoptosis per se but rather in the determination of the pattern of apoptosis. Neither the expression of c-Rel nor that of its I kappa B alpha inhibitor are grossly modified in talpid3 limb buds, suggesting that the talpid3 mutation does not affect any of these genes. They are mostly expressed in epidermal, endodermal and striated muscle cells in control and in talpid3 limb buds as well. C-Rel was also detected in some scarce mesenchymal cells that could be apoptotic, in both control and mutant embryos. The only slight difference between control and talpid3 limbs lies in the perichondrium which is not fully differentiated in talpid3 embryos: c-Rel and I kappa B alpha are only faintly expressed in talpid3 perichondrial cells, whereas they are both detected in control perichondrial cells. Taken together, these results suggest that c-Rel could participate in several developmental processes, especially in the differentiation of perichondrial cells, besides its already documented involvement in apoptosis and haematopoeisis.

Presacral myelolipoma is a rare benign tumour of unknown aetiology, composed of mature adipose tissue with intermixed normal haematopoietic cells. Computed tomography is of help in the diagnosis but biopsy is mandatory in order to avoid unnecessary surgery. A case is reported.

Congenital hepatic fibrosis (CHF), is an autosomal recessive disease, presenting principally in childhood with portal hypertension and/or cholangitis, and often associated with renal malformations. The forms presenting later in adults are rare, and illustrated herein by 4 cases with dominant cholangitis, and one latent form. Biological tests and radiological imaging are often normal. The histopathologic diagnosis, sometimes difficult on liver needle biopsy is based on fibrous enlargement of portal areas, with numerous and tortuous bile ducts, lined by regular, cuboidal epithelium. Interportal fibrosis can mimic cirrhosis. In CHF, cholangitis are favoured by intrahepatic biliary dilatation, sometimes related to Caroli's disease, associated in 25% of cases. Suppurative complications, sometimes fatal explain the severity of cholangitis forms of CHF, contraindicating inopportune cholangiography and biliary surgery.

Spi-1/PU.1 is a member of the Ets family of transcription factors important in regulation of hematopoiesis. We have isolated a chicken cDNA homologuous to the mammalian Spi-1/PU.1 gene with an open reading frame of 250 amino acids (aa). The chicken Spi-1/PU.1 protein is 14 aa and 16 aa shorter than its human and mouse counterparts but is extremely well conserved with 78.8% and 75.2% identity respectively. The carboxy terminal DNA binding region, or ETS binding domain, is 100% identical to that of human and mouse. Some differences with the mammalian homologues are seen in the N-terminal part of the protein and in the PEST connecting domain. However, the differences are mainly conservative and all the features underlying functional aspects seem preserved. The major discrepancy lies in a 12 aa deletion in an already poorly conserved part of the PEST sequence. Spi-1/PU.1 transcripts were detected at high levels in spleen and Fabricius bursa of chick embryos by Northern blot and in situ hybridization. Our results show that the chicken Spi-1/PU.1 protein behaves like a bonafide Spi-1/PU.1 transcription factor in its DNA binding and transactivating properties.

Transcription factors of the Rel/NF-kappaB family are widely involved in the immune system. In this study, we investigate the in vivo expression of the avian protein c-Rel in the T-cell lineage during thymus development. The majority of thymocytes do not express the c-Rel protein. However, lymphocyte precursor cells that colonize the thymus express the c-Rel protein shortly after their homing in the organ and before they begin to differentiate. c-Rel is also detected in different subsets of antigen-presenting cells such as epithelial cells, dendritic cells, and macrophages. In vitro studies have shown that Rel/NF-kappaB proteins are sequestered in an inactive form in the cytoplasm by interaction with the IkappaBalpha inhibitory protein. By immunocytochemistry, we show that in vivo c-Rel is localized in the cytoplasm of antigen-presenting cells but in both the cytoplasm and nucleus of lymphocyte precursor cells. The cytoplasmic localization of c-Rel in antigen-presenting cells correlates with a high expression of IkappaBalpha, whereas the nuclear localization of c-Rel in lymphocyte precursor cells correlates with a much lower expression of IkappaBalpha. These results suggest that c-Rel might be constitutively activated in lymphocyte precursor cells.

From the sequences of Rel/NF-kappa B and I kappa B proteins, we constructed an alignment of their Rel Homology Domain (RHD) and ankyrin repeat domain. Using this alignment, we performed tree reconstruction with both distance matrix and parsimony analysis and estimated the branching robustness using bootstrap resampling methods. We defined four subfamilies of Rel/NF-kappa B transcription factors: (i) cRel, RelA, RelB, Dorsal and Dif; (ii) NF-kappa B1 and NF-kappa B2; (iii) Relish and (iv) NF-AT factors, the most divergent members. Subfamilies I and II are clustered together whereas Relish diverged earlier than other Rel/NF-kappa B proteins. Three subfamilies of I kappa B inhibitors were also defined: (i) NF-kappa B1 and NF-kappa B2; (ii) close to subfamily I, the short I kappa B proteins I kappa B alpha, I kappa B beta and Bcl-3; (iii) Relish that diverged earlier than other I kappa B inhibitors. Our definition of groups and subfamilies fits to structural and functional features of the Rel/NF-kappa B and I kappa B proteins. We also showed that ankyrin repeats of NF-kappa B1, NF-kappa B2 and Relish are short I kappa B-specific ankyrin motifs. These proteins defining a link between Rel/NF-kappa B and I kappa B families, we propose that all these factors evolved from a common ancestral RHD-ankyrin structure within a unique superfamily, explaining the specificities of interaction between the different Rel/NF-kappa B dimers and the various I kappa B inhibitors.

This study investigates the involvement of the avian transcription factor c-Rel in thymocyte apoptosis occurring either in vivo or in organotypic culture. In vivo, only a few cortical thymocytes express the c-Rel protein. Their number, localization and morphology resemble that of apoptotic cells evidenced by TUNEL staining. In organotypic culture, the expression of c-Rel is induced in medullary thymocytes as apoptosis is triggered. This induction would be post-transcriptional since no increase in the c-rel gene expression is detected. Moreover, c-Rel translocates into the nucleus of medullary thymocytes during the time course of apoptosis. This translocation is preceded by a decrease in ikba expression, the gene which encodes the avian homologue of IkappaBalpha. Altogether these results suggest that the proto-oncogene c-rel could take an active part in apoptosis of cortical thymocytes occurring in vivo during T-cell selection as well as in experimentally-induced apoptosis of medullary thymocytes.

Objective: To determine the incidence and the clinical importance of gut-bacterial translocation after portal triad clamping for liver resection., Design: Cohort study., Setting: Multispecialty referral center., Patients: Five cirrhotic and 10 noncirrhotic patients requiring liver resection., Interventions: Elective liver resection under normothermic ischemic conditions (mean +/- SD duration, 40.2 +/- 13.1 minutes). Simultaneous sampling for qualitative culture of the systemic and portal blood, the upper gastrointestinal tract fluid, and a mesenteric lymph node (MLN) before and after liver resection., Main Outcome Measures: Positive culture rate, type of organism isolated, and septic complications rate., Results: Before resection, blood cultures and MLNs were sterile in all but 1 patient; this culture-positive patient had had a recent colon resection for occlusive carcinoma and was excluded from further analysis. After resection, systemic and portal blood cultures were sterile in all cases. Conversely, the MNLs were culture positive in 6 (43%) of 14 patients. Coagulase-negative staphylococci were the most common isolates. A weak correlation was observed between the organisms isolated from the MLNs and those simultaneously present in the upper gastrointestinal tract fluid. There was no relationship between bacterial translocation and the outcome as patients with culture-positive MLNs showed no evidence of intraperitoneal septic complications and the only patient with a septic complication (a subphrenic abscess) had negative cultures after resection., Conclusion: A significant bacterial translocation in the MLNs occurs after portal triad clamping and liver resection, although not clinically relevant.

Five cases of adenomatoid tumors of the uterus (ATU) are reported. These benign lesions are discovered in 1% of the hysterectomy specimens, performed on 20- to 85-years-old women. Their frequency is certainly underestimated, since ATU have the same macroscopic appearance as leiomyomas. Histologically, ATU are formed by gland-like and pseudovascular lumens, lined by regular, cuboidal or flattened cells, and surrounded by hyperplastic smooth muscle bundles. Immunohistochemical coexpression of cytokeratin and vimentin confirms with a mesothelial histogenesis. The ultrastructural study, showing luminal microvilli and desmosomes supports the hamartomatous development of ATU, corresponding to mesothelial inclusions from the peritoneum into the myometrium. Some giant or diffuse ATU, which are clinically disturbing, are differentiated from carcinomatous or vascular proliferations by frozen section examination. The treatment is made by surgical excision.

Objective: To review the role of prosthetic replacement after resection of the suprarenal portion of the inferior vena cava (IVC)., Design: Retrospective review of a series of six patients with malignant infiltration of the suprarenal IVC undergoing operation in the last 11 years., Setting: Multispecialty referral center., Patients: One primary leiomyosarcoma and five involvements of the IVC by liver carcinoma (n = 2), adrenal carcinoma (n = 2), and recurrent renal carcinoma (n = 1)., Interventions: En bloc resection of the tumor with the IVC under total vascular exclusion of the liver in four cases, combined major liver resection in four cases, venous resection including the renal confluence in four cases, prosthetic venous replacement in four cases, and no venous replacement in two cases., Main Outcome Measures: Mortality, venous patency, clinical assessment, and malignant recurrence., Results: One postoperative death (renal failure) following extended resection with right nephrectomy and ligature of the left renal vein. Graft patency was controlled in survivors, with good functional result. Among two patients without venous replacement, one with complete caval obstruction and marked collateral circulation has had a good result, and one with partial caval obstruction experienced transient symptoms of venous insufficiency. Malignant recurrence led to death in four patients (4, 6, 37, and 42 months after surgery)., Conclusions: Suprarenal IVC reconstruction is justified in selected cases, with good functional results. When the renal confluence is resected along with the IVC, renal vein reconstruction may be needed to avoid acute renal failure. The oncologic results of such extensive resections are poor. Adjuvant therapy should be evaluated.

A case of acute Budd-Chiari syndrome in a 26-year-old woman is reported. After a mesocaval shunt, the patient remained asymptomatic for 21 months, but ascites and hepatomegaly reappeared due to inferior vena cava stenosis subsequently treated by balloon dilation. Recurrence of stenosis indicated the need for a cavoatrial shunt with an expanded polytetrafluoroethylene prosthesis, which was followed by a complete recovery during the next 29 months. Radiological follow-up with magnetic resonance imaging demonstrated progressive hepatomegaly, thrombosis of the cavoatrial shunt, and stenosis of the mesocaval shunt. A transjugular intrahepatic portosystemic shunt was carried out, despite the absence of any patent residual hepatic vein at the usual level, by perforating the inferior vena cava and liver up to the right portal vein. An expandable 12-mm stent was successful in decreasing liver congestion. Dilation of the transjugular intrahepatic portosystemic shunt was done 15 months later, and the patient remains asymptomatic after a follow-up of 18 months.

Objectives: Currently, there is a trend towards emergency colectomy in patients requiring immediate care for lesions involving the large bowel. However, the therapeutic indications have not been fully identified. We therefore retrospectively evaluated our experience with 123 emergency situations., Methods: Among 745 cases requiring colonic surgery from January 1985 to August 1992, 123 were seen in emergency for intestinal obstruction (n = 69; 56.1%), peritonitis (n = 41; 33.3%) or haemorrhage (n = 13; 10.6%). The mean age of the patient was 71 years and 50% were over 75. The left colon was involved in 76.4% of the cases. Diverticulitis was seen in 43.1% and 39% had cancer of the colon., Results: Emergency resection and anastomosis was performed in 55 cases (44.7%) without colostomy. In 62 patients (50.4%) a colostomy was created; 46 were later removed. In 61 cases, the patients underwent emergency surgery within 24 hours and in the other 62, delayed surgery was performed after one day of hospitalization. Overall hospital mortality was 11.4% (14/123), 20% for patients over 75 and 3.2% for those under 75. Mortality after delayed operations was lower (6.5%) than after emergency surgery (17.2%). There was also a higher rate of colon resections without colostomy in delayed procedures (62.9% vs 26.2%)., Conclusions: Our experience leads us to recommend delayed surgery whenever possible in order to decrease operative mortality and number of operations.

The authors reviewed their recent experience with major hepatic resection in order to evaluate the role of abdominal drainage in the development and treatment of postoperative complications. Fifty-one patients underwent major hepatectomy with abdominal drainage; 44 of these patients (86%) for malignancy (average age at operation: 59 years). Drains were removed after a median period of 4 days. Major complications occurred in 16 patients (31%), and 3 patients (6%) had a fatal outcome. Twenty patients (39%) experienced minor complications, including 6 cases (12%) of ascitic leak from the insertion site. Considering the type and extent of liver resections reported in this series, these results suggest that abdominal drainage, if technically adequate and maintained for a short period, is not responsible for a high rate of postoperative complications. Its use, although questionable after limited resections, is, therefore, still recommended after difficult and extended hepatectomies.