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Background and Aims: Hepatitis C virus (HCV) management in Inflammatory Bowel Disease (IBD) is uncertain. The ECCO guidelines 2021 recommended HCV treatment but warn about the risk of IBD reactivation. We aimed to evaluate 1) the effectiveness and safety of direct-acting antivirals (DAAs) in IBD; 2) the interaction of DAAs with IBD drugs., Methods: Multicentre study of IBD patients and HCV treated with DAAs. Variables related to liver diseases and IBD, as well as adverse events (AEs) and drug interactions, were recorded. McNemar's test was used to assess differences in the proportion of active IBD during the study period., Results: We included 79 patients with IBD and HCV treated with DAAs from 25,998 IBD patients of the ENEIDA registry. Thirty-one (39.2 %) received immunomodulators/biologics. There were no significant differences in the percentage of active IBD at the beginning (n = 11, 13.9 %) or at the 12-week follow-up after DAAs (n = 15, 19 %) (p = 0.424). Sustained viral response occurred in 96.2 % (n = 76). A total of 8 (10.1 %) AEs occurred and these were unrelated to activity, type of IBD, liver fibrosis, immunosuppressants/biologics, and DAAs., Conclusions: We demonstrate a high efficacy and safety of DAAs in patients with IBD and HCV irrespective of activity and treatment of IBD., Competing Interests: Conflict of interest Dr. A. Martín‐Cardona has received financial support for conference attendance, educational activities, and research support from Abbvie, Biogen, Faes Farma, Ferring, Jannsen, MSD, Pfizer, Takeda, Dr. Falk Pharma and Tillotts. Dra. MJ Casanova has received research or education funding from Pfizer, Takeda, Janssen, MSD, Ferring, Abbvie, Biogen, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi and Norgine. Dr. C. González-Muñoza has received financial support for travel and educational activities from Pfizer, Takeda, MSD, Norgine, Janssen, Tillots, and Kern Pharma. Dra. M. Piqueras has served as a speaker or has received research or education funding from Takeda, Abbvie and Janssen. Dr. I. Rodríguez-Lago has received financial support for travelling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Dr. Falk Pharma, Ferring, Faes Farma, Janssen, Galapagos, MSD, Otsuka Pharmaceutical, Pfizer, Roche, Takeda, and Tillotts Pharma. Dra. N. Manceñido Marcos has served as a speaker and consultant for or has received financial support for educational activities from Janssen, AbbVie, Pfizer, Takeda, Ferring, Faes Farma, Dr. Falk Pharma and Tillotts Pharma. Dra. B. Sicilia has received research or education funding or advisory fees from Abbvie, FAES, Chiesi, Dr. Falk, MSD, Tillots Pharma, Khern Pharma, Janssen, Pfizer and Takeda. Dr. E. Domènech has served as a speaker or has received research or education funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, Imidomics, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda and Tillots. Dra. M. Esteve has received support for conference attendance and research support from Abbvie, Biogen, Faes Farma, Ferring, Jannsen, MSD, Pfizer, Takeda, and Tillotts. The remaining authors report no conflicts of interest related to this manuscript., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

We describe the clinical and pathological features of a brain collision tumour consisting of a fibrous meningioma and an anaplastic oligoastrocytoma in a 14-year-old male neutered French Bulldog. Computed tomography of the brain revealed a poorly defined, intra-axial lesion affecting the left frontal lobe. Following euthanasia, histological examination showed an anaplastic oligoastrocytoma invading the brain parenchyma and an adjacent fibrous meningioma. As synchronous intracranial tumours are rare in animals, the aims of this report are to describe the clinical, imaging and histopathological features of an intracranial collision tumour in a dog and highlight the importance of a complete histopathological study despite the imaging findings., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is a highly aggressive malignant brain tumor currently without an effective treatment. Inspired by the recent advances in cell membrane biomimetic nanocarriers and by the key role of macrophages in GBM pathology, we developed macrophage membrane liposomes (MML) for GBM targeting. For the first time, it was assessed the role of macrophage polarization states in the effectiveness of these drug delivery systems. Interestingly, we observed that MML derived from M2 macrophages (M2 MML) presents higher uptake and increased delivery of the anticarcinogenic drug doxorubicin compared to M1 macrophage-derived nanocarriers (M1 MML) and control liposomes (CL). Moreover, the lowest uptake by macrophages of MML reveals promising immune escaping properties. Notably, M2 macrophages unveiled a higher expression of integrin CD49d, a crucial protein involved in the bilateral communication of macrophages with tumor cells. Therefore, our findings suggest the potential of using M2 macrophage membranes to develop novel nanocarriers targeting GBM., Competing Interests: Declaration of competing interest There are no conflicts to declare. Authors declare there are no commercial associations (current and within the past five years) that might pose a potential, perceived or real conflict of interest (including grants, patent licensing arrangements, consultancies, stock or other equity ownership, advisory board memberships, or payments for conducting or publicizing the study)., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Hepatitis C virus (HCV) therapy with direct-acting antivirals (DAA) achieves high rates of sustained virological response in people living with human immunodeficiency virus (HIV) (PLWH). Information on its long-term clinical impact is scarce. The aim of this study was to analyse liver fibrosis and immune response evolution after DAA treatment., Methods: Retrospective, single centre cohort study of HIV-HCV co-infected patients treated with DAA between June 2013 and June 2018. We analysed the changes during follow up in liver fibrosis (assessed by transient elastography (TE), aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scores) and immunity (CD4 and CD8 cells counts and CD4/CD8 ratio)., Results: We included 410 patients; 75% (308/407) men with a mean age of 50 years (SD 8); 78% (318/410) had long chronic HCV infection (median 21 years, interquartile range (IQR) 6-27 years) and 27% (107/393) had liver cirrhosis. Liver fibrosis improvement based on the decrease in TE value compared with the baseline occurred in 43% (131/302) of patients and 31% of patients based on biological scores (APRI: 124/398; FIB-4: 104/398) (p < 0.0001), being more frequent in those with advanced baseline fibrosis (83/144). The higher decrease was observed at 6 months after DAA therapy (-0.23; 95% CI -0.29 to -0.18), but a continuum in fibrosis regression of at least 30% from baseline value of TE was observed along the follow up (32% of patients at month 6, 51% at month 24 and 55% at month 48). Regarding the immunological profile, there was a significant decrease in CD8 counts at month 48 (-62.38; 95% CI -106.77 to -17.99; p 0.0001) and a progressive rise in the CD4/CD8 ratio after 24 months of follow up reaching an increment of +0.07 (95% CI 0.03-0.10, p 0.0001) at month 48., Conclusions: HCV treatment with DAA in PLWH is associated with significant progressive improvement in liver fibrosis and recovery of the immune system with an increase in the CD4/CD8 ratio in long-term follow up., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies., (© 2021 by The American Society of Hematology.)

Background: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274)., Patients and Methods: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D., Results: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m 2 , three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m 2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3., Conclusions: The lenvatinib RP2D was 14 mg/m 2 . Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)., Competing Interests: Disclosure SGM: personal fees from Loxo Oncology, Bayer, and EUSA Pharma, outside the submitted work. FL: consultant or advisory role for Novartis, Amgen, Bellicum Pharmaceuticals, and Pfizer; honoraria for speaking at symposia from Amgen, Novartis, bluebird bio, Miltenyi, Bellicum Pharmaceuticals, and Jazz Pharmaceuticals. FB: consultant or advisory role for Bayer, Amgen, Roche, Sanofi, and EUSA Pharma; honoraria for speaking at symposia from Amgen and Jazz Pharmaceuticals; support for attending symposia from Takeda, EUSA Pharma, Shire, and Jazz Pharmaceuticals. CR: consultant or advisory role for Amgen, Bristol Myers Squibb (BMS), Celgene, Genentech, Novartis, Pfizer, and Roche. ACN: personal fees from Bayer and EUSA Pharma, outside of the submitted work. AL: nonfinancial support and ‘other’ from PharmaMar; grants and nonfinancial support from Takeda, during the conduct of the study. SJS: consultant or advisory role for Lilly outside the submitted work. CO: employee of Eisai Ltd. CH: employee of Eisai Inc. LD: employee of Eisai Inc. MC: advisory roles for AstraZeneca, Bayer, BMS, Eisai, Lilly, and Roche outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Different techniques have been developed for the remediation of Cu contaminated soils, being the phytoremediation a sustainable and environmentally friendly strategy, but its use in mine tailings is scarce. Arbuscular mycorrhizal fungi (AMF) can decrease the Cu concentration in plants by favouring the stabilization of this metal through different mechanisms such as the production of glomalin, immobilization in the fungal wall of hyphae and spores, and the storage of Cu in vacuoles. Additionally, the use of organic amendments promotes the beneficial effects produced by AMF and improves plant growth. Based on the above, the aim of this study was to determine the effect of AMF inoculation and compost application at different doses on the growth of Oenothera picensis in a Cu mine tailing. One group of plants were inoculated with Claroideoglomus claroideum (CC) and other was non-inoculated (NM). Both CC and NM were grown for two month under greenhouse conditions in pots with the Cu mine tailing, which also had increasing compost doses (0%, 2.5%, 5%, and 10%). Results showed greater biomass production of O. picensis by CC up to 2-fold compared with NM. This effect was improved by the compost addition, especially at doses of 5% and 10%. Therefore, the increase of mycorrhizal and nutritional parameters in O. picensis, and the decreasing of Cu availability in the mine tailing, promoted the production of photosynthetic pigments together with the plant growth, which is of importance to accomplish phytoremediation programs in Cu mine tailings., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Whey permeate (WP) is a lactose-rich waste effluent, generated during cheese manufacturing and further valorization steps, such as protein extraction. The production of ethanol by WP fermentation has been proposed to increase cost-competitiveness of dairy waste processing. In previous work, the Escherichia coli W strain was selected for its efficient growth in dairy waste and it was engineered to convert lactose into ethanol as the main fermentation product from WP and concentrated WP (CWP). To improve its performance, here the lactate dehydrogenase, fumarate reductase and pyruvate formate lyase fermentative routes were disrupted, obtaining new deletion strains. In test tubes, growth and fermentation profiles obtained in standard laboratory media and CWP showed large differences, and were affected by oxygen, medium and ethanologenic gene expression level. Among the tested strains, the one with triple deletion was superior in both high-oxygen and low-oxygen test tube fermentations, in terms of ethanol titer, rate and yield. The improved performance was due to a lower inhibition by medium acidification rather than an improved ethanol flux. The parent and triple deletion strains showed similar performance indexes in pH-controlled bioreactor experiments. However, the deletion strain showed lower base consumption and residual waste, in terms of both dry matter and chemical oxygen demand after distillation. It thus represents a step towards sustainable dairy wastewater valorization for bioenergy production by decreasing process operation costs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Previous studies have demonstrated the presence of Leishmania infantum amastigotes in the colonic mucosa of seropositive sick dogs. However, there are no studies that have investigated the presence of L. infantum infection in dogs diagnosed with inflammatory bowel disease (IBD). The aims of this study were: (1) to investigate retrospectively the presence of Leishmania spp. antigen by immunohistochemistry (IHC) in biopsy samples taken from the colon of dogs with IBD in an area endemic for leishmaniosis, and (2) to describe the main histopathological findings in these cases. Clinicopathological data and histopathological results were reviewed from 106 cases of canine colitis. IHC to detect Leishmania spp. antigen had been performed at the time of diagnosis in 13 cases and we performed IHC in 56 more cases. Five of the 69 cases (7.2%) were positive for Leishmania spp. antigen by IHC. Two positive biopsy samples had histiocytic inflammation and three had lymphoplasmacytic inflammation. The number of amastigotes was variable and independent of the type and grade of inflammatory infiltrate. The results suggest that Leishmania spp. infection is associated with chronic colitis in areas endemic for the infection. Therefore, Leishmania IHC should be used routinely as a diagnostic tool when evaluating colonic biopsy samples from dogs in endemic areas, to exclude or confirm an infection by this parasite in dogs with chronic colitis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A French bulldog with a previous history of leishmaniosis was presented due to respiratory distress associated with a laryngeal mass. The mass was excised and cytological and histopathological examination revealed pyogranulomatous inflammation with Leishmania spp. amastigotes. After surgery, the respiratory condition resolved; however, 3 months later the dog developed clinicopathological signs of leishmaniosis, which improved with systemic treatment. This case shows an atypical presentation of leishmaniosis with a focal tumour-like mass in the vocal folds as the only clinical sign., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mitigating the environmental effects of global population growth, climatic change and increasing socio-ecological complexity is a daunting challenge. To tackle this requires synthesis: the integration of disparate information to generate novel insights from heterogeneous, complex situations where there are diverse perspectives. Since 1995, a structured approach to inter-, multi- and trans-disciplinary(1) collaboration around big science questions has been supported through synthesis centres around the world. These centres are finding an expanding role due to ever-accumulating data and the need for more and better opportunities to develop transdisciplinary and holistic approaches to solve real-world problems. The Australian Centre for Ecological Analysis and Synthesis (ACEAS ) has been the pioneering ecosystem science synthesis centre in the Southern Hemisphere. Such centres provide analysis and synthesis opportunities for time-pressed scientists, policy-makers and managers. They provide the scientific and organisational environs for virtual and face-to-face engagement, impetus for integration, data and methodological support, and innovative ways to deliver synthesis products. We detail the contribution, role and value of synthesis using ACEAS to exemplify the capacity for synthesis centres to facilitate trans-organisational, transdisciplinary synthesis. We compare ACEAS to other international synthesis centres, and describe how it facilitated project teams and its objective of linking natural resource science to policy to management. Scientists and managers were brought together to actively collaborate in multi-institutional, cross-sectoral and transdisciplinary research on contemporary ecological problems. The teams analysed, integrated and synthesised existing data to co-develop solution-oriented publications and management recommendations that might otherwise not have been produced. We identify key outcomes of some ACEAS working groups which used synthesis to tackle important ecosystem challenges. We also examine the barriers and enablers to synthesis, so that risks can be minimised and successful outcomes maximised. We argue that synthesis centres have a crucial role in developing, communicating and using synthetic transdisciplinary research., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Intensification of the use of natural resources is a world-wide trend driven by the increasing demand for water, food, fibre, minerals and energy. These demands are the result of a rising world population, increasing wealth and greater global focus on economic growth. Land use intensification, together with climate change, is also driving intensification of the global hydrological cycle. Both processes will have major socio-economic and ecological implications for global water availability. In this paper we focus on the implications of land use intensification for the conservation and management of freshwater ecosystems using Australia as an example. We consider this in the light of intensification of the hydrologic cycle due to climate change, and associated hydrological scenarios that include the occurrence of more intense hydrological events (extreme storms, larger floods and longer droughts). We highlight the importance of managing water quality, the value of providing environmental flows within a watershed framework and the critical role that innovative science and adaptive management must play in developing proactive and robust responses to intensification. We also suggest research priorities to support improved systemic governance, including adaptation planning and management to maximise freshwater biodiversity outcomes while supporting the socio-economic objectives driving land use intensification. Further research priorities include: i) determining the relative contributions of surface water and groundwater in supporting freshwater ecosystems; ii) identifying and protecting freshwater biodiversity hotspots and refugia; iii) improving our capacity to model hydro-ecological relationships and predict ecological outcomes from land use intensification and climate change; iv) developing an understanding of long term ecosystem behaviour; and v) exploring systemic approaches to enhancing governance systems, including planning and management systems affecting freshwater outcomes. A major policy challenge will be the integration of land and water management, which increasingly are being considered within different policy frameworks., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

Background: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma., Patients and Methods: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement., Results: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions., Conclusion: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists., Clinical Trials Number: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18years, Epstein-Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5h. Mean serum creatinine levels at 1, 3 and 6months were 1.76±0.59, 1.55±0.60 and 1.49±0.60mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

CYLD is a tumor-suppressor gene mutated in the skin appendage tumors cylindromas, trichoepitheliomas, and spiradenomas. We have performed in vivo metastasis assays in nude mice and found that the loss of the deubiquitinase function of CYLD in squamous cell carcinoma (SCC) cells greatly enhances the lung metastatic capability of these cells. These metastases showed several characteristics that make them distinguishable from those carrying a functional CYLD, such as robust angiogenesis, increased expression of tumor malignancy markers of SCCs, and a decrease in the expression of the suppressor of metastasis Maspin. Restoration of Maspin expression in the epidermal SCC cells defective in CYLD deubiquitination function significantly reduces their ability to form metastases, thereby suggesting that the decrease in the levels of Maspin expression plays an important role in the acquisition of metastatic potential of these cells. In addition, we have characterized Maspin downregulation in cylindromas, trichoepitheliomas, and spiradenomas carrying functional inactivating mutations of CYLD, also providing an evidence of the correlation between impaired CYLD function and Maspin decreased expression in vivo in human tumors.

Nonmelanoma skin cancer (NMSC) is by far the most frequent type of cancer in humans. NMSC includes several types of malignancies with different clinical outcomes, the most frequent being basal and squamous cell carcinomas. We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC. Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA, either in wild-type or Ha-ras mutated backgrounds. After several weeks of treatment, mice with transposition developed more malignant tumors with decreased latency compared with control mice. Transposon/transposase animals also developed basal cell carcinomas. Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples, which may represent novel candidate cancer genes. We observed alterations in the expression levels of some of these genes in human tumors. Our results show that inactivating mutations in Notch1 and Nsd1, among others, may have an important role in skin carcinogenesis.

Soft tissue tumors in very young children pose diagnostic and therapeutic challenges. Vascular tumors are the most prevalent soft tissue neoplasms in the neonatal period. They are generally benign tumors, but may exhibit aggressive behaviour and cause life-threatening complications. Fibroblastic tumors of intermediate prognosis, more prevalent in very young children (especially infantile fibrosarcoma), are locally aggressive. Since metastases are unusual in this group of tumors, complete surgical resection is generally curative. However, these tumors often present a therapeutic challenge because of the location which makes complete surgical resection difficult. Among the malignant soft tissue tumors, rhabdomyosarcoma is most frequent. It is an aggressive high-grade tumor, with local invasiveness and a propensity to metastasize. These tumors respond to chemotherapy and radiotherapy. Neonates with rhabdomyosarcoma seem to have a worse prognosis than in older age groups. This may be a result of inappropriate dosing of chemotherapeutic agents and decreased use of radiation therapy among other factors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Worldwide, hypertensive disease of pregnancy is one of the most frequent causes of admission of obstetric patients to the ICU. Maternal mortality risk related to Hypertension during pregnancy in Latin America is significantly higher than in developed countries., Objectives: To describe the characteristics and outcomes of pregnant-postpartum patients with hypertensive disease of pregnancy admitted to ICU METHODS:, Design: Multicenter case series study., Population: pregnant-postpartum (<42days) patients with hypertensive disease of pregnancy admitted to ICU., Setting: 3 ICUs in Argentina, 2 from the Public (P1) and 1 from the Private Health Sector (P2)., Statistics: Continuous data are presented as mean±SD or median [IQR], and categorical data as number (%). Comparisons among continuous data were performed with unpaired t test or Mann-Whitney U test. Categorical variables were analyzed by Chi-square test or Fisher exact test as appropriate. A two-sided α<0.05 was considered as significant. SPSS version 15 was used., Results: One hundred and eighty four patients were included, 161(87.5%) from P1. General characteristics are shown in the Table. Gestational age was 34±5 weeks. Risk factors for preeclampsia not included in Charlson score were chronic hypertension (22;12%), Obesity (6;3%) and preeclampsia in previous pregnancy (5;3%). ICU admission was postpartum in 80%(145). Causes of admission were eclampsia (63;34%), severe preeclampsia (61;33%), HELLP (33;18%), Eclampsia-HELLP (18;10%), Chronic Hypertension (5;3%) and Gestational Hypertension (4;2%). Predictive mortality according with APACHEII was 14%. Antenatal care was present in 115/142(81%) patients; 97/124(78%) in P1 vs 18/18 (100%) in P2; p0.024. Antenatal care was appropriate in 77/108(71.3%) of patients; 59/90(65.5%) in P1 vs 18/18(100%) in P2; p0.001. Maternal deaths (6) occurred in the Public sector and none of the patients had received antenatal care. Causes of mortality were hemorrhagic stroke (3) and multiple organ dysfunction (3) Table 1., Conclusion: Most patients were from the public health sector and the majority did not have any comorbidity according with the Charlson score. Nevertheless, 18% presented risk factors for preeclampsia, not included in the mentioned score. Two-thirds of patients were admitted with eclampsia and severe preeclampsia. APACHEII overpredicted mortality. Half of deaths were related with hemorrhagic stroke, complication almost eradicated from developed countries. None of the patients who died had received antenatal care., (Copyright © 2012. Published by Elsevier B.V.)

IKKbeta is a subunit of the IkappaB kinase (IKK) complex required for NF-kappaB activation in response to pro-inflammatory signals. NF-kappaB regulates the expression of many genes involved in inflammation, immunity, and apoptosis, and also controls cell proliferation and differentiation in different tissues; however, its function in skin physiopathology remains controversial. In this study we report the alterations caused by increased IKKbeta activity in skin basal cells of transgenic mice. These animals suffered chronic inflammation with abundant macrophages and other CD45(+) infiltrating cells in the skin, which resulted in epidermal basal cell injury and degeneration of hair follicles. They showed histological features characteristic of interface dermatitis (ID). This phenotype is accompanied by an increased production of inflammatory cytokines by transgenic keratinocytes. Accordingly, transcriptome studies show upregulation of genes associated with inflammatory responses. The inflammatory phenotype observed as a consequence of IKKbeta overexpression is independent of T and B lymphocytes, as it also arises in mice lacking these cell types. In summary, our data indicate the importance of IKKbeta in the development of ID and in the homeostasis of stratified epithelia. Our results also support the idea that IKKbeta might be a valid therapeutic target for the treatment of skin inflammatory diseases.

Background: Fatal opioid overdose is a significant cause of mortality among injection drug users (IDUs)., Methods: We evaluated an overdose prevention and response training programme for IDUs run by a community-based organisation in Los Angeles, CA. During a 1-h training session participants learned skills to prevent, recognise, and respond to opioid overdoses, including: calling for emergency services, performing rescue breathing, and administering an intramuscular injection of naloxone (an opioid antagonist). Between September 2006 and January 2008, 93 IDUs were trained. Of those, 66 (71%) enrolled in the evaluation study and 47 participants (71%) completed an interview at baseline and 3-month follow-up., Results: Twenty-one percent of participants were female, 42% were white, 29% African American, and 18% Latino. Most were homeless or lived in temporary accommodation (73%). We found significant increases in knowledge about overdose, in particular about the use of naloxone. Twenty-two participants responded to 35 overdoses during the follow-up period. Twenty-six overdose victims recovered, four died, and the outcome of five cases was unknown. Response techniques included: staying with the victim (85%), administering naloxone (80%), providing rescue breathing (66%), and calling emergency services (60%). The average number of appropriate response techniques used by participants increased significantly from baseline to follow-up (p<0.05). Half (53%) of programme participants reported decreased drug use at follow-up., Conclusion: Overdose prevention and response training programmes may be associated with improved overdose response behaviour, with few adverse consequences and some unforeseen benefits, such as reductions in personal drug use., (Copyright 2009 Elsevier B.V. All rights reserved.)

Virgin olive oil is one of the essential products for the economy of Mediterranean countries. The possible residues of pesticides that can reach the oil may be a risk to public health, thus causing the prohibition of its marketing by the health authorities. This paper is a preliminary study on photochemical degradation of pesticide residues using a small-scale prototype (1L capacity). The method presents an effective alternative for the complete photodegradation or reduction of these chemicals using ultraviolet light without harming the quality parameters of the virgin olive oil. The photodegradation yields have varied within the range 7-80% depending on the time and temperature applied.

Formaldehyde is a naturally occurring biological compound that is present in tissues, cells, and bodily fluids. It is also a potent nasal irritant, a cytotoxicant at high doses, and a nasal carcinogen in rats exposed to high airborne concentrations. The normal endogenous concentration of formaldehyde in the blood is approximately 0.1 mM in rats, monkeys, and humans, and it is 2- to 4-fold higher in the liver and nasal mucosa of the rat. Inhaled formaldehyde enters the one-carbon pool, and the carbon atom is rapidly incorporated into macromolecules throughout the body. Oxidation to formate catalyzed by glutathione-dependent and -independent dehydrogenases in nasal tissues is a major route of detoxication and generally precedes incorporation. The possibility that inhaled formaldehyde might induce various forms of distant-site toxicity has been proposed, but no convincing evidence for such toxicity has been obtained in experimental studies. This review summarizes the biological evidence that pertains to the issue of leukemia induction by formaldehyde, which includes: (1) the failure of inhaled formaldehyde to increase the formaldehyde concentration in the blood of rats, monkeys, or humans exposed to concentrations of 14.4, 6, or 1.9 ppm, respectively; (2) the lack of detectable protein adducts or DNA-protein cross-links (DPX) in the bone marrow of normal rats exposed to [3H]- and [14C]formaldehyde at concentrations as high as 15 ppm; (3) the lack of detectable protein adducts or DPX in the bone marrow of glutathione-depleted (metabolically inhibited) rats exposed to [3H]- and [14C]formaldehyde at concentrations as high as 10 ppm; (4) the lack of detectable DPX in the bone marrow of Rhesus monkeys exposed to [14C]formaldehyde at concentrations as high as 6 ppm; (5) the failure of formaldehyde to induce leukemia in any of seven long-term inhalation bioassays in rats, mice, or hamsters; and (6) the failure of formaldehyde to induce chromosomal aberrations in the bone marrow of rats exposed to airborne concentrations as high as 15 ppm or of mice injected intraperitoneally with formaldehyde at doses as high as 25 mg/kg. Biological evidence that might be regarded as supporting the possibility of leukemia induction by formaldehyde includes: (1) the detection of cytogenetic abnormalities in circulating lymphocytes in seven studies of human subjects exposed to ambient concentrations in the workplace (but not in seven other studies of human subjects or in rats exposed to 15 ppm); (2) the induction of leukemia in rats in a single questionable drinking water study with formaldehyde concentrations as high as 1.5 g/L (but not in three other drinking water studies with concentrations as high as 1.9 or 5 g/L); (3) the detection of chromosomal aberrations in the bone marrow of rats exposed to very low concentrations of formaldehyde (0.4 or 1.2 ppm) (but not in another study at concentrations as high as 15 ppm); and (4) an apparent increase in the fraction of protein-associated DNA (assumed to be due to DPX) in circulating lymphocytes of humans exposed to ambient concentrations in the workplace (1-3 ppm). This evidence is regarded as inconsequential for several reasons, including lack of reproducibility, inadequate reporting of experimental methods, inconsistency with other data, or insufficient analytical sensitivity, and therefore, it provides little justification for or against the possibility that inhaled formaldehyde may be a leukemogen. In contrast to these inconclusive findings, the abundance of negative evidence mentioned above is undisputed and strongly suggests that there is no delivery of inhaled formaldehyde to distant sites. Combined with the fact that formaldehyde naturally occurs throughout the body, and that multiple inhalation bioassays have not induced leukemia in animals, the negative findings provide convincing evidence that formaldehyde is not leukemogenic.

Background: Only a few reports on the clinical features and management of childhood leiomyosarcoma are available. To contribute additional information on the management of this rare tumor, we report on a series of 16 pediatric patients treated from 1982 to 1998 by the Soft Tissue Sarcoma Italian Cooperative Group., Patients and Methods: Primary surgery was conservative in all but two patients, and consisted of biopsy--three cases, non-radical excision--four, and radical resection--nine (involving a primary re-excision in 4 of 9). In two cases secondary radical surgery was performed after primary chemotherapy. Chemotherapy was administered to 9 of 16 patients, radiotherapy to three., Results: After a median follow-up of seven years (range 3-18), the five-year event-free survival (EFS) and overall survival were 56.3% and 72.9%, respectively; 12 of 16 patients were alive (nine of them in continuos complete remission). Univariate analysis was performed to compare EFS according to different subgroups: size represented the most significant prognostic factor., Conclusions: Complete surgical resection is the mainstay of treatment for leiomyosarcoma. The role of both adjuvant chemotherapy and radiotherapy has yet to be established, and awaits cooperative multicentric studies.

Background: New criteria for classifying nasopharyngeal carcinoma were defined in the 5th edition of the American Joint Committee on Cancer (AJCC) staging manual. We investigated the clinical implications of the new system by comparing it with the 4th edition in a cohort of pediatric undifferentiated nasopharyngeal carcinoma (UNPC)., Patients and Methods: We retrospectively restaged 54 patients younger than 17 years who had biopsy-proven UNPC, treated between 1965 and 1999 in a single institution., Results: Using the 5th edition an overall downstaging of the population according to T status, N status, and stage grouping was evident along with a better correlation with likelihood of survival. The comparison between local and advanced disease according to T stage (T1+T2 vs. T3+T4) became highly significant in the new system (P = 0.0011 vs. P = 0.067 in the 4th edition)., Conclusions: As far as prognostic categories are concerned, the 5th edition of the AJCC staging manual appears to be an improvement over the previous classification, even though for pediatric patients a uniform distribution among stages cannot be observed because most children present with advanced disease. The overall downstaging should be taken into consideration for the stratification of patients in future trials.

Background: Alveolar soft part sarcoma (ASPS) is a rare malignant tumor and little is known about its clinical features and management. We report on a series of 19 pediatric patients managed over 20 years., Patients and Methods: Primary conservative surgery was performed in all patients and was radical in nine, non-radical in three; seven patients underwent biopsy alone (3 unresectable tumors, 4 metastatic disease). In two cases radical surgery was performed after primary chemotherapy. Radiotherapy was delivered to 8 patients, chemotherapy to 15., Results: After a median follow-up of 74 months, the five-year survival was 80% for the whole series, 91% for patients with localized disease, 100% for patients with tumor < or = 5 cm, and 31% for those > 5 cm; 16 of 19 patients were alive (12 of 12 with grossly-resected tumor in first continuous remission). Chemotherapy achieved two partial remission among seven evaluable patients., Conclusions: Pediatric ASPS has a more favorable prognosis than its adult counterpart. In this series, tumor size correlates with metastatic disease at onset and is the major factor influencing survival. Surgery is the mainstay of therapy. The effectiveness of adjuvant therapy remains to be established, though radiotherapy may be advisable in cases of inadequate surgery.

The oxygenated fuel additive methyl tertiary-butyl ether (MTBE) induced hepatocellular adenomas in female but not male CD-1 mice exposed to 8000 ppm; liver cancer was not induced in female or male mice exposed to 3000 or 400 ppm. Since MTBE is metabolized by cytochrome P450 to formaldehyde (HCHO), a potentially mutagenic intermediate capable of forming DNA-protein cross-links (DPX), the formation of DPX and of another HCHO derivative, RNA-formaldehyde adducts (RFA), from MTBE was investigated using freshly isolated hepatocytes from female CD-1 mice incubated with MTBE-(O-methyl-14C). DPX and RFA were detected, but the adduct yields were very small and were independent of the concentration of MTBE in the hepatocyte suspension over a wide concentration range (0.33-6.75 mM). Similar results were obtained using hepatocytes from male B6C3F1 mice and male F344 rats. Induction of cytochrome P450 by pretreatment of mice with MTBE prior to isolation of hepatocytes did not result in a measurable increase in the yields of either DPX or RFA. In contrast to the absence of concentration-dependent DPX and RFA formation from MTBE, there was a marked, concentration-dependent increase in the yields of both DPX and RFA when [14C]formaldehyde was added directly to the medium. These results suggest that the metabolism of MTBE to HCHO approaches saturation at concentrations below 0.33 mM, and that the rate of HCHO production from metabolism of MTBE is slow relative to the rate of HCHO metabolism. The lack of concentration dependence and the absence of species or sex differences in the formation of DPX and RFA from MTBE indicate that metabolism of MTBE to HCHO is not a critical component of its carcinogenic mechanism in mice.

Background: Childhood Hodgkin's disease (HD) in low-income countries has been reported to have distinct presenting features, including a high prevalence of the mixed cellularity subtype, which also seems to be associated with poorer prognosis. Further investigations are needed to evaluate these issues. Another controversial aspect of childhood HD is the use of radiotherapy (RT) in its treatment and the growing concern about its serious adverse side effects. In this paper, data on the diagnosis and outcome of children treated without RT in a low-income country (Nicaragua) are reported., Patients and Methods: Forty-eight consecutive children aged 0-15 years, diagnosed at 'La Mascota' Hospital of Managua (Nicaragua) from January 1990 to October 1995. entered this study. Follow-up was updated in May 1996. Clinical and histopathological staging was performed according to Ann Arbor and Rye criteria, respectively. Treatment consisted of COPP (six cycles) for stages I or IIA, or COPP-ABV hybrid): eight cycles for stages IIB or III, and ID cycles for stage IV. Total cumulative doses of adriamycin and bleomycin in this protocol are, respectively, 200 and 80 mg:sqm for stages II B or III and 250 and 100 mg/sqm for stage IV., Results: The median age of the 48 patients at diagnosis was seven years, and the mean age was 7.9 years (range 3-15 years). Clinical stages were IA in 5, IIA in 9, IIB in 6, IIIA in 5, IIIB in 14, and IVB in 9. Histopathologically, 25 cases presented with mixed cellularity, 15 with nodular sclerosis, 5 with lymphocytic predominance and 3 with lymphocytic depletion. Four patients did not proceed with treatment and were lost to follow-up. Two patients (stages IIIB and IVB), who never achieved complete remission (CR) during treatment, presented progressive disease at the end of the scheduled chemotherapy. The remaining 42 patients were in complete remission at the end of chemotherapy. Following discontinuation of therapy, one patient (stage IA) was lost to follow-up and two patients with stage IIIB, who were in CR after the second chemotherapy cycle, relapsed 20 and 9 months following the diagnosis. EFS at three years is 100% for the 25 patients with stages I, II, IIIA and 74.9% for the 23 patients with stages IIIB or IV., Conclusion: The presenting features found in these patients are similar to those reported from other low-income countries. In our experience, however, the high prevalence of the mixed cellularity subtype was not associated with poorer prognosis. Satisfactory results have been achieved in patients with stages I, II or IIIA HD using COPP or COPP-ABV (hybrid) regimens without RT. The treatment was also well tolerated and can thus be recommended for these patients in low-income countries, where RT facilities may be scarce or unavailable. The use of more aggressive treatment schedules and/or RT on involved fields in front-line treatment may, however, be needed for the more advanced stages IIIB or IV. Large studies with adequate follow-up are needed to evaluate whether, if RT is omitted, higher cumulative doses of more toxic drugs are required and thus compare the long-term toxic effects of different treatment modalities.

To test the hypothesis of anomalous anatomy in posterior brain regions associated with language and reading, the corpus callosum was imaged in the midsagittal plane with magnetic resonance. The areas of the anterior, middle, and posterior segments were measured in 21 dyslexic men (mean age 27 yrs, SD 6) and in 19 matched controls. As predicted, the area of the posterior third of the corpus callosum, roughly equivalent to the isthmus and splenium, was larger in dyslexic men than in controls. No differences were seen in the anterior or middle corpus callosum. The increased area of the posterior corpus callosum may reflect anatomical variation associated with deficient lateralization of function in posterior language regions of the cortex and their right-sided homologues, hypothesized to differ in patients with dyslexia.

Affective disorders are associated with maladaptive response to stressful life events. Based on the observation that a transient increase in brain polyamine metabolism is a common response to stressful stimuli, our hypothesis is that a maladaptive polyamine stress response may be involved in the pathophysiology of affective disorders. Our current research efforts, therefore, concentrate on the characterization of this PA response, and on its pharmacological regulation. The present preliminary study is the first to measure the polyamines, putrescine, spermidine, and spermine, and their metabolizing enzymes, ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine/spermine N1 acetyltransferase, in brain autopsy samples from people who suffered from depressive disorders or schizophrenia, or from those who committed suicide. The data of affected individuals did not reveal significant differences when compared to those of suicide cases, or to those of people with no known neurologic or psychiatric abnormalities. The following regional differences were observed: spermidine concentrations and ornithine decarboxylase activity were higher, but S-adenosylmethionine decarboxylase activity was lower in the hippocampus as compared to the frontal cortex. Preliminary studies with rat brain indicate that an increase in polyamine metabolizing enzyme activities occurs within several hours after death and persists for at least 48 hours. These observations, in turn, indicate that earlier autopsies are crucial for detection of changes in polyamine metabolism. We conclude that further studies to test the polyamine hypothesis are warranted.

The dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was found to be decreased in the anterior cingulate cortex of individuals with schizophrenia compared with normal controls. The finding does not appear to be solely related to the presence of antipsychotic medications, age, postmortem interval, or freezer time. No changes in norepinephrine and its metabolites were found.

We investigated dopamine transporter receptor ligand binding in the prefrontal cortex as a function of age in schizophrenic and control postmortem brains. [3H]GBR 12935 binding constants were calculated by Scatchard analysis from the autopsied brains from 29 individuals with schizophrenia, and 28 control subjects. There were wide interindividual variations in Bmax and KD that were not related to gender, age, or postmortem interval (PMI) in controls. While there were no significant associations between gender, PMI, and Bmax, or KD in individuals with schizophrenia, there was a significant negative correlation between age and Bmax (r = -.44, p = .02). The slope of the regression lines between age and Bmax for the two groups was significantly different. The results suggest a differential effect of age, or something associated with age, on [3H]GBR 12935 binding sites in the prefrontal cortex of controls and individuals with schizophrenia.

RNA isolated from frozen human postmortem brain tissue was evaluated for its utility in molecular biological studies. Samples varying in postmortem interval, delay period before freezing, and long-term freezer storage were analyzed. It was found that storage of human postmortem brain at -70 degrees C for more than 5 years may compromise its use for oligo-dT primed library construction and in vitro expression studies. Although biological competency of the messenger RNA may be affected by long-term freezer storage of human brain, enough full-length or partial transcripts remained for amplification by the polymerase chain reaction. We conclude that human postmortem brain collections will continue to be valuable resources for the study of gene expression and isolation of nucleotide sequences.

Postmortem cerebellar and frontal cortical membrane homogenates from human alcoholics, control subjects without neurological or psychiatric illnesses, and rats that chronically drank alcohol were studied to determine the binding characteristics of an imidazobenzodiazepine, [3H]Ro 15-4513. This ligand binds to classical gamma-aminobutyric acidA (GABAA)/benzodiazepine receptors, as well as to a "diazepam-insensitive" site associated with the GABAA receptor complex in the cerebellar granule cell layer. There were no differences in the density of the binding sites between alcoholics and their controls, between alcohol-drinking AA rats that had a choice between 10% alcohol or water for about 10 weeks and their controls, or between Wistar rats that had been given 20% alcohol as their only fluid for 4 months and their controls, which were pair-fed isocalorically with sucrose. The affinity for the cerebellar binding of [3H]Ro 15-4513 was higher in the alcoholics than the controls. No differences were observed in the frontocortical binding. No affinity differences were observed in the rat models. There were no differences between the groups in the characteristics of [3H]Ro 15-4513 binding to human cerebellum in the presence of micromolar diazepam, thus revealing the diazepam-insensitive binding. When this component was subtracted from the total cerebellar binding, to reveal the diazepam sensitive binding, both the KD and Bmax were lower in the alcoholic than the control group. The binding of [3H]muscimol, a GABAA agonist, tended to be higher in the frontal cortices of alcoholics; a similar trend for greater effects was observed in the alcoholics for the GABA inhibition of [3H]Ro 15-4513 binding. These results suggest that no drastic changes occur through chronic alcohol abuse in the numbers of cerebellar and frontocortical benzodiazepine receptors in humans and rodent models; however, the data indicate that the alcoholics have either acquired or innate differences in classical benzodiazepine recognition sites of the cerebellum and in the coupling of these sites to GABAA sites in the frontal cortex, without any differences in cerebellar granule cell-specific diazepam-insensitive [3H]Ro 15-4513 binding sites.

Although previous studies have reported differences in computed tomography (CT) scan attenuation values between patients with schizophrenia and controls, interpretation of these findings has been hindered by methodological shortcomings such as the failure to control for head size, scanner calibration differences, and other confounding variables. In the present study of CT attenuation values in multiple brain regions in 20 patients with chronic schizophrenia and an equal number of age- and sex-matched normal subjects we controlled for head size and normalized the attenuation values for each scan to an internal standard. No significant differences emerged between the patients with schizophrenia and the controls. However, in the controls only, the mean density of white matter in the left frontal area was significantly higher (t = -2.83, p = 0.01) than that in the right. The results, although possibly suggestive of deviant lateralization in schizophrenia, raise questions about the sensitivity and validity of regional CT attenuation values in detecting subtle anatomic abnormalities in patients with this illness.

Drugs such as phencyclidine (PCP) that interact with PCP and sigma binding sites can produce psychotomimetic effects that resemble some symptoms of schizophrenia. Therefore, it has been suggested that PCP and sigma receptors may be important in the clinical manifestations of schizophrenia. Assays of these two binding sites in human postmortem brains showed consistent significant reductions in the density of sigma, but not PCP sites, in schizophrenics as compared with age-matched and postmortem interval-matched normal and suicide controls. Reductions in the density of sigma binding sites in schizophrenia were most prominent in temporal cerebral cortex, and were accompanied by a small increase in affinity for the ligand [3H]haloperidol. These data provide the first evidence for alterations in sigma binding sites in schizophrenia, and suggest that selective sigma ligands may be useful in the treatment of the disorder.

The expression of nonphosphorylated neurofilaments (nPNFs) and phosphorylated neurofilaments (PNFs) was examined in cerebella during development of C57/Bl/6J mice prenatally exposed to ethanol. The length of nPNF immunoreactive portions of primary and secondary dendrites of Purkinje neurons was reduced during early postnatal developmental stages. This difference disappeared by 2 months of age. These results indicate a delay in the maturation of nPNFs in Purkinje neurons of ethanol-exposed mice. There also appeared to be some underdevelopment of basket cell axons in terms of PNF expression, during early postnatal stages, as compared to normal control litters. These findings may reflect a general delay in neuronal maturation after ethanol exposure. Prenatal exposure to ethanol may, therefore, have profound effects on developmental events occurring during early postnatal life. We could not, however, exclude the possibility that the disturbances in neurofilament expression were due to malnutrition in the alcohol-treated animals.