Extremophiles in an Antarctic Marine Ecosystem

Recent attempts to explore marine microbial diversity and the global marine microbiome have indicated a large proportion of previously unknown diversity. However, sequencing alone does not tell the whole story, as it relies heavily upon information that is already contained within sequence databases. In addition, microorganisms have been shown to present small-to-large scale biogeographical patterns worldwide, potentially making regional combinations of selection pressures unique. Here, we focus on the extremophile community in the boundary region located between the Polar Front and the Southern Antarctic Circumpolar Current in the Southern Ocean, to explore the potential of metagenomic approaches as a tool for bioprospecting in the search for novel functional activity based on targeted sampling efforts. We assessed the microbial composition and diversity from a region north of the current limit for winter sea ice, north of the Southern Antarctic Circumpolar Front (SACCF) but south of the Polar Front. Although, most of the more frequently encountered sequences were derived from common marine microorganisms, within these dominant groups, we found a proportion of genes related to secondary metabolism of potential interest in bioprospecting. Extremophiles were rare by comparison but belonged to a range of genera. Hence, they represented interesting targets from which to identify rare or novel functions. Ultimately, future shifts in environmental conditions favoring more cosmopolitan groups could have an unpredictable effect on microbial diversity and function in the Southern Ocean, perhaps excluding the rarer extremophiles

Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress

Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pattern (DAMP) and inflammatory cytokines such as HMGB1 and TNF alpha, were not affected by rALR. Furthermore, we evaluated infiltration of inflammatory cells into liver tissue after IRI and found no change in CD3 or gamma delta TCR positive cells, or expression of IL17/IFN gamma by gamma delta TCR cells. The quantity of Gr-1 positive cells (neutrophils), and therefore, myeloperoxidase activity, was lower in rALR-treated mice. Moreover, we found under hypoxic conditions attenuated ROS levels after ALR treatment in RAW264.7 cells and in primary mouse hepatocytes. Application of rALR also led to reduced expression of chemo-attractants like CXCL1, CXCL2 and CCl2 in hepatocytes. In addition, ALR expression was increased in IR mouse livers after 3 h and in biopsies from human liver transplants with minimal signs of tissue damage. Therefore, ALR attenuates IRI through reduced neutrophil tissue infiltration mediated by lower expression of key hepatic chemokines and reduction of ROS generation

Diagnostik und Therapie von Lebermetastasen bei kolorektalem Primärtumor

Contrast-enhanced multislice computer tomography (MSCT) has established itself as the standard tomographic imaging method both for diagnosis and for treatment monitoring of hepatic lesions. To clarify local conditions before partial liver resection, diffusion-weighted magnetic resonance tomography (DWI-MRT) can also provide important additional information. In order to meet the criteria for a R0 resection, a margin of 0.5 mm seems to be sufficient. Neoadjuvant chemotherapy aiming to reduce tumour size can be given in parallel with portal artery embolisation without adversely affecting perioperative morbidity and mortality. As far as the management of primary resectable liver metastases is concerned, there is an urgent need for more studies. Despite the relatively limited evidence, adjuvant chemotherapy is currently more widely favoured in Germany than perioperative chemotherapy. There is also considerable need for studies concerning preoperative therapy in patients with liver metastases that are not (yet) resectable. In KRAS wild-type tumours, high response rates (in terms of a reduction in the size of metastases) are achieved with a cetuximab/chemotherapy combination. Bevacizumab/chemotherapy combinations lead to high rates of pathohistological complete and partial remissions. What the best parameter for judging the success of preoperative therapy is remains unknown, and so comparison studies using survival as a `hard' endpoint must be carried out

Weaning of immunosuppression in liver transplant recipients

Immunosuppression has been sporadically discontinued by noncompliant liver allograft recipients for whom an additional 4 1/2 years of follow-up is provided. These anecdotal observations prompted a previously reported prospective drug withdrawal program in 59 liver recipients. This prospective series has been increased to 95 patients whose weaning was begun between June 1992 and March 1996, 8.4±4.4 (SD) years after liver replacement. A further 4 1/2 years follow-up was obtained of the 5 self-weaned patients. The prospectively weaned recipients (93 livers; 2 liver/kidney) had undergone transplantation under immunosuppression based on azathioprine (AZA, through 1979), cyclosporine (CsA, 1980-1989), or tacrolimus (TAC, 1989-1994). In patients on CsA or TAC based cocktails, the adjunct drugs were weaned first in the early part of the trial. Since 1994, the T cell-directed drugs were weaned first. Three of the 5 original self-weaned recipients remain well after drug-free intervals of 14 to 17 years. A fourth patient died in a vehicular accident after 11 years off immunosuppression, and the fifth patient underwent retransplantation because of hepatitis C infection after 9 drug-free years; their allografts had no histopathologic evidence of rejection. Eighteen (19%) of the 95 patients in the prospective series have been drug free for from 10 months to 4.8 years. In the total group, 18 (19%) have had biopsy proved acute rejection; 7 (7%) had a presumed acute rejection without biopsy; 37 (39%) are still weaning; and 12 (13%, all well) were withdrawn from the protocol at reduced immunosuppression because of noncompliance (n=8), recurrent PBC (n=2), pregnancy (n=1), and renal failure necessitating kidney transplantation (n=1). No patients were formally diagnosed with chronic rejection, but 3 (3%) were placed back on preexisting immunosuppression or switched from cyclosporine (CsA) to tacrolimus (TAC) because of histopathologic evidence of duct injury. Two patients with normal liver function died during the trial, both from complications of prior chronic immunosuppression. No grafts suffered permanent functional impairment and only one patient developed temporary jaundice. Long surviving liver transplant recipients are systematically overimmunosuppressed. Consequently, drug weaning, whether incomplete or complete, is an important management strategy providing it is done slowly under careful physician surveillance. Complete weaning from CsA-based regimens has been difficult. Disease recurrence during drug withdrawal was documented in 2 of 13 patients with PBC and could be a risk with other autoimmune disorders

Spezielle Therapiesituationen beim metastasierten kolorektalen Karzinom

Specific Treatment Situations in Metastatic Colorectal Cancer As far as the management of primary resectable liver metastases is concerned, three approaches are currently competing with each other: surgery alone, surgery with pre- and postoperative chemotherapy, and surgery with postoperative chemotherapy alone. The core of the argument for pre- and postoperative chemotherapy in these patients is the European Organisation for Research and Treatment of Cancer (EORTC) 40983 study, which concluded that, in comparison with surgery alone, perioperative chemotherapy improved the 3-year progression-free survival (PFS) by 7 months. In contrast to this, there are two smaller studies - at a somewhat lower strength of evidence - indicating that adjuvant chemotherapy extends PFS by 9.1 months compared with surgery alone. In Germany, the adjuvant approach continues to be favored in many places; this can also be seen in the formulation of the S3 guideline. In patients with unresectable liver metastases - with the associated difficulty of classification due to the lack of clear and definitive criteria preoperative systemic therapy to induce `conversion' is indicated, in order to allow secondary resection. In KRAS wild-type tumors, high response rates ( in terms of a reduction in size of the metastases, such as according to RECIST ( Response Evaluation Criteria in Solid Tumors)) and a high conversion rate are achieved using a cetuximab/chemotherapy combination. Triple chemotherapy combinations with 5-fluorouracil (5-FU), oxaliplatin and irinotecan also produce high response rates. Bevacizumab/chemotherapy combinations have led to a high number of complete and partial pathohistological remissions in phase II studies; these seem to correlate with long survival times. In the absence of long-term survival data, it therefore seems to remain unclear as to what is the best parameter to use in order to assess the success of preoperative treatment. Lung metastases, too, or local peritoneal carcinomatosis can nowadays be operated on in selected patients with a good prospect of long-term remission or even cure. The surgery should, however, generally only be carried out in experienced centers, especially in the case of peritoneal carcinomatosis. For synchronous metastasization, the appropriate management depends on the size and extent of liver metastases and of the primary tumor. Small, peripherally lying and safely resectable liver metastases can be removed before or at the same time as the primary tumor, especially if a hemicolectomy is being carried out. If the metastases are unresectable and there is no bleeding or stenosis, the primary tumor can also be left in situ and systemic chemotherapy can be carried out first. However, it should be borne in mind that, according to current data, palliative resection of the primary tumor combined with systemic therapy leads to longer overall survival than does chemotherapy alone. Whether resection or chemotherapy should be done first therefore depends on the patient's clinical situation

The INDEX Project - Critical Appraisal of the Setting and Implementation of Indoor Exposure Limits in the EU

The INDEX project (Critical Appraisal of the Setting and Implementation of Indoor Exposure Limits in the EU), coordinated by the EU/JRC and funded by DG SANCO, has been finished in December 2004. The project was carried out in collaboration with a Steering Committee of leading European experts in the area of indoor air pollution. Scope of INDEX was to identify priorities and to assess the needs for a Community strategy and action plan in the area of indoor air pollution. The key issues that have been addressed within the project are: - the setting up of a list of compounds to be measured and regulated in indoor environments with priority, on the basis of health impact criteria - to provide suggestions and recommendations on potential exposure limits for these compounds and - to provide information on links with existing knowledge, ongoing studies, legislation etc. at world scale. Suggestions and recommendations on potential exposure limits or other exposure control actions were defined for five prioritised compounds; formaldehyde, nitrogen dioxide, carbon monoxide, benzene, and naphthalene.JRC.I.5-Physical and chemical exposure