N-acetyl-L-cysteine improves the performance of chronic cyclic heat-stressed finisher broilers but has no effect on tissue glutathione levels.

1. It was hypothesised that dietary N-acetyl-L-cysteine (NAC) in feed, as a source of cysteine, could improve the performance of heat-stressed finisher broilers by fostering glutathione (GSH) synthesis. GSH is the most abundant intracellular antioxidant for which the sulphur amino acid cysteine is rate limiting for its synthesis.2. In the first experiment, four levels of NAC: 0, 500, 1000 and 2000 mg/kg were added to a diet with a suboptimal level of sulphur amino acids in the finisher phase. In the second experiment, NAC was compared to other sulphur amino acid sources at equal molar amounts of digestible sulphur amino acids. Birds were allocated to four groups: control, 2000 mg/kg NAC, 1479 mg/kg L-cystine, and 2168 mg/kg Ca-salt of 2-hydroxy-4-(methylthio)butanoic acid. A chronic cyclic heat stress model (temperature was increased to 34°C for 7 h daily) was initiated at 28 d of age.3. In the first experiment, growth performance and feed efficiency in the finisher phase were significantly improved by graded NAC. ADG was 88.9, 92.2, 93.7 and 97.7 g/d, and the feed-to-gain ratio was 2.18, 1.91, 1.85 and 1.81 for the 0, 500, 1000 and 2000 mg/kg NAC treatments, respectively. However, liver and heart GSH levels were not affected by NAC. On d 29, liver gene transcript of cystathionine-beta-synthase like was reduced by NAC, which suggested reduced trans-sulphuration activity. The second experiment showed that L-cystine and Ca-salt of 2-hydroxy-4-(methylthio) butanoic acid were more effective in improving performance than NAC.4. In conclusion, N-acetyl-L-cysteine improved dose-dependently growth and feed efficiency in heat-stressed finishing broilers. However, this was not associated with changes in tissue GSH levels, but more likely worked by sparing methionine and/or NAC's and cysteine's direct antioxidant properties.

Effects of feeding guanidinoacetic acid on oxidative status and creatine metabolism in broilers subjected to chronic cyclic heat stress in the finisher phase.

Dietary guanidinoacetic acid (GAA) has been shown to affect creatine (Cr) metabolic pathways resulting in increased cellular Cr and hitherto broiler performances. Yet, the impact of dietary GAA on improving markers of oxidative status remains equivocal. A model of chronic cyclic heat stress, known to inflict oxidative stress, was employed to test the hypothesis that GAA could modify bird's oxidative status. A total of 720-day-old male Ross 308 broilers were allocated to 3 treatments: 0, 0.6 or 1.2 g/kg GAA was added to corn-SBM diets and fed for 39 d, with 12 replicates (20 birds each) per treatment. The chronic cyclic heat stress model (34°C with 50-60% RH for 7 h daily) was applied in the finisher phase (d 25-39). Samples from 1 bird per pen were taken on d 26 (acute heat stress) and d 39 (chronic heat stress). GAA and Cr in plasma were linearly increased by feeding GAA on either sampling day, illustrating efficient absorption and methylation, respectively. Energy metabolism in breast and heart muscle was greatly supported as visible by increased Cr and phosphocreatine: ATP, thus providing higher capacity for rapid ATP generation in cells. Glycogen stores in breast muscle were linearly elevated by incremental GAA, on d 26 only. More Cr seems to be directed to heart muscle as opposed to skeletal muscle during chronic heat stress as tissue Cr was higher in heart but lower in breast muscle on d 39 as opposed to d 26. The lipid peroxidation marker malondialdehyde, and the antioxidant enzymes superoxide dismutase and glutathione peroxidase showed no alterations by dietary GAA in plasma. Opposite to that, superoxide dismutase activity in breast muscle was linearly lowered when feeding GAA (trend on d 26, effect on d 39). Significant correlations between the assessed parameters and GAA inclusion were identified on d 26 and d 39 using principal component analysis. To conclude, beneficial performance in heat-stressed broilers by GAA is associated with enhanced muscle energy metabolism which indirectly may also support tolerance against oxidative stress.

Guanidinoacetic acid supplementation improves feed conversion in broilers subjected to heat stress associated with muscle creatine loading and arginine sparing.

It was hypothesized that dietary guanidinoacetic acid (GAA), the precursor of creatine (Cr), would be beneficial to heat-stressed finisher broilers owing to improved cellular energy status and arginine sparing effects. A total of 720 one-day-old male Ross 308 broilers were allocated to 3 treatments, 0 (control), 0.6, or 1.2 g/kg of GAA added to complete corn-soybean meal diets, and were fed for 39 D, with 12 replicates (20 birds each) per treatment. A chronic cyclic heat stress model (at a temperature of 34°C and 50 to 60% relative humidity for 7 h daily) was applied in the finisher phase (day 25-39). Samples were taken on day 26 and 39 to determine thrombocyte, white blood cell, corticosterone, protein and amino acid levels in blood and Cr, phosphocreatine (PCr), and adenosine triphosphate levels in the breast muscle. Meat quality was assessed on day 40 after overnight fasting. Guanidinoacetic acid at a dose of 1.2 g/kg decreased feed-to-gain ratio compared with the control in the grower phase (1.32 vs. 1.35, respectively; P <0.05). In the finisher period, the supplementation of 1.2 g/kg of GAA reduced feed intake compared with the control (-3.3%, P <0.05), whereas both GAA supplementation levels improved feed efficiency markedly (1.76, 1.66, and 1.67 for 0 [control], 0.6, and 1.2 g/kg of GAA, respectively, P <0.05). Mortality outcomes highlight that GAA feeding improved survival during heat stress, supported by lower panting frequency (linear effect, P <0.05). Plasma arginine was higher with increase in dietary GAA concentration on day 26 (+18.3 and + 30.8% for 0.6 and 1.2 g/kg of GAA, respectively; P <0.05). This suggests enhanced availability of arginine for other metabolic purposes than de novo GAA formation. In the breast muscle, PCr (day 39, P <0.05), free Cr (day 39, P <0.05), total Cr (both days, P <0.05), and PCr-to-adenosine triphosphate ratio (day 39, P <0.05) levels were increased with higher GAA content in diet. Guanidinoacetic acid supplementation improved feed conversion and survival during chronic cyclic heat stress, which may be associated with enhanced breast muscle energy status and arginine sparing effect.

Effects of methionine and guanidinoacetic acid supplementation on performance and energy metabolites in breast muscle of male broiler chickens fed corn-soybean diets.

1. Guanidinoacetic acid (GAA) is the single endogenous precursor of creatine, which plays a critical role in energy homeostasis of cells. Since GAA is endogenously converted to creatine by methylation, it was hypothesised that the effects of dietary GAA supplementation might determine the methionine (Met) availability in corn-soybean based diets. 2. A total of 540, one-day-old male Ross 308 broilers were allocated to nine dietary treatments with six replicates (10 birds each) in a 3 × 3 factorial arrangement with three graded levels of supplementary Met (+0.4 g/kg per level), whilst cystine was equal across groups, resulting in a low, medium and high level of total sulphur amino acids, and with three levels of GAA (0, 0.6 and 1.2 g/kg). Birds were fed for 42 days. 3. Increasing levels of supplemental Met enhanced performance indices in all rearing periods, although there was no effect on feed conversion ratio in the grower or feed intake in the finisher periods. Final body weight was 8.8% and 14.6% higher in the birds fed medium and high Met diets, respectively, compared to the low Met level. Relative breast weight and protein content in muscle on d 25 linearly increased with higher levels of Met. At low and high Met levels, growth in the finisher phase was negatively affected by supplementing GAA at 1.2 g/kg. It was suggested that disturbances in methylation homeostasis and/or changes in Arg metabolism might explain these findings. At the end of the grower phase, muscle creatine content was higher when feeding GAA at 0.6 and 1.2 g/kg (4464 and 4472, respectively, vs. 4054 mg/kg fresh muscle in the control group). 4. The effects of dietary GAA supplementation were influenced by the dietary Met level only in the finisher period, which indicates the need for proper sulphur amino acid formulation in diets when feeding GAA.

Impact of a dietary challenge with peroxidized oil on the glutathione redox status and integrity of the small intestine in weaned piglets.

Glutathione (GSH) is considered to play an important role in maintaining the integrity of the small intestine. In piglets, altered mucosal GSH levels might therefore be involved in weaning-induced changes of the small intestinal morphology and barrier function. To test this hypothesis, we aimed to challenge the mucosal GSH redox status during the first 28 days after weaning, by feeding diets containing 5% fresh linseed oil (CON), or 2.5% (OF1) or 5% (OF2) peroxidized linseed oil (peroxide value 225 mEq O2/kg oil) and exploring the effects on gut integrity. Piglets were pair-fed and had a total daily feed allowance of 32 g/kg BW. A fourth treatment included animals that were fed the control diet ad libitum (ACON). Animals were sampled at days 5 and 28 post-weaning. The malondialdehyde (MDA) concentration and GSH redox status (GSH/GSSG Eh) were determined in blood, liver and small intestinal mucosa. Histomorphology of the duodenal and jejunal mucosa was determined, and Ussing chambers were used to assess fluorescein isothiocyanate dextran (FD4) and horseradish peroxidase (HRP) fluxes across the mucosa. Results show that peroxidized linseed oil imposed an oxidative challenge at day 28, but not at day 5 post-weaning. At day 28, increasing levels of dietary peroxides to pair-fed pigs linearly increased MDA levels in duodenal and jejunal mucosa. Moreover, FD4 fluxes were significantly increased in OF1 (+75%) and OF2 (+64%) in the duodenum, and HRP fluxes tended (P=0.099) to show similar differences, as compared to CON. This co-occurred with a significant 11 mV increase of the hepatic GSH/GSSG Eh, potentiated by a significantly increased GSH peroxidase activity for treatments OF1 (+47%) and OF2 (+63%) in liver as compared to CON. Furthermore; duodenal HRP flux significantly correlated with the hepatic glutathione disulphide (GSSG) level (r=0.650), as also observed in the jejunum for hepatic GSSG (r=0.627) and GSH/GSSG Eh (r=0.547). The jejunal permeability was not affected, but FD4 and HRP fluxes significantly correlated with the local GSH (r=0.619; r=0.733) and GSSG (r=0.635; r=0586) levels. Small intestinal histomorphology was not affected by dietary lipid peroxides, nor were there any correlations found with the GSH redox system. To conclude, under oxidative stress conditions, jejunal barrier function is related to the local and hepatic GSH redox system. It is suggested that the hepatic GSH system participates in the elimination of luminal peroxides, and thereby impacts on duodenal barrier function.

Inflammatory cell distribution in colon mucosa as a new tool for diagnosis of irritable bowel syndrome: A promising pilot study.

BACKGROUND: Currently, there are no histological criteria to diagnose irritable bowel syndrome (IBS). Our aims were (i) to examine the distribution of inflammatory cells in the colon of healthy and IBS subjects and (ii) to find histological diagnosis criteria for IBS. METHODS: Colonic biopsies were taken from four distinct regions of the colon from 20 controls (HC) and 11 patients with IBS (4 with constipation (IBS-C) and 7 with diarrhea (IBS-D) and embedded in paraffin. Macrophages, mast cells, eosinophils, and T lymphocytes were immunostained and positive cells counted. KEY RESULTS: In both HC and IBS patients, global cellularity decreased from the cecum to the rectum (P < .01) which is attributed to reduced number of macrophages (P < .05) and eosinophils (P < .001) but not T cells. Mast cells were reduced in IBS (P < .05) but not in HC, particularly in IBS-D (P < .05). Results showed higher number of macrophages in the left colon of IBS subjects than HC (P < .05). CONCLUSION & INFERENCES: Here we report a decreasing gradient of immune cells from the cecum to the rectum of the human colon. Although global cellularity cannot be used to distinguish between IBS and HC, closer analysis of macrophages and mast cells may be useful markers to confirm IBS histologically and to differentiate between IBS-C and IBS-D when clinical presentation alternates between constipation and diarrhoea. This pilot study remains to be confirmed with greater number of patients.

Controlled release of chlorhexidine from a mesoporous silica-containing macroporous titanium dental implant prevents microbial biofilm formation.

Roughened surfaces are increasingly being used for dental implant applications as the enlarged contact area improves bone cell anchorage, thereby facilitating osseointegration. However, the additional surface area also entails a higher risk for the development of biofilm associated infections, an etiologic factor for many dental ailments, including peri-implantitis. To overcome this problem, we designed a dental implant composed of a porous titanium-silica (Ti/SiO2) composite material and containing an internal reservoir that can be loaded with antimicrobial compounds. The composite material consists of a sol-gel derived mesoporous SiO2 diffusion barrier integrated in a macroporous Ti load-bearing structure obtained by powder metallurgical processing. The antimicrobial compounds can diffuse through the porous implant walls, thereby reducing microbial biofilm formation on the implant surface. A continuous release of µM concentrations of chlorhexidine through the Ti/SiO2 composite material was measured, without initial burst effect, over at least 10 days and using a 5 mM chlorhexidine solution in the implant reservoir. Metabolic staining, CFU counting and visualisation by scanning electron microscopy confirmed that Streptococcus mutans biofilm formation on the implant surface was almost completely prevented due to chlorhexidine release (preventive setup). Moreover, we demonstrated efficacy of released chlorhexidine against mature Streptococcus mutans biofilms (curative setup). In conclusion, we provide a proof of concept of the sustained release of chlorhexidine, one of the most widely used oral antiseptics, through the Ti/SiO2 material thereby preventing and eradicating biofilm formation on the surface of the dental implant. In principle, our flexible design allows for the use of any bioactive compound, as discussed.

Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes.

BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.

Fibroadenoma of the Breast With Xanthomatous Features: Report of a Case.

Xanthomas are common in cutaneous sites but may also be seen in unusual locations. In view of the paucity of reported cases, the occurrence of such lesions within the breast stroma would appear to be either unusual, underreported, or ignored. Indeed, most reports of the few breast xanthomas and of the even fewer xanthomatous fibroadenomas reported have appeared in the older literature. Herein, a case of fibroadenoma with multiple foci of xanthoma is reported, the literature is briefly reviewed, and the apparent difference between the previous cases and the current case is highlighted.

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

Antioxidant enzyme activities, plasma hormone levels and serum metabolites of finishing broiler chickens reared under high ambient temperature and fed lemon and orange peel extracts and Curcuma xanthorrhiza essential oil.

The negative effects of high ambient temperature during some months of the year on poultry production have been of great concern in many countries. Dietary modifications are among the most practical ways to alleviate the effects of high temperature. Possible effects of dietary supplementation with 200 or 400 mg/kg feed of lemon peel extract (LPE), orange peel extract (OPE) and Curcuma xanthorrhiza essential oil (CXEO) under hot conditions (34 °C with 50% relative humidity for 5 h daily starting from day 28 until day 38 of age) on blood antioxidant enzyme activities, biochemical parameters and antibody titres of broiler chickens were investigated. All extracts are rich in phenolic compounds and highly available. Compared to control, supplementation with OPE at 400 mg/kg and CXEO significantly increased erythrocyte glutathione peroxidase and superoxide dismutase activity, plasma growth hormone concentrations and serum phosphorus, total protein and chloride concentrations and decreased serum low-density lipoprotein and cholesterol concentrations in chickens at 38 days of age. Regarding antibody titres, CXEO supplementation at 400 mg/kg caused a significant increase in bronchitis antibody titres. Supplementation with LPE and OPE gave more inconsistent results. Most interesting, 400 mg/kg LPE significantly increased 3,5,3'-triiodothyronine and GH concentration as compared to the control. In conclusion, the herbal extracts tested in this study, in particular CXEO at 400 mg/kg, may relieve some of the changes in blood composition induced by increased ambient temperatures.

Gene expression of heat shock protein 70 and antioxidant enzymes, oxidative status, and meat oxidative stability of cyclically heat-challenged finishing broilers fed Origanum compactum and Curcuma xanthorrhiza essential oils.

Heat stress in poultry is a serious problem in many countries and has been associated with oxidative stress. Hence, nutritional interventions with antioxidants might be beneficial. Therefore, the effects of dietary Curcuma xanthorrhiza (CX) and Origanum compactum (OC) essential oils on mRNA levels of heat shock protein 70 and antioxidant enzymes, oxidative status, and meat oxidative stability of heat-challenged broilers were studied. Starting on d 25 of age, a control diet and 4 diets containing 200 or 400 mg/kg feed of CX or OC (CX200, CX400, OC200, OC400 diets) were fed to 3 pen replicates of 20 Ross 308 chickens each. From d 28 of age on, the temperature was increased from 22 to 34°C with 50% RH for 5 h daily during 2 wk. Dietary CX or OC did not affect zootechnical performance. Feeding CX400 and both levels of OC increased the a* value in stored breast meat (P < 0.05), and OC diets tended to decrease the thiobarbituric acid reactive substances values in fresh breast meat (P = 0.061). Compared with control, at d 31, feeding CX400 and OC400 reduced mRNA levels of heat shock protein 70 and increased mRNA levels of catalase in kidney and liver (P < 0.05). The mRNA levels of superoxide dismutase were increased at d 31 on the OC400 diet in kidney and on the CX400 diet in heart (P < 0.05). In heart, at d 31, both dietary levels of CX and OC200 resulted in higher glutathione peroxidase activity (P < 0.05). Feeding CX400 increased superoxide dismutase activity in liver, kidney, and heart at d 31 (P < 0.05). Catalase activity was increased in the CX200 and OC400 groups at d 42 (P < 0.05). Feeding CX at both levels and OC200 decreased plasma malondialdehyde concentrations at d 42 (P < 0.05). In conclusion, dietary essential oils rich in simple phenolic compounds offer potential for improving the antioxidant defense against heat stress-induced changes.

Duplex ultrasound, clinical score, thrombotic risk, and D-dimer testing for evidence based diagnosis and management of deep vein thrombosis and alternative diagnoses in the primary care setting and outpatient ward.

Deep vein thrombosis (DVT) has an annual incidence of 0.2% in the urban population. First episodes of calf vein thrombosis (CVT) and proximal DVT are frequently elicited by risk factors, including varicose veins, cancer, pregnancy/postpartum, oral contraceptives below the age of 50 years, immobility or surgery. Leg pain and tenderness in the calf and popliteal fossa on physical examination may result from other conditions than DVT labeled as alternative diagnosis (AD) Congenital venous thrombophilia is present in every third first DVT, increased FVIII in every fourth first DVT, and FV Leiden/FII mutation in 40% of women on oral anticonceptive pill before reaching the menopause. Routine thrombophilia testing for FV Leiden/prothrombin mutation and FVIII as main risk factor for venous thrombosis is recommended. Primary superficial venous thrombosis (SVT) and DVT patients with a autosomal dominant family history of DVT are candidates for thrombophilia testing for congenital AT, PC and PS deficiency. The requirement for a safe diagnostic strategy of CVT and DVT should be based on an objective post-test incidence of venous thromboembolism (VTE) of less than 0.1% with a negative predictive value for exclusion of DVT of 99.9% during 3 months follow-up. Modification of the Wells score by elimination of the "minus 2 points" for AD is mandatory and will improve the diagnostic accuracy of CVT/DVT suspicion in the primary care setting and outpatient ward. The sequential use of complete DUS, ELISA D-dimer testing and modified clinical Wells' score assessment is safe and effective for the exclusion and diagnosis of CVT, DVT and AD. About 10% to 20% of patients with DVT develop overt post-thrombotic syndrome (PTS) at one year post-DVT, and both PTS and DVT recurrences further increase to about 30% during long-term follow-up. Objective risk stratification of PTS complications using DUS for recanalization and reflux and D-dimer testing will become an integral part in routine clinical practice to assess the optimal duration of wearing medical elastic stockings and anticoagulation for the prevention DVT recurrence as the best option to reduce the incidence and costs of suffering from irreversible PTS.

CXCR7-mediated progression of osteosarcoma in the lungs.

BACKGROUND: Osteosarcoma (OS) is the most frequent primary malignant bone tumour in children and adolescents with a high propensity for lung metastasis. Chemokines and chemokine receptors have been described to have an important role in many malignancies including OS. The aim of this study was to investigate the expression of CXCR7 receptor in OS tissues and its role in the progression of the disease in the lungs. METHODS: Immunohistochemistry was used to study CXCR7 expression in primary tumours and metastatic tissues from patients with OS. Its contribution to tumour expansion in the lungs has been also assessed using animal models and synthetic-specific CXCR7 ligands. RESULTS: CXCR7 was expressed on human primary bone tumours and on lung metastases. Its expression was predominantly located on tumour-associated blood vessels. Mice challenged with OS cells and systematically treated with synthetic CXCR7 ligands presented a significant reduction of lung nodules compared with untreated mice. CONCLUSION: This study shows that CXCR7 has a critical role in OS progression in the lungs, where are expressed CXCR7 ligands, especially CXCL12. Moreover, we highlight that synthetic CXCR7 ligands could represent a powerful therapeutic tool to impede lung OS progression.

CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver.

BACKGROUND: Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Chemokine-receptor pairs have a critical role in determining the metastatic progression of tumours. Our hypothesis was that disruption of CXCR7/CXCR7 ligands axis could lead to a decrease in CRC metastases. METHODS: Primary tumours and metastatic tissues from patients with CRC were tested for the expression of CXCR7 and its ligands. Relevance of CXCR7/CXCR7 ligands for CRC metastasis was then investigated in mice using small pharmacological CXCR7 antagonists and CRC cell lines of human and murine origins, which - injected into mice - enable the development of lung and liver metastases. RESULTS: Following injection of CRC cells, mice treated daily with CXCR7 antagonists exhibited a significant reduction in lung metastases. However, CXCR7 antagonists failed to reduce the extent of liver metastasis. Moreover, there were subtle differences in the expression of CXCR7 and its ligands between lung and liver metastases. CONCLUSION: Our study suggests that the activation of CXCR7 on tumour blood vessels by its ligands may facilitate the progression of CRC within lung but not within liver. Moreover, we provide evidence that targeting the CXCR7 axis may be beneficial to limit metastasis from colon cancer within the lungs.

Changes in the pig small intestinal mucosal glutathione kinetics after weaning.

Glutathione (GSH) serves as a major endogenous antioxidant and its kinetics have been poorly described in the weaned pig. This study was to assess the effect of birth weight, sex, and days postweaning on the small intestine (SI) mucosal GSH kinetics. At weaning (18.8 ± 0.44 d) 34 pairs of intrauterine growth restricted (IUGR) and normal birth weight sex-matched littermates were selected and fed a starter diet ad libitum until 1 h before sampling at 0, 2, 5, 12 and 28 d postweaning. Mucosa was collected from 2 SI sites, at 5% and at 75% of total length, to determine GSH and glutathione disulfide (GSSG), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), and plasm GSH-Px and MDA. At both 5 and 75% of total length, the GSH-Px activity and GSH concentrations increased gradually with increasing days postweaning to peak at day 12 (P < 0.05). The GSH-Px activity and GSH concentrations at 5% of SI length were consistently higher as compared to 75% of SI length (e.g., at day 12, 43.2 and 28.9 units/mg protein and 21.5 and 15.4 µmol/g protein, respectively). The GSSG:GSH ratio at 5% of total length was 2-fold higher at day 5 compared to all other days (P < 0.05), possibly indicating that the mucosal redox balance was disturbed in that time window. The higher GSH-Px activity, GSH content, and GSSG:GSH ratio in the proximal SI might illustrate the higher need for antioxidant action at that site. Plasma MDA and GSH-Px activity followed a comparable pattern as in the small intestine.

Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study.

AIMS: Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification. METHODS: A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival. RESULTS: The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 ± 0.4 in PPTID grade II, 11.2 ± 2.0 in PPTID grade III, 36.4 ± 6.2 in PB; P < 0.0001). However, there was no statistically significant difference in either overall or disease-free survival evaluated by the Kaplan-Meier method for patients with different grade tumours or Ki67 LI, possibly due to the different clinical management of patients in different centres. CONCLUSIONS: The Ki67 LI may be a useful additional tool for grading PPTs, more particularly in small tumour samples.

RET gene mutations are not involved in the origin of human testicular seminoma.

Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET.