Salvatore Florio

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma.Patients and MethodsThirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m2 followed by weekly infusions at 250 mg/m2. Patients were followed for toxicity, treatment response, and survival.ResultsTreatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively.ConclusionAlthough well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Ochratoxin A (OTA) is a powerful mycotoxin found in various foods and feedstuff, responsible for subchronic and chronic toxicity, such as nephrotoxicity, hepatotoxicity, teratogenicity, and immunotoxicity to both humans and several animal species. The severity of the liver damage caused depends on both dose and duration of exposure. Several studies have suggested that oxidative stress might contribute to increasing the hepatotoxicity of OTA, and several antioxidants, including curcumin (CURC), have been tested to counteract the toxic hepatic action of OTA in various classes of animals. Therefore, the present study was designed to evaluate the protective effect of CURC, a bioactive compound with different therapeutic properties on hepatic injuries caused by OTA in rat animal models. CURC effects were examined in Sprague Dawley rats treated with CURC (100 mg/kg), alone or in combination with OTA (0.5 mg/kg), by gavage daily for 14 days. At the end of the experiment, rats treated with OTA showed alterations in biochemical parameters and oxidative stress in the liver. CURC dosing significantly attenuated oxidative stress and lipid peroxidation versus the OTA group. Furthermore, liver histological tests showed that CURC reduced the multifocal lymphoplasmacellular hepatitis, the periportal fibrosis, and the necrosis observed in the OTA group. This study provides evidence that CURC can preserve OTA-induced oxidative damage in the liver of rats.

Abstract Imatinib (IM) is considered the gold standard for chronic myeloid leukemia (CML) treatment, although resistance is emerging as a significant problem. The proinflammatory cytokines interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) play an important role in cell proliferation, survival, and resistance to glucocorticoid‐mediated cell death. Several transcription factors such as NF‐KB and AP‐1 are activated in response to physiopathological increases and modulation of intracellular calcium levels. Our previous study demonstrated that lymphocytes from CML patients showed dysregulated calcium homeostasis and oxidative stress. Alteration in ionized calcium concentration in the cytosol has been implicated in the initiation of secretion, contraction, and cell proliferation. In this study, we hypothesized that IL‐6, IL‐8, NF‐kB, AP‐1, and intracellular calcium may be used as selective and prognostic factors to address the follow‐up in CML patients treated with imatinib. Our results demonstrated a significant down‐regulation in IL‐6 and IL‐8 release as well as NF‐kB and AP‐1 activation in lymphomonocytes from Imatinib‐treated patients, compared to samples from untreated patients. In parallel, IM treatment, in vivo and in vitro, were able to modulate the intracellular calcium concentration of peripheral blood mononuclear cells of CML patients by acting at the level of InsP 3 receptor in the endoplasmic reticulum and at the level of the purinergic receptors on plasma membrane. The results of this study show that measurements of NF‐kB, AP‐1, IL‐6, IL‐8, and intracellular calcium in CML patients treated with Imatinib may give important information to the hematologist on diagnostic criteria and are highly predictive in patients with newly diagnosed CML. J. Cell. Physiol. 227: 2798–2803, 2012. © 2011 Wiley Periodicals, Inc.

Plural logic is widely assumed to have two important virtues: ontological innocence and determinacy. It is claimed to be innocent in the sense that it incurs no ontological commitments beyond those already incurred by the first‐order quantifiers. It is claimed to be determinate in the sense that it is immune to the threat of non‐standard (Henkin) interpretations that confronts higher‐order logics on their more traditional, set‐based semantics. We challenge both claims. Our challenge is based on a Henkin‐style semantics for plural logic that does not resort to sets or set‐like objects to interpret plural variables, but adopts the view that a plural variable has many objects as its values. Using this semantics, we also articulate a generalized notion of ontological commitment which enables us to develop some ideas of earlier critics of the alleged ontological innocence of plural logic.

Ochratoxin A (OTA) is a powerful nephrotoxin and the severity of its damage to kidneys depends on both the dose and duration of exposure. According to the scientific data currently available, the mechanism of action still is not completely clarified, but it is supposed that oxidative stress is responsible for OTA-induced nephrotoxicity. Bioactive compound use has emerged as a potential approach to reduce chronic renal failure. Therefore, curcumin (CURC), due to its therapeutic effects, has been chosen for our study to reduce the toxic renal effects induced by OTA. CURC effects are examined in Sprague Dawley rats treated with CURC (100 mg/kg), alone or in combination with OTA (0.5 mg/kg), by gavage daily for 14 days. The end result of the experiment finds rats treated with OTA show alterations in biochemical and oxidative stress parameters in the kidney, related to a decrease in the Glomerular Filtration Rate (GFR). Conversely, the administration of CURC attenuates oxidative stress and prevents glomerular hyperfiltration versus the OTA group. Furthermore, kidney histological tests show a reduction in glomerular and tubular damage, inflammation and tubulointerstitial fibrosis. This study shows that CURC can mitigate OTA-induced oxidative damage in the kidneys of rats.

Ochratoxin A (OTA) is a fungal toxin of critical concern for food safety both for human health and several animal species, also representing a cancer threat to humans. Curcumin (CURC) is a natural polyphenol that has anti-apoptotic, anti-inflammatory, and antioxidant effects. The aim of this study was to investigate the cytoprotective effect of CURC against OTA-induced nephrotoxicity and hepatotoxicity through the study of the nitrosative stress, pro-inflammatory cytokines, and deoxyribonucleic acid (DNA) damage. Sprague Dawley rats were daily treated with CURC (100 mg/kg b.w.), OTA (0.5 mg/kg b.w), or CURC with OTA by oral gavage for 14 days. Our results demonstrated that OTA exposure was associated with significant increase of pro-inflammatory and DNA oxidative-damage biomarkers. Moreover, OTA induced the inducible nitric oxide synthase, (iNOS) resulting in increased nitric oxide (NO) levels both in kidney and liver. The co-treatment OTA + CURC counteracted the harmful effects of chronic OTA treatment by regulating inflammation, reducing NO levels and oxidative DNA damage in kidney and liver tissues. Histology revealed that OTA + CURC treatment determinates mainly an Iba1+ macrophagic infiltration with fewer CD3+ T-lymphocytes in the tissues. In conclusion, we evidenced that CURC exerted cytoprotective and antioxidant activities against OTA-induced toxicity in rats.

Abstract Plural logic has become a well-established subject, especially in philosophical logic. This book explores its broader significance for philosophy, logic, and linguistics. What can plural logic do for us? Are the bold claims made on its behalf correct? After introducing plural logic and its main applications, the book provides a systematic analysis of the relation between this logic and other theoretical frameworks such as set theory, mereology, higher-order logic, and modal logic. The applications of plural logic rely on two assumptions, namely that this logic is ontologically innocent and has great expressive power. These assumptions are shown to be problematic. The result is a more nuanced picture of plural logic’s applications than has been given so far. Questions about the correct logic of plurals play a central role in the last part of the book, where traditional plural logic is rejected in favor of a “critical” alternative. The most striking feature of this alternative is that there is no universal plurality. This leads to a novel approach to the relation between the many and the one. In particular, critical plural logic paves the way for an account of sets capable of solving the set-theoretic paradoxes.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by the fungi of the Fusarium genera, and is a contaminant of cereals and plant products. ZEN and its metabolites are considered endocrine disruptors, and could have various toxic effects on animals and humans. In recent years, there has been a significant demographic increase in wild boar (Sus scrofa) in many mountainous and hilly areas of Italy, including the Campania region, mainly due to global climate change. The wild boar can be defined as a generalist and omnivorous species capable of varying its diet; therefore, it can play a role as an environmental bioindicator towards contaminants such as mycotoxins. This study was conducted to evaluate, for the first time, the concentrations of ZEN and its metabolites in the liver, kidney, and muscle of 82 wild boars shot in their habitat by hunters with hunting permits in different localities of Avellino province (Campania region, Southern Italy) from 2021 to 2022. The samples were collected and analyzed with an SPE clean-up and high-pressure liquid chromatography method with fluorescence detection. The results indicated that ZEN and α-Zearalenol were present in most of the samples, suggesting that a plan to monitor these mycoestrogens is essential to achieve the goals of “One Health”.

Cyclosporine A (CsA) is the first-line immunosuppressant used in transplant patients and in auto- immune diseases. Nephrotoxicity is the major limitation of CsA use. Although the mechanisms of nephrotoxicity have not been completely defined, some evidence suggests that reactive oxygen species (ROS) play a causal role. The present study was designed to investigate in vivo effects of hydroxytyrosol (DOPET), a natural olive oil antioxidant, on oxidative stress, renal histology and haemodynamic alterations induced in rats by CsA treatment.Adult Sprague-Dawley rats were treated i.p. with CsA (15 mg/kg) alone or in combination with DOPET (20 mg/kg) for 3 weeks. At the end of the treatment, superoxide concentration within the cells of the abdominal aorta and renal artery was quantified from the oxidation of dihydroethidium (DHE) using fluorescence microscopic imaging analysis. In kidney tissues, lipid peroxidation was measured by thiobarbituric acid-reacting substances (TBARS) assay, glutathione level was assessed enzymatically and the expression of haem oxygenase-1 (HO-1) gene was evaluated by semiquantitative RT-PCR. Renal morphology was studied by classical histological techniques, while the glomerular filtration rate (GFR) was estimated by inulin clearance. Systemic blood pressure was monitored by the tail method and through the catheterization of the carotid artery.CsA administration increased superoxide concentration both in the aorta and in the renal artery, while DOPET completely prevented this effect. Higher levels of TBARS, a significant decrease in GSH and an upregulation of HO-1 mRNA were observed in the kidneys of CsA-treated rats. DOPET treatment reversed quantitatively these effects. However, CsA-dependent changes in renal histology were only partially reversed by DOPET. Finally, CsA induced a severe reduction in GFR and a significant increase in both systolic and diastolic blood pressure; the DOPET treatment had no significant effect on these haemodynamic alterations.The reported data indicate that effective DOPET protection from CsA-induced oxidative stress is associated with a mild effect on histological damages and does not affect the altered glomerular function and the hypertension, thus indicating that kidney injury by CsA is only in part dependent on oxidative stress.

Abstract Semantic interpretations of both natural and formal languages are usually taken to involve the specification of a domain of entities with respect to which the sentences of the language are to be evaluated. A question that has received much attention of late is whether there is unrestricted quantification, quantification over a domain comprising absolutely everything there is. Is there a discourse or inquiry that has absolute generality? After framing the debate, this article provides an overview of the main arguments for and against the possibility of unrestricted quantification, highlighting some of the broader implications of the debate.

ABSTRACT Cyclosporine A (CsA) is a powerful immunosuppressive drug used to prevent allograft rejection after organ transplantation as well as in human and veterinary medicine. Unfortunately, its use is hampered by its nephrotoxic effects. The mechanisms of CsA‐induced hypertension and nephrotoxicity are not clear, but several studies suggest the possible involvement of free radicals. In this review we have summarized the effect of some antioxidants that we have used in the recent years, in combination with CsA, to better understand the exact mechanism of action of CsA and to try to open new perspectives in the treatment of CsA nephrotoxicity. J. Cell. Biochem. 116: 364–369, 2015. © 2014 Wiley Periodicals, Inc.

Abstract In this work, we investigated the effects of red orange and lemon extract (RLE) on ochratoxin A (OTA)‐induced nephrotoxicity. In particular, we analyzed the change in renal function and oxidative stress in Sprague–Dawley rats treated with OTA (0.5 mg/kg body weight, b.w.) and with RLE (90 mg/kg b.w.) by oral administration. After OTA treatment, we found alterations of biochemical and oxidative stress parameters in the kidney, related to a severe decrease of glomerular filtration rate. The RLE treatment normalized the activity of antioxidant enzymes and prevented the glomerular hyperfiltration. Histopathological examinations revealed glomerular damages and kidney cortex fibrosis in OTA‐rats, while we observed less severe fibrosis in OTA plus RLE group. Then, we demonstrated that oxidative stress could be the cause of OTA renal injury and that RLE reduces this effect.

The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to a variety of cultured cells may alter their ability to proliferate and die. In a previous study we demonstrated that TCDD induced proliferation in Madin-Darby Bovine Kidney (MDBK) cells where no signs of apoptosis were observed, but herein, analysis of MDBK cell morphology, in a large number of exposed cells, revealed some alterations, as expanded cytoplasm, an increase of intercellular spaces and many pyknotic nuclei. Hence, the aim of the current study was to elucidate the influences of dioxin on cell proliferation and cell death. We found that dioxin increased proliferation, as well as, activated cell death with autophagy, as we detected by increased amount of LC3-II, an autophagosome marker. Furthermore, formation of acidic vesicular organelles was observed by fluorescence microscopy following staining with the lysosomotropic agent acridine orange. These results were accompanied by down-regulation of telomerase activity, bTERT and c-Myc. Key tumor-suppressor protein p53 and expression of cell cycle inhibitor p21Waf1/Cip1 were activated after TCDD exposure. These changes occurred with activation of ATM phosphorylation in the presence of a decrease in Mdm2 protein levels. Taken together, these results support the idea that TCDD in MDBK cells, may exert its action, in part, by enhancing cell proliferation, but also by modulating the incidence of induced cell death with autophagy.

ABSTRACT Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species (ROS) and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O 2 − ) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine‐induced adverse effect. In this study, we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate (GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O 2 − concentration, and on nitric oxide (NO) production. We have demonstrated that CsA administration increases superoxide concentration in the aorta, decreases the NO concentration, reduces GFR and the Jv in PT, and induces a significant increase in BP. Moreover, we have shown that Apocynin treatment restores these hemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and BP from toxic effects induced by CsA through the inhibition of NADPH oxidase activity. J. Cell. Biochem. 116: 1848–1856, 2015. © 2015 Wiley Periodicals, Inc.

Imatinib induces a complete cytogenetic regression in a large percentage of patients affected by chronic myeloid leukemia (CML) until mutations in the kinase domain of BCR-ABL appear. Alternative strategies for CML patients include the inhibition of phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, which is constitutively activated in leukemia cells and seems important for the regulation of cell proliferation, viability, and autophagy. In this study, we verified the effect of imatinib mesylate (IM), alone or in association with LY294002 (LY) (a specific PI3K protein tyrosine kinase inhibitor) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) (a Src tyrosine kinase inhibitor), on viability, intracellular calcium mobilization, apoptosis, and autophagy, in order to verify possible mechanisms of interaction. Our data demonstrated that PP1 and LY interact synergistically with IM by inducing apoptosis and autophagy in Bcr/Abl+ leukemia cells and this mechanism is related to the stress of the endoplasmic reticulum (ER). Our findings suggest a reasonable relationship between apoptotic and autophagic activity of tyrosine kinase inhibitors (TKIs) and the functionality of smooth ER Ca (2+)-ATPase and inositol triphosphate receptors, independently of intracellular calcium levels. Therapeutic strategies combining imatinib with PI3K and/or Src kinase inhibitors warrant further investigations in Bcr/Abl+ malignancies, particularly in the cases of imatinib mesylate-resistant disease.

Abstract Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder caused by the oncogenic activity of the Bcr‐Abl protein, a deregulated tyrosine kinase. Calcium may act directly on cellular enzymes and in conjunction with other cellular metabolites, such as cyclic nucleotides, to regulate cell functions. Alteration in the ionized calcium concentration in the cytosol has been implicated in the initiation of secretion, contraction, and cell proliferation as well as the production of reactive oxygen species (ROS) has been correlates with normal cell proliferation through activation of growth‐related signaling pathways. In this study we evaluated in peripheral blood leukocytes from CML patients the role of the balance between intracellular calcium and oxidative stress in CML disease in order to identify possible therapeutic targets in patients affected by this pathology. Our results demonstrated that peripheral blood mononuclear cells derived from CML patients displayed decreased intracellular calcium [Ca 2+ ] i fluxes both after InsP 3 as well as ATP and ionomycin (IONO) administration. CML cells showed lower levels of superoxide dismutase (SOD) activity and significantly higher malondialdehyde levels (MDA) than peripheral blood mononuclear cells derived from control patients. Finally we showed that resveratrol is able to down‐regulate InsP3 and ATP effects on intracellular calcium [Ca 2+ ] i fluxes as well as the effects of ATP and IONO on oxidative stress in CML cells. J. Cell. Physiol. 224: 443–453, 2010. © 2010 Wiley‐Liss, Inc.

A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)3 binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UV-melting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment.

Ochratoxin A (OTA) is a natural mycotoxin, involved in the development of important human and animal diseases. In this work we have studied the role of oxidative stress in the development of OTA nephrotoxicity and the effect of a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) to prevent kidney damage induced by OTA. Blood pressure, glomerular filtration rate and renal histology were analyzed in control rats and in OTA treated rats. In addition, lipid peroxidation, catalase and superoxide dismutase productions were measured. Our data showed that animals treated with OTA presented hypertension and reduction of glomerular filtration rate (GFR). These effects are most probably related to an increase in the reactive oxygen species (ROS) productions. In fact, we have shown that treatment with rMnSOD restored the levels of blood pressure and GFR simultaneously. Moreover, we have noted that OTA induced alteration on glomerular and tubular degeneration and interstitial infiltrates and that use of rMnSOD combined with OTA prevent this renal histological damage confirming the potential therapeutic role in the treatment of rMnSOD OTA nephrotoxicity.

Zearalenone (ZEN) is a mycotoxin produced by fungi belonging to the genera Fusarium spp. and commonly found in feed and food. It is frequently related to reproductive disorders in farm animals and, occasionally, to hyperestrogenic syndromes in humans. Nowadays, knowledge about ZEN effects on wild boars (Sus scrofa) is extremely scarce, despite the fact that they represent one of the most hunted game species in Italy. The aim of this study was to investigate how ZEN affects the liver, kidney, and muscle oxidative status and morphology of wild boars hunted in various locations throughout the province of Avellino, Campania Region, Southern Italy, during the 2021-2022 hunting season. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, as well as the malondialdehyde (MDA) levels, were assessed by colorimetric assays; tissue morphology was evaluated by hematoxylin-eosin and Masson's stains. Our data showed that ZEN contamination might result in oxidative stress (OS) and some histopathological alterations in wild boars' livers and kidneys rather than in muscles, emphasizing the importance of developing a wildlife monitoring and management strategy for dealing not only with the problem of ZEN but the surveillance of mycotoxins in general.

Cyclosporine A (CsA) is one of the most frequently used anticalcineurinic drugs for preventing graft rejection and autoimmune disease. Its use is hampered by nephrotoxic effects, namely an impairment of the glomerular filtration rate (GFR) and hypertension. Evidence suggests that reactive oxygen species (ROS) play a causal role in the nephrotoxicity. The present study aims to investigate in vivo the effects of a new recombinant mitochondrial manganese-containing superoxide dismutase (rMnSOD), a strong antioxidant, on the CsA-induced nephotoxicity.Rats were treated with CsA (25 mg/kg/day) alone or in combination with rMnSOD (10 µg/kg/day) for 7 days. At the end of the treatment, GFR was estimated by inulin clearance (mL/min/100 g b.w.) and the mean arterial pressure (MAP) was recorded through a catheter inserted in the carotid artery. Superoxide concentration within the cells of the abdominal aorta was quantified from the oxidation of dihydroethidium (DHE). In kidney tissues, ROS levels were measured by the 2'7' dichloroflurescin diacetate assay. Renal morphology was examined at the histochemistry level.CsA-treated rats showed a severe decrease in GFR (0.34 ± 0.17 versus 0.94 ± 0.10 in control, P < 0.001) which was prevented by rMnSOD co-administration (0.77 ± 0.10). CsA-injected animals presented with higher blood pressure which was unaffected by rMnSOD. ROS levels both in the aorta and in renal tissue were significantly increased by CsA treatment, and normalized by the co-administration with rMnSOD. This effect was, partly, paralleled by the recovery from CsA-induced morphological lesions.Administration of rMnSOD prevents CsA-mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS.

In light of the close connection between the ontological hierarchy of set theory and the ideological hierarchy of type theory, Øystein Linnebo and Agustín Rayo have recently offered an argument in favour of the view that the set-theoretic universe is open-ended.In this paper, we argue that, since the connection between the two hierarchies is indeed tight, any philosophical conclusions cut both ways.One should either hold that both the ontological hierarchy and the ideological hierarchy are open-ended, or that neither is.If there is reason to accept the view that the set-theoretic universe is open-ended, that will be because such a view is the most compelling one to adopt on the purely ontological front.

To overcome the drug resistance phenomenon induced by Imatibib (IM), in clinical practice, are often used second generation of tyrosine kinase inhibitors as Nilotinib (NIL); a such potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS), a inhibitor of BCR/ABL kinase, and inhibitor SrC family kinase. In this study we evaluated the in vivo effect of DAS, NIL, and IM on intracellular calcium concentration, oxidative stress, and apoptosis in peripheral blood leukocytes of 45 newly diagnosed patients with chronic myeloid leukaemia (CML‐PBM). Our data demonstrated that treatment with DAS and NIL showed an higher modulating potential than IM on intracellular calcium concentration by inhibiting the thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) inhibitor, and Lithium (Li) an inositol 1,4,5‐triphosphate (InsP3) receptor inhibitor activities. Moreover our data demonstrated that NIL and DAS have significantly increased apoptosis more than IM by involving both intracellular calcium signaling as well as oxidative stress. The acquisition of the oxidative stress and calcium channels receptors values data could help the hematologist to modulate and improve the treatment of chronic myeloid leukaemia (CML) pathology. J. Cell. Physiol. 231: 680–687, 2016. © 2015 Wiley Periodicals, Inc.

Ochratoxin A (OTA), is a natural contaminant of the food chain worldwide involved in the development of different type of cancers in animals and humans. Several studies suggested that oxidative damage might contribute to increase the cytotoxicity and carcinogenicity capabilities of OTA. The aim of this study was to evaluate the possible protective effect of δ-tocotrienol (Delta), a natural form of vitamin E, against OTA-induced nephrotoxicity. Male Sprague-Dawley rats were treated with OTA and/or Delta by gavage for 14 days. Our results shown that OTA treatment induced the increase of reactive oxigen species production correlated to a strong reduction of Glomerular Filtration Rate (GFR) and absoluted fluid reabsorption (Jv) with conseguent significant increase in blood pressure. Consistent, we noted in the kidney of rats treated with OTA, an increase in malondialdheyde and dihydroethidium production and a reduction of the activity of the catalase, superoxide dismutase, and glutathione peroxidase. Conversly, in the rat group subjected to the concomitant treatment OTA plus Delta, we observed the restored effect, compared the OTA treatment group, on blood pressure, GFR, Jv, and all activities of renal antioxidant enzymes. Finally, as far as concern the tissue damage induced by OTA and measured evaluating fibronectin protein levels, we observed that in OTA plus Delta group this effect is not restored. Our findings releval that a mechanism underlying the renal toxicity induced by OTA is the oxidative stress and provide a new rationale to use a Delta in order to protect, at least in part, against OTA-induced nephrotoxicity.

Sentences that exhibit sensitivity to order (e.g. John and Mary arrived at school in that order and Mary and John arrived at school in that order) present a challenge for the standard formulation of plural logic. In response, some authors have advocated new versions of plural logic based on fine-grained notions of plural reference, such as serial reference [Hewitt 2012] and articulated reference [Ben-Yami 2013]. The aim of this article is to show that sensitivity to order should be accounted for without altering the standard formulation of plural logic. In particular, sensitivity to order does not call for a fine-grained notion of plural reference. We point out that the phenomenon in question is quite broad and that current proposals are not equipped to deal with the full range of cases in which order plays a role. Then we develop an alternative and unified account, which locates the phenomenon not in the way in which plural terms can refer, but in the meaning of special expressions such as in that order and respectively.

© 2014, Salvatore Florio This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License According to a traditional view, reality is singular. Socrates and Plato are philosophers; each of them has the property of being a philosopher.1 Being a philosopher is a singular property in that it is instantiated separately by Socrates and by Plato. The property of being a philosopher, like the property of being human, has the higher-order property of being instantiated. The property of being instantiated is singular too. It is instantiated separately by the property of being a philosopher and by the property of being human. If we generalize these ideas, we obtain what may be called the singular conception of reality. This is the view that reality encompasses entities belonging to two main categories: objects and singular properties of various orders.2 The singular conception of reality offers a simple picture of what there is, and it offers a simple picture of the semantics of singular predication. A basic predication of the form S(t), composed of a singular term t and a singular predicate S, is true in a given interpretation of the language if and only if, relative to that interpretation, the object denoted by t instantiates the property denoted by S. A broader conception of reality, however, has been advocated. The Romans conquered Gaul. This is not something that any Roman did separately. They conquered Gaul jointly. According to advocates of the broader conception of reality, conquering Gaul is a plural property, one that is instantiated jointly by the Romans. This broader conception of reality, which admits the existence of plural properties in addition to singular ones, has been called the plural conception of reality (Yi 2006). An attractive feature of the plural conception of reality is that it offers a straightforward way of handling the semantics of plural predication. Consider an atomic formula, P(tt), composed of a plural term tt and a plural predicate P. If plural properties are available, one may hold that P(tt) is true in a given interpretation of the language if and

Abstract The paradox that appears under Burali–Forti’s name in many textbooks of set theory is a clever piece of reasoning leading to an unproblematic theorem. The theorem asserts that the ordinals do not form a set. For such a set would be–absurdly–an ordinal greater than any ordinal in the set of all ordinals. In this article, we argue that the paradox of Burali–Forti is first and foremost a problem about concept formation by abstraction, not about sets. We contend, furthermore, that some hundred years after its discovery the paradox is still without any fully satisfactory resolution. A survey of the current literature reveals one key assumption of the paradox that has gone unquestioned, namely the assumption that ordinals are objects. Taking the lead from Russell’s no class theory, we interpret talk of ordinals as an efficient way of conveying higher-order logical truths. The resulting theory of ordinals is formally adequate to standard intuitions about ordinals, expresses a conception of ordinal number capable of resolving Burali–Forti’s paradox, and offers a novel contribution to the longstanding program of reducing mathematics to higher-order logic.

Abstract In clinical practice for the treatment of chronic myeloid leukemia, second generation of tyrosine kinase inhibitors such as Nilotinib (NIL) specific and potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS) a inhibitor of BCR/ABL and Src family kinase were developed to clinically overcome imatinib resistance. In this study, we wanted to test the ability of some antioxidants such Resveratrol (RES) or a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) or δ‐tocotrienol (δ‐TOCO) to interact with DAS and NIL on viability, reactive oxygen species (ROS) production, lipid peroxidation, and apoptosis. To test the possible mechanisms of action of such antioxidants, we utilized N‐acetyl‐L‐cysteine (NAC) a specific inhibitor ROS production or PP1 a specific Src tyrosine kinase inhibitor or BAPTA a specific chelator of intracellular calcium. Our data demonstrated: 1) RES, rMnSOD, δ‐TOCO, and NAC, at dose used, significantly reduced the intracellular levels of MDA induced by DAS or NIL; 2) RES, rMnSOD, and δ‐TOCO increased the intracellular ROS levels; 3) The increase ROS levels is related to higher levels of oligonucleosomesi induced by DAS and NIL and that NAC significantly reduced this activity. Interestingly, our data showed that apoptotic activity of DAS and NIL have significantly increased the production of oligonucleosomes by triggering excessive ROS generation as well as functionality of SERCA receptors.

Abstract A prominent objection against the logicality of second-order logic is the so-called Overgeneration Argument. However, it is far from clear how this argument is to be understood. In the first part of the article, we examine the argument and locate its main source, namely, the alleged entanglement of second-order logic and mathematics. We then identify various reasons why the entanglement may be thought to be problematic. In the second part of the article, we take a metatheoretic perspective on the matter. We prove a number of results establishing that the entanglement is sensitive to the kind of semantics used for second-order logic. These results provide evidence that by moving from the standard set-theoretic semantics for second-order logic to a semantics which makes use of higher-order resources, the entanglement either disappears or may no longer be in conflict with the logicality of second-order logic.

Abstract Background The persistently patent ductus arteriosus represents a well-known common congenital heart defect; it is uncommon in adult patients, and in any case, it debuts with atrial fibrillation. Case presentation A 75-year-old woman suffering from persistent ductus arteriosus (PDA) was admitted to the cardiology department because of atrial fibrillation, dyspnea and exercise intolerance. A PDA was detected on echocardiography and globally assessed through ECG-gated CT angiography. Conclusions Patent ductus arteriosus is an uncommon clinical finding in adulthood, and atrial fibrillation, as a consequence of chronic, progressive left atrial enlargement, may be the initial symptom. We describe the ECG-gated CT angiography imaging features of unknown patent ductus arteriosus in an elderly patient who debuted with atrial fibrillation.

[reaction: see text] The stereoselective synthesis of novel alpha-epoxy-beta-amino acids is described by a route that combines the chemistry of oxazolinyloxiranyllithiums with that of nitrones. The intermediate trioxadiazadispiro[2.0.4.3]undecanes 4 have been isolated and converted by hydrolysis into epoxy-5-isoxazolidinones 5 which can be transformed into the alpha-epoxy-beta-amino acids 8 by N-O reduction.

Semantic theories based on a hierarchy of types have prominently been used to defend the possibility of unrestricted quantification. However, they also pose a prima facie problem for it: each quantifier ranges over at most one level of the hierarchy and is therefore not unrestricted. It is difficult to evaluate this problem without a principled account of what it is for a quantifier to be unrestricted. Drawing on an insight of Russell's about the relationship between quantification and the structure of predication, we offer such an account. We use this account to examine the problem in three different type‐theoretic settings, which are increasingly permissive with respect to predication. We conclude that unrestricted quantification is available in all but the most permissive kind of type theory.

CyclosporinA (CsA) is an immunosuppressive drug which induces severe adverse effects such as cardiotoxicity and nephrotoxicity. In several therapeutic protocols CsA is used in association with corticosteroids to obtain better therapeutic results. Recently, our studies showed that CsA increases blood pressure while inhibit Nitric Oxide (NO) production in vivo. In this study we evaluated in rat cardiomyocytes the effects of CsA, used alone or in association with Hydrocortisone (HY), on intracellular calcium concentration, NO production and lipid peroxidation (MDA level). Our results demonstrated that CsA increased intracellular calcium and such effect was dose-dependent. HY used alone, slightly decreased intracellular calcium, while dramatically reduced CsA-induced calcium fluxes. CsA (3.2 microM) increased lipid peroxidation and this effect was blunted by HY. Both CsA and HY inhibited NO production in rat cardiomyocytes acting on this pathway synergically. Our results demonstrated that in rat cardiomyocytes, CsA toxicity is due to a calcium overload, which in turn induce lipid peroxidation and determines oxidative stress-induced cell injury. Treatment with HY effectively inhibits CsA-induced toxicity, decreasing lipid peroxidation as well as calcium intracellular concentration. Our findings seem to suggest that glucocorticoids may be effective in reducing CsA-induced cardiotoxicity at concentrations which are consistent with current therapeutic doses.

Abstract Dioxin—2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD) is a common environmental toxin of current interest. In the last years, higher levels of TCDD than those permitted in UE [European Commission. 2002. European Commission Recommendation 2002/201/CE. Official Gazette, L 67/69] were detected in milk samples from cow, water buffalo, goat, and sheep raised on some areas of Campania Region (South Italy). Dioxin often causes immunosuppression and might render the animal liable to viral infections. In addition, viral infections are able to alter the pattern of dioxin distribution in different organs of the exposed animals. Bovine Herpesvirus type‐1 (BHV‐1) is a widespread pathogen, which causes infectious rhinotracheitis and infectious pustular vulvovaginitis in cattle. Herein, we have studied the effects of TCDD and BHV‐1 infection, in Madin‐Darby Bovine Kidney (MDBK) cells, alone as well as in association, so as cellular proliferation, apoptosis, and virus replication. We have observed an increase in cell viability of confluent monolayers at low TCDD concentrations. TCDD treated cells demonstrated increased viability compared to controls as evaluated by MTT test. TCDD exposure increased cell proliferation but induced no changes on apoptosis. Cells exposed to TCDD along with BHV‐1 showed a dose‐dependent increase in cytopathy, represented by ample syncytia formation with the elimination of the cellular sheets and increased viral titer. These results suggest that TCDD increases viral replication in MDBK cells while BHV‐1 further decreases viability of TCDD exposed cells. Since very low concentrations (0.01 pg/ml) are sufficient to augment BHV‐1 titer, TCDD may contribute to reactivate BHV‐1 from latency, leading to recurrent disease and increase virus transmission. J. Cell. Biochem. 103: 221–233, 2008. © 2007 Wiley‐Liss, Inc.

Lead, cadmium and mercury were detected in liver and kidney tissue of dogs from an urban habitat. Samples were digested in a microwave system and analyzed by atomic absorption spectroscopy. Results of the current study showed that at least one of the three heavy metals was detected in tissues of all examined dogs. These findings make us suppose that humans are exposed to the same heavy metals similar to those of dogs that are exposed since they share the same environment. Mercury concentrations detected in kidney of household dogs were higher than stray dogs, therefore the involvement of pet food in exposure to mercury can be supposed.

ABSTRACT Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium that represent toxic real threat for human beings and animal health. In this study we evaluated the effect of a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) on oxidative stress and on the alterations of fluid reabsorption in renal proximal tubule (PT) as possible causes of OTA nephrotoxicity. Finally, we have measured the concentration of O 2 − in the kidney through dihydroethidium assay (DHE) and nitric oxide (NO) concentration through nitrites and nitrates assay. Male Sprague Dawley rats weighing 120–150 g were treated for 14 days by gavage, as follows: Control group, 12 rats received a corresponding amount of saline solution (including 10% DMSO); rMnSOD group, 12 rats treated with rMnSOD (10 µg/kg bw); OTA group, 12 rats treated with OTA (0.5 mg/kg bw) dissolved in 10% DMSO and then scaled to required volume with corn oil; rMnSOD + OTA, 12 rats treated with rMnSOD (10 µg/kg bw) plus OTA (0.5 mg/kg bw). Our results have shown that rMnSOD restores the alteration of reabsorption in PT in rats treated with OTA plus rMnSOD, probably through the response to pressure natriuresis, where nitric oxide plays a key role. Moreover, rMnSOD prevents the nephrotoxicity induced by OTA probably restoring the balance between superoxide and NO that is most probably the cause of hypertension and renal functional alterations through the inhibition of NO synthase. In conclusion these data provide important information for understanding of mechanism of toxic action of OTA. J. Cell. Biochem. 119: 424–430, 2018. © 2017 Wiley Periodicals, Inc.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) influences infection of kidney cells (MDBK) with Bovine Herpesvirus 1 (BHV-1) through an increase in virus replication and an acceleration of BHV-1-induced apoptosis. Previously our group demonstrated that BHV-1, in the early stages of infection, significantly up-regulates telomerase activity in MDBK cells, while, in the late phases of infection, when BHV-1-induced apoptosis occurred, a down-regulation of telomerase activity was detected. Hence, herein, for the first time, we described the influences of TCDD on telomerase activity during virus infection. In kidney cells (MDBK) infected with BHV-1 and exposed to different doses of TCDD we explored telomerase activity by TRAP assay. Concomitantly, we examined protein levels of both bTERT and c-Myc by Western blot analysis. In all groups, TCDD induced an acceleration in down-regulation of telomerase activity. Particularly, TCDD drastically and significantly decreased telomerase activity when virus-induced apoptosis took place. This result was accompanied from an accelerated down-regulation of bTERT and c-Myc. Finally, in the presence of TCDD, we evidenced a dose-dependent overexpression of aryl hydrocarbon receptor. Hence, our data suggest that TCDD, through a significant acceleration in down-regulation of telomerase activity, bTERT and c-Myc, may contribute to accelerated BHV-1-induced apoptosis.

Abstract Our previous studies have demonstrated that 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) increases Bovine Herpesvirus 1 (BHV‐1) replication through a dose‐dependent increase in cytopathy and increased viral titer. Furthermore, TCDD was able to trigger BHV‐1‐induced apoptosis by up‐regulating the activation of initiator caspases 8 and 9, as well as of effector caspase 3. Since TCDD activates caspase 3 after 4 h of infection, we have hypothesized an involvement of BHV‐1 infected cell protein 0 (bICP0) in this process. Such protein, the major transcriptional regulatory protein of BHV‐1, has been shown to indirectly induce caspase 3 activation and apoptosis. In order to elucidate the role of bICP0 in this apoptotic pathway, here we have analyzed the effects of TCDD on bICP0 expression. Following infection of bovine cells with BHV‐1, we detected apoptotic features already at 12 h after infection, only in TCDD exposed groups. Furthermore, in the presence of different doses of TCDD, we observed a time‐dependent modulation and increase of bICP0 gene expression levels, as revealed by RT‐PCR analysis. Western blot analysis and immunocytochemistry revealed that TCDD induced an increase of bICP0 protein levels in a dose‐dependent manner, compared to unexposed groups. Moreover, Western blot analysis of nuclear and cytosolic fractions of infected cells revealed that TCDD anticipated the presence of bICP0 protein in the cytoplasm. In conclusion, both the increase of replication of BHV‐1 and anticipation of BHV‐1‐induced apoptosis could be the result of a relationship between TCDD and bICP0. J. Cell. Biochem. 111: 333–342, 2010. © 2010 Wiley‐Liss, Inc.

Gastric distension in anaesthetized pigs reflexly elicits peripheral vasoconstriction and an increase in plasma renin activity (PRA), with vagal afferent and sympathetic efferent limbs. The aim of the present study was to quantify the contribution of the renin‐angiotensin system to the peripheral vasoconstriction. In pigs anaesthetized with α‐chloralose, changes in anterior descending coronary, superior mesenteric and left external iliac blood flow caused by stomach distension before and after blockade of angiotensin II receptors with losartan were assessed using electromagnetic flowmeters. Gastric distension for periods of 30 min was performed by injecting 0.8 l warm Ringer solution into balloons positioned within the viscus. Changes in heart rate and renal blood flow were prevented by atrial pacing and injection of phentolamine into the renal arteries, and changes in regional perfusion pressure and in baroreceptor activity were minimized by aortic constriction and denervation of the carotid sinuses. PRA was assessed by radioimmunoassay of angiotensin I. Before blockade of angiotensin II receptors by administration of losartan, stomach distension decreased coronary blood flow by 14.2% in six pigs and mesenteric and iliac blood flow by 11% and 17.3%, respectively, in another six pigs. After administration of losartan, these decreases were significantly reduced to 7.4%, 6.8% and 8.7%, respectively. The above responses were abolished by bilateral section of the subdiaphragmatic vagal nerves. These results show that the peripheral vasoconstriction reflexly caused by stomach distension was significantly contributed to by the concomitant activation of the renin‐angiotensin system.

In order to determine the ability of bovine herpesvirus type 1 (BHV-1) to suppress apoptosis, we examined the effects of BHV-1 infection on sorbitol-induced apoptosis on Madin-Darby bovine kidney (MDBK) cells. BHV-1 suppresses sorbitol-induced apoptosis in a manner similar to that of herpes simplex virus type 1 (HSV-1), indicating that BHV-1 has one or more anti-apoptotic genes. To elucidate the molecular mechanisms of apoptosis, expression of some genes encoding apoptosis-inhibiting and -promoting factors were analyzed on BHV-1 infected cells during the process of sorbitol-induced apoptosis. Our results revealed that the expression of bcl-2 and bcl-x(L) decreased after 5 and 3 h p.i., respectively; while bax and procaspase-3 expression increased with respect to control as a function of p.i. times and at 7 h p.i. they were not observed. We further show that the expression of p53 gene was also enhanced, suggesting that this apoptotic mechanism is p53 dependent. From these results, we propose that BHV-1 has one or more genes encoding apoptosis-inhibiting factors which interfere with the involvement of bcl-2 gene family members and apoptotic pathway, depending upon caspase-3, triggered by sorbitol.

Abstract Cyclosporin A (CsA) is the prototype of immunosuppressant drugs that have revolutionized the management of all transplantation and autoimmune diseases. Side effects of CsA mainly affecting the kidney but also observed in liver and heart, limit the therapeutic use of this drug after organ transplantation. The renal toxicity of CsA is attributed to reduced renal blood flow which leads to hypoxia‐reoxygenation injury accompanied by excessive generation of oxygen‐derived free radicals. In several therapeutic protocols, CsA is used in association with corticosteroids to obtain better therapeutic results. Recently, our studies showed that hydrocortisone (HY) has a protective effect on CsA‐induced cardiotoxicity. In fact our previous results demonstrated that in rat cardiomyocytes, CsA toxicity is due to a calcium overload, which in turn induce lipid peroxidation and determines oxidative stress‐induced cell injury. Treatment with HY effectively inhibits CsA‐induced toxicity, decreasing lipid peroxidation as well as calcium intracellular concentration. In this study we evaluated in vivo the effects of CsA, used alone or in association with HY, on some parameters of renal dysfunction (blood urea nitrogen; BUN, creatinine, and cholesterol), malondialdheyde (MDA) levels, antioxidant enzyme catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and apoptosis. CsA administration for 24 days resulted in a marked renal oxidative stress, which significantly deranged the renal functions. Treatment with CsA in association with HY significantly improved the renal dysfunction and renal oxidative status. This study clearly suggests the role of oxidative stress in the pathogenesis of CsA‐induced nephrotoxicity. J. Cell. Biochem. 113: 997–1004, 2012. © 2011 Wiley Periodicals, Inc.

Hepatoblastoma incidence has been associated with different environmental factors even if no data are reported about a correlation between aflatoxin exposure and hepatoblastoma initiation. Considering that hepatoblastoma develops in infants and children and aflatoxin M1 (AFM1), the aflatoxin B1 (AFB1) hydroxylated metabolite, can be present in mothers’ milk and in marketed milk products, in this study we decided to test the effects of AFM1 on a hepatoblastoma cell line (HepG2). Firstly, we evaluated the effects of AFM1 on the cell viability, apoptosis, cell cycle, and metabolomic and cytokinomic profile of HepG2 cells after treatment. AFM1 induced: (1) a decrease of HepG2 cell viability, reaching IC50 at 9 µM; (2) the blocking of the cell cycle in the G0/G1 phase; (3) the decrease of formiate levels and incremented level of some amino acids and metabolites in HepG2 cells after treatment; and (4) the increase of the concentration of three pro-inflammatory cytokines, IL-6, IL-8, and TNF-α, and the decrease of the anti-inflammatory interleukin, IL-4. Our results show that AFM1 inhibited the growth of HepG2 cells, inducing both a modulation of the lipidic, glycolytic, and amino acid metabolism and an increase of the inflammatory status of these cells.

Programmed cell death (PCD), or apoptosis, is initiated in response to various stimuli, including virus infection. A number of studies have shown that deregulation of apoptosis is an important feature of virus-induced immunosuppression for various viral diseases. In the present study, CapHV-1 was found to cause apoptosis in mitogen-stimulated as well as nonstimulated caprine peripheral blood mononuclear cells (PBMC). Apoptotic index, as quantified by fluorescent dyes, revealed a significant increase in the percentage of apoptotic cells at 24 and 48 h postinfection as compared to their respective noninfected controls. Apoptosis specific internucleosomal laddering in DNA from CapHV-1 infected PBMC was seen in agarose gel electrophoresis. No DNA fragmentation was observed in control noninfected PBMC. Virus-induced apoptosis was reduced by Z-VAD-FMK, an aspecific caspase inhibitor, by AC-DEVD-CHO (caspase-3-specific) and AC-VEID-CHO (caspase-6-specific) treatment. PCD in CapHV-1 infected peripheral blood mononuclear cells occurs at the G0/G1 phase of the cell cycle. However, penetration of virus particles and infection was not required for PCD, as UV-inactivated CapHV-1 induced apoptosis of mitogen-stimulated bovine peripheral blood mononuclear cells in vitro.

An elevation in angiotensin II (Ang II) levels is a common occurrence in spontaneously hypertensive rats (SHRs). Infusions of Ang II and a high salt diet increase the activity of NADPH oxidase that stimulates superoxide anion (O(-2)) generation and increases the expression of certain subunits of NADPH oxidase. Apocynin, an NADPH oxidase inhibitor with antihypertensive effects, is able to inhibit the release of superoxide anion by inhibiting NADPH oxidase activity and blocking the migration of p47 phox to the mitochondrial membrane. The aim of our study was to evaluate the antihypertensive effects of apocynin in SHRs and Wistar rats (WKYs) using a micropuncture technique. After microperfusion of both the proximal and distal tubules, we found that SHRs treated with apocynin showed a decrease in the free-flow collection of the proximal tubule (PT), which was not affected in WKYs. Moreover, significant differences were not demonstrated in the distal tubule (DT), probably due a mechanism of compensation that occurs in the loop of Henle. In conclusion, it is possible that the mechanisms of reabsorption in the PT are controlled by the interactions of O(-2) and nitric oxide (NO). These data could suggest a higher activity of NADPH oxidase and increase in reactive oxygen species (ROS) production in the PT during hypertension.

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease, worldwide, and oxidative stress has been recognized as a key factor in the pathogenesis and progression of DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has the most important contribution to reactive oxygen species generation during the development of DN. Bioactive compound use has emerged as a potential approach to reduce chronic renal failure. Therefore, a red orange and lemon extract (RLE) rich in anthocyanins was chosen in our study, to reduce the toxic renal effects during the development of DN in Zucker diabetic fatty rat (ZDF). RLE effects were examined daily for 24 weeks, through gavage, in ZDF rats treated with RLE (90 mg/kg). At the end of the experiment, ZDF rats treated with RLE showed a reduction of the diabetes-associated up-regulation of both NOX4 and the p47-phox and p22-phox subunits, and restored the BAX/BCL-2 ratio respect to ZDF rats. Furthermore, RLE was able to reduce the oxidative DNA damage measured in urine samples in ZDF rats. This study showed that RLE could prevent the renal damage induced by DN through its capacity to inhibit NOX4 and apoptosis mechanisms.

Chronic myeloid leukemia (CML) is a myeloproliferative disease that activates multiple signaling pathways, causing cells to produce higher levels of reactive oxygen species (ROS). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a major generator of ROS in leukemia, and marine natural products have shown promising activities for the treatment of hematopoietic malignancies. In the present study, we investigated the effect of the marine microalga Skeletonema marinoi (S.M.), a ubiquitous diatom that forms massive blooms in the oceans, on the human leukemia cell line K562. The effects of S.M. extract on cell viability, production of ROS, nitric oxide (NO), and apoptosis were examined. In this preliminary work, S.M. was able to decrease cell viability (p &lt; 0.05) and increase apoptosis levels (p &lt; 0.05) in K562 cells after 48 h of treatment. In addition, the levels of NOX, NO, and malondialdehyde (MDA) were reduced in K562-treated cells (p &lt; 0.05), whereas the levels of SOD, CAT, and GPx increased during treatment (p &lt; 0.05). Finally, analyzing Bax and Bcl-2 expression, we found a significant increase in the proapoptotic protein Bax and a sustained decrease in the antiapoptotic protein Bcl-2 (p &lt; 0.05) in the K562-treated cells.

Gonadotropin-releasing hormone (GnRH) agonist exert "in vivo" an inhibitory action on the growth of hormone-dependent canine mammary tumours (Lombardi et al. [1999] J. Vet. Pharmacol Ther. 22(1):56-61). The present experiments have been performed "in vitro" in order to investigate the mechanisms involved in this direct antiproliferative action of GnRH agonists. In particular, the aim was to study whether these compounds might exert their antiproliferative effect by interfering with the stimulatory action of epidermal growth factor (EGF). To this purpose, the effects of GnRH agonist, Goserelin (GnRH-A), on the mitogenic action of EGF, on EGF-activated intracellular signaling mechanisms (intracellular calcium and nitric oxide production) as well as on ATP induced cell proliferation and signalling, and on the binding of EGF receptors have been evaluated in primary culture of canine mammary tumour cells. The results of these "in vitro" studies show that GnRH-A counteracts the mitogenic action of EGF and ATP, decreases the EGF/ATP-induced calcium signalling and reduces EGF binding, probably by means of NO-induced [Ca2+]i downregulation. These data suggest that GnRH agonists may inhibit the proliferation of the tumour cells by interfering with the stimulatory action of EGF.

1. We used the patch-clamp technique to study voltage-activated transient potassium currents in freshly dispersed and cultured chick dorsal root ganglion (DRG) cells. Whole-cell and cell-attached patch currents were recorded under conditions appropriate for recording potassium currents. 2. In whole-cell experiments, 100-ms depolarizations from normal resting potentials (-50 to -70 mV) elicited sustained outward currents that inactivated over a time scale of seconds. We attribute this behavior to a component of delayed rectifier current. After conditioning hyperpolarizations to potentials negative to -80 mV, depolarizations elicited transient outward current components that inactivated with time constants in the range of 8-26 ms. We attribute this behavior to a transient outward current component. 3. Conditioning hyperpolarizations increased the rate of activation of the net outward current implying that the removal of inactivation of the transient outward current allows it to contribute to early outward current during depolarizations from negative potentials. 4. Transient current was more prominent on the day the cells were dispersed and decreased with time in culture. 5. In cell-attached patches, single channels mediating outward currents were observed that were inactive at resting potentials but were active transiently during depolarizations to potentials positive to -30 mV. The probability of channels being open increased rapidly (peaking within approximately 6 ms) and then declined with a time constant in the range of 13-30 ms. With sodium as the main extracellular cation, single-channel conductances ranged from 18 to 32 pS. With potassium as the main extracellular cation, the single-channel conductance was approximately 43 pS, and the channel current reversed near 0 mV, as expected for a potassium current. 6. We conclude that the transient potassium channels mediate the component of transient outward current seen in the whole-cell experiments. This current is a relatively small component of the net current during depolarizations from normal resting potentials, but it can contribute significant outward current early in depolarizations from hyperpolarized potentials.

The electrophoretic patterns of the serum enzymes lactate dehydrogenase and creatine kinase from water buffalo calves are described. Differences in total activities as well as their relative distribution were seen at ages ranging from 1 to 10 weeks. While total lactate dehydrogenase activity increased by over 100%, total creatine kinase increased by almost 400%. The relative activities of lactate dehydrogenase 1 and 5 decreased with age. Lactate dehydrogenase 2 and 3 increased and lactate dehydrogenase 4 did not change. In relation to creatine kinase, the prevalent isoenzyme was creatine kinase-MM, but it's relative activity gradually decreased in comparison to the other two isoenzymes (creatine kinase-MB and creatine kinase-BB). Creatine kinase-BB was completely absent until the 3rd week of age. The percentage modifications of creatine kinase isoenzymes were correlated to age. The results suggest that isoenzymatic separation and characterization of lactate dehydrogenase and creatine kinase in relation to the various tissues can significantly contribute to the diagnosis of diseases which are linked to tissue damage.

Failure of chemotherapy with anthracyclines as a result of drug resistance and toxicity is a major problem in the clinical management of neoplasia. The aim of the present study was to evaluate the activity of medroxyprogesterone acetate (MPA) as a chemosensitiser on anthracycline cytotoxicity. The study investigated whether such an effect could be related to an increase in lipid peroxidation, nitric oxide production, membrane fluidity and intracellular anthracycline concentration. The results showed that anthracyclines decreased nitric oxide production but increased membrane viscosity (polarisation constant) and lipid hydroperoxide formation in canine mammary tumour cells. Moreover, it was found that both drug-induced cytotoxicity and membrane viscosity increased in the presence of MPA. Conversely, lipid hydroperoxides decreased in MPA-supplemented cells. Medroxyprogesterone acetate did not show any effect on nitric oxide production. The two anthracyclines used (doxorubicin and idarubicin) showed differential intranuclear accumulation in canine mammary tumour cells, and MPA significantly modified intracellular concentration of anthracyclines.

Abstract What is the relation between some things and the set of these things? Mathematical practice does not provide a univocal answer. On the one hand, it relies on ordinary plural talk, which is implicitly committed to a traditional form of plural logic. On the other hand, mathematical practice favors a liberal view of definitions which entails that traditional plural logic must be restricted. We explore this predicament and develop a “critical” alternative to traditional plural logic.

Abstract In linguistics, the dominant approach to the semantics of plurals appeals to mereology. However, this approach has received strong criticisms from philosophical logicians who subscribe to an alternative framework based on plural logic. In the first part of the article, we offer a precise characterization of the mereological approach and the semantic background in which the debate can be meaningfully reconstructed. In the second part, we deal with the criticisms and assess their logical, linguistic, and philosophical significance. We identify four main objections and show how each can be addressed. Finally, we compare the strengths and shortcomings of the mereological approach and plural logic. Our conclusion is that the former remains a viable and well-motivated framework for the analysis of plurals.

Aflatoxin B1 (AFB1), the mainly Aspergillus fungi derived mycotoxin, is well known for its carcinogenic effects on liver, and frequently occurs in food supplies, leading to fatal consequences in both farm animals and humans. Poultry, one of the most important segments of agro-industry, has been demonstrated to be extremely sensitive to AFB1 intake, which results in chickens’ low performance, decreased quality of both eggs and meat and a negative economic feedback. Oxidative stress caused by AFB1 plays a crucial role in chickens’ kidney damage by generating lipid peroxidation accompanied by a concomitant increase in the antioxidant enzymes involved in ROS metabolism (NADPH oxidase isoform 4 (NOX4) and its regulatory subunit p47-phox). The aim of the present work was to investigate the benefits of dietary supplementation, in chickens affected by AFB1 mycotoxicosis, using a new Feed additive (FA) containing a mixture of a tri-octahedral Na-smectite with a ligno-cellulose-based material an antioxidant adjuvant. Exposure of AFB1-treated chickens to the feed additive induced a significant down-regulation of both NOX4 and p47-phox genes expression levels. This trend was confirmed by their protein expression, demonstrating the great potential of the FA to counteract oxidative stress. To conclude, these results could open new perspectives in the methods of feeding chickens, using eco-friendly dietary supplements able to reduce AFB1-induced mycotoxicosis and to ameliorate poultry performances.

A well-known proof by Alonzo Church, first published in 1963 by Frederic Fitch, purports to show that all truths are knowable only if all truths are known.1 This is the Paradox of Knowability. If we take it, quite plausibly, that we are not omniscient, the proof appears to undermine metaphysical doctrines committed to the knowability of truth, such as semantic anti-realism. Since its rediscovery by Hart and McGinn (1976), many solutions to the paradox have been offered. In this article, we present a new proof to the effect that not all truths are knowable, which rests on different assumptions from those of the original argument published by Fitch. We highlight the general form of the knowability paradoxes, and argue that anti-realists who favour either an hierarchical or an intuitionistic approach to the Paradox of Knowability are confronted with a dilemma: they must either give up anti-realism or opt for a highly controversial interpretation of the principle that every truth is knowable.

Anthracyclines are one of the most used drugs in the therapy of several malignant tumors. Unfortunately, its use is still limited by their cardio-toxicity and by the presence of cancer cells resistant to these drugs. In the present study we evaluated the ability of a chemo-sensitizer agent, MPA (Medroxyprogesterone Acetate), to modify anthracyclines intranuclear uptake in normal leukocytes (NL) and in chronic lymphatic leukemia leukocytes (CLL). Moreover we evaluated the role of lipid peroxidation and nitric oxide (NO) production on antracyclines activity and on their combination with MPA. Our data show that MPA significantly increases anthracyclines uptake only in CLL cells and decreases anthracyclines induced lipid peroxidation.

Abstract The caspase family of protease is speculated to have a crucial role in apoptosis. The effect of treatment with Idarubicin (IDA) and Medroxyprogesterone acetate (MPA), used alone or in combination, on the activation of Caspase‐3 in canine Chronic Lymphatic Leukaemia (CLL) cells was investigated, in order to clarify the mechanism of chemo‐ and hormone‐therapy mediated apoptosis. Caspase activity was determined by a quantitative fluorimetric assay. Apoptosis was monitored by propidium iodide (PI) and nucleosomes assay. Treatment of CLL cells for 24 h with MPA 5 μM did not significantly activate caspase‐3 but its activity was increased almost 5‐fold more with IDA 1 μM ( P &lt; 0.05) than control. Treatment of CLL cells with IDA 1 μM in equimolecular association with MPA was able to increase the activation of caspase‐3 induced by IDA of the 61.2% ( P &lt; 0.05) in comparison with IDA alone. The activation of caspase‐3 was confirmed evaluating apoptosis by PI and nucleosomes assay. Furthermore, both caspase‐3 activation and apoptosis triggered by IDA alone or in combination with MPA were significantly inhibited by specific caspase‐3 inhibitor AC‐DEVD‐CMK. These findings provide an explanation for IDA and MPA induced‐apoptosis mechanism. J. Cell. Biochem. 89: 747–754, 2003. © 2003 Wiley‐Liss, Inc.

Crepis lacera is a plant from the Asteraceae family that is common in the Mediterranean region. Farmers believe that this plant may be deadly to small ruminants in areas of southern Italy. However, scientific evidence is lacking, and no proof exists that C. lacera is toxic to ruminants. Necropsies conducted on four sheep revealed lesions in their livers and kidneys. In the current study, we described sheep poisoning and isolated secondary metabolites from Crepis lacera to assess the metabolites’ biological activity both in vitro and in vivo. Phytochemical study of the aerial portions of Crepis lacera led to the isolation of five sesquiterpene lactones and two phenolic compounds. Cellular viability was evaluated in cell cultures of the bovine kidney cell line Madin Darby Bovine Kidney (MDBK) after incubation with phytochemicals. Our results showed that three sesquiterpene lactones, 8-epidesacylcynaropicrin-3-O-β-glucopyranoside (2), 8-epigrosheimin (3), and 8-β-hydroxydehydrozaluzanin C (4), were cytotoxic after 48 h of incubation. In addition, in the in vivo study, animals that received 1 mg/kg body weight (bw) of Crepis lacera extract and were then sacrificed after 48 h showed significant lesions in their liver, lungs and kidneys. These lesions were also found in rats that received 2 mg/kg bw of the same extract and sacrificed after 24 and 48 h. These results validate the hypothesis that C. lacera is potentially dangerous when ingested in large quantities by grazing small domestic ruminants. Further studies are necessary to clarify the molecular mechanisms of Crepis spp. toxicity in animals.

Ochratoxin A (OTA) is a mycotoxin which represents an emerging problem for both animal and human health, due to its high presence in feed and foods. Exposure to OTA is associated with oxidative stress-induced nephrotoxicity. Therefore, the identification of new antioxidant or adsorbent substances with protective action constitutes one of the main challenges to reduce the negative effects induced by mycotoxins. For this purpose, we investigated the effect of two innovative feed additives, a bio-organoclay (CHS) and a mixture of a tri-octahedral Na-smectite with a ligno-cellulose based material (MIX) alone or in combination with OTA in kidneys of treated chickens. Real-Time PCR analyses for NADPH oxidase 4 (NOX) and p47-phox were performed to evaluate oxidative stress. Our results demonstrated an increase in NOX and p47-phox levels in OTA-treated chickens. Moreover, CHS, more than MIX, was able to reduce OTA-induced toxicity, restoring NOX levels. Taken together, these findings highlight the potential beneficial role of CHS in reverting OTA-induced nephrotoxicity in chickens and could lead to the production of healthier foods with beneficial consequences for human and animal health.

Journal Article Untyped Pluralism Get access Salvatore Florio Salvatore Florio Kansas State University florio@ksu.edu florio@ksu.edu Search for other works by this author on: Oxford Academic Google Scholar Mind, Volume 123, Issue 490, April 2014, Pages 317–337, https://doi.org/10.1093/mind/fzu069 Published: 20 August 2014

Abstract What is absolutely unrestricted quantification? We distinguish two theoretical roles and identify two conceptions of absolute generality: maximally strong generality and maximally inclusive generality. We also distinguish two corresponding kinds of absolute domain. A maximally strong domain contains every potential counterexample to a generalisation. A maximally inclusive domain is such that no domain extends it. We argue that both conceptions of absolute generality are legitimate and investigate the relations between them. Although these conceptions coincide in standard settings, we show how they diverge under more complex assumptions about the structure of meaningful predication, such as cumulative type theory. We conclude by arguing that maximally strong generality is the more theoretically valuable conception.

Abstract Quine maintained that philosophical and scientific theorizing should be conducted in an untyped language, which has just one style of variables and quantifiers. By contrast, typed languages, such as those advocated by Frege and Russell, include multiple styles of variables and matching kinds of quantification. Which form should our theories take? In this article, I argue that expressivity does not favour typed languages over untyped ones.

The binding of 125I-labeled prolactin (PRL) to membranes from the bursa of Fabricius of male and female chicks of different ages (15-30-45 and 60 days) was studied. In male chicks the binding was very low in 15 day-old animals and slightly increased in more aged animals. In female chicks the binding was more evident in young animals and decreased in 60 day-old animals. The binding showed a hormonal specificity and Scatchard analysis of the binding revealed the presence of binding sites with low capacity and high affinity. The presence of PRL receptors in the bursa of the chick, a structure that confers immunological competence to birds, gives further support to the involvement of the hormone in the immune processes.

Abstract Introduction: Prostate cancer (PC) is the most commonly diagnosed cancer in males in the Western world and the third leading cause of cancer in men. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) shows a wide range of severe adverse effects in animal models, including immunotoxicity, developmental and reproductive toxicity, teratogenicity, and carcinogenicity. The exposure to TCDD early in development may increase susceptibility to PC and the exposure to TCDD in aged rats can cause greater epithelial proliferation, accompanied by morphological alterations manifested as lobe-specific prostatic hyperplasia. The administration of TCDD to a variety of cultured cells may alter their ability to proliferate and die. Autophagy is an evolutionarily conserved cellular pathway playing a critical role in cellular homeostasis. Defects of autophagy are involved in the pathogenesis of different diseases, including cancer. One of the well-known autophagy markers is the microtubule associated light chain protein 3 (LC3). We have previously demonstrated that exposure of Madin-Darby Bovine Kidney cells to TCDD increased cell proliferation and autophagy. The aim of this study is to evaluate the biological effects of TCDD exposure on a highly metastatic prostate cancer cell line (PC-3). Methods: PC3 cells were exposed to different concentrations of TCDD (D1=0.1 pg/ml, D2=1 pg/ml and D3=100 pg/ml) and cell viability was assessed by Trypan Blue exclusion after 24, 48, and 72 hours of exposure. Autophagy was evaluated using the following: (a) detection of acidic vesicular organelles (AVOs) by acridine orange staining; (b) immunoflurescence analysis (IF) of LC3; (c) LC3 gene expression by real-time PCR; and (d) study of autophagic flux by chloroquine (CQ) autophagy inhibitor (10μM). Results: When compared with their relative controls, only D3 exposure at 24, 48, and 72 hours caused the following: (1) statistically significant increase of cell proliferation (CP) (CP24h =20.3%, CP48h =54.5% and CP72h =52.4%); (2) detection of AVOs; (3) LC3 IF positivity; and (4) LC3 over expression (expression ratio24h =1.4, expression ratio48h =6.2 and expression ratio72h =11.4). When PC-3 cells were D3 exposed and treated with CQ at 24, 48, and 72 hours, LC3 expression ratios compared with controls (dioxin treatment) decreased (CQ24h =-12.8, CQ48h =-28.1 and CQ72h =-2.8). Conclusions: While increased incidence of PC in men exposed to TCDD is known, the molecular mechanisms of carcinogenesis of this compound have not been fully investigated. Our preliminary study demonstrated that treatment of PC-3 with TCDD results in enhanced cell proliferation and activation of autophagy, potentiating the transformed phenotype of these cancer cells. Comparison of the normal primary prostate epithelial cells with PC-3 will further clarify the oncogenic mechanisms of TCDD in PC. Citation Format: Giovanna Elvira Granato, Roberto Ciarcia, Filomena Fiorito, Salvatore Florio, Ugo Pagnini, Luisa De Martino, Antonio Giordano, Giuseppe Russo. Enhanced cell proliferation and induced autophagy in PC-3 prostate cancer cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1675. doi:10.1158/1538-7445.AM2013-1675

One of the major problems in cancer treatment is the progressive desensitization of cancer cells to chemotherapeutic drugs. Several hypotheses have been advanced to explain this property of cancer cells. In recent years different calcium channel blockers and other chemosensitizing agents like synthetic progestins have been used to revert drug resistance. In our experiments we evaluated the effects of Doxorubicin and Idarubicin on membrane fluidity and depolarization using normal lymphocytes, chronic lymphatic leukemia lymphocytes, normal breast and hormone dependent breast cancer cells and cardiomyocytes. The drugs were used alone or in combination with Verapamil and Medroxyprogesterone acetate. We showed that MPA enhances DOXO and IDA biochemical effects, acting not only on the membrane lipid bilayer, but also on ion channels. VERA instead does not seem to act through the same mechanism.

Gonadotropin-releasing-hormone (GnRH) analogues are synthetic compounds derived from decapeptide neurohormones (LHRH; LH/FSH-RH). They have a key role in hormone dependent cancer, particularly breast and prostate cancer. GnRH analogues produce an efficient inhibition of gonadotropins and sex steroid hormones. Their use in cancer therapy result in a, pharmacological castration (i.e. ovariectomy and orchiectomy), providing an androgen and estrogen ablation. GnRH exert an inhibitory action on the growth of hormone-dependent human and canine mammary tumor. Mammary tumors can produce growth factor that potentially could modulate their own proliferation in an autocrine fashion (i.e. TGF-alpha and TGF-beta or with a paracrine mechanism (i.e. EGF, IGF, FGF). The expression of EGF receptors is related in mammary tissues to the action of oestrogen and progesteron and to the presence of functional receptors for oestrogen (ER) and progesteron (PR). The present review elucidate the role of GnRH receptors in cancer and their connection with steroid hormones. Besides we showed the link between GnRH and signal transductions pathways: Estrogen-receptors, GnRH-receptors, EGF-receptors signal transduction pathways. A very tight link exists between steroid hormones and GnRH analogues both on central pituitary gonadal axis and on tumor receptors peripherically. This last mechanism could be explained either locally activating GnRH receptors or locally interacting with EGF receptor-Intracellular NitricOxide system.

Purpose: Microscopic evaluation of cartilage histopathology is a critical method used in Osteoarthritis (OA) research. The standard histology procedure involves sample decalcification which can be time consuming and harmful to the matrix content depending on the reagent of choice. Histological investigation of OA progression requires accurate inter- and intra-sample localised cartilage evaluation at both macro-and microscopic levels. The present study aimed to develop a histopathological evaluation method based on a new macroscopic grading system and a modified OARSI microscopic grading system using undecalcified human osteochondral tissue. Methods: Femoral heads of patients with hip OA (N=35) or hip fracture without OA (Control, N=7) were collected from total hip arthroplasty surgeries. For OA group, osteochondral plugs (4mm diameter) were sampled according to regional disease severity based on a macroscopic grading system (Table I, Macro 1 to 5) developed for this study. For Control group, femoral heads were carefully examined to ensure no visible cartilage damage was present at the articular surfaces, before plugs were extracted from three fixed sites: superior, anterior and posterior. The subchondral bone of the plugs was trimmed to about 1 mm in length without articular cartilage being affected. Plugs were fixed in formalin without decalcification step, and then processed for paraffin embedding with a 15 hours’ protocol. Before and during sectioning, paraffin blocks were cooled and moisturised with ice-cold water. A microtome blade designed for hard tissue sectioning was used. The cutting direction was parallel to the cartilage-bone junction, the blade angle was set to 5°, and section thickness was 7 μm. After trimming to desired level, sections were picked up and floated on a 40°C water bath to be flattened. Sections were transferred to Superfrost Plus microscope slides (3-4 sections per slide, randomly picked), then slides were vertically incubated at 40°C for better adherence. Safranin O - Fast Green staining was utilized for microscopic evaluation of osteochondral sections. A modified OARSI grading system was used (Table II), indicating severity of cartilage degradation from Grade 0 to 6, with 0.5 interval except between 0 and 1. Macroscopic Grade 5 and microscopic Grade 5 to 6 were not included in this study as there was no cartilage left. Three scorers were trained with the modified OARSI method and went through a brief practice on about 50 slides. In total 295 slides were graded by each scorer blinded with sample origin and macroscopic grade. Two of the scorers scored 100 slides twice with 8 weeks’ interval. The inter- and intra-observer variability were evaluated via intraclass correlation coefficient (ICC). The correlation between macro- and microscopic grades was analysed by linear regression. Results: The undecalcified osteochondral tissue sections obtained were of excellent quality for histologic evaluation. Cartilage surface integrity and/or fibrillation, chondrocyte morphology, pericellular, intra- and interterritorial matrix were neatly presented. The subchondral cortical plate and calcified cartilage were shattered in many cases, but it did not affect the hyaline cartilage above the tidemark even in the worst degenerative sections (Figure 1). Minor crumpling/folding and artificial lesions were observed on some sections. For microscopic evaluation, intra-observer ICC was 0.97 for both scorers, and inter-observer ICC was 0.96 between all 3 scorers. The scoring systems developed were very sensitive and able to distinguish between Control and comparatively normal regions in OA (Macro 1); overall there was a significant and strong correlation (P<0.0001, R2=0.85) between macro- and microscopic grading (Figure 2). Conclusions: We have developed a relatively quick method for histopathological investigation of undecalcified osteochondral tissue and showed that the method is highly reproducible for macro- and microscopic evaluation of cartilage histopathology. The macroscopic grading system developed accurately reflects regional disease severity as demonstrated by the modified OARSI microscopic grading system.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Three decades after their contemporary rediscovery, abstraction principles continue to be at the center of one of the most active areas of research in philosophy of mathematics. The present special issue bears witness to this fact. It collects some of the work presented at two events held in 2014. The first was the workshop ‘Abstractionism / Neologicism’ organized by Marcus Rossberg at the University of Connecticut (April 26–27). The second was the summer school and workshop ‘Abstraction: Philosophy and Mathematics’ organized by Øystein Linnebo and me at the University of Oslo (May 22–24). The events were generously supported by the host universities. Additional funding for the summer school was provided by Kansas State University. Given the thematic and temporal closeness of the two events, it felt natural to give all speakers an opportunity to publish their work side by side. We are very grateful to Philosophia Mathematica for accepting the proposal of a special issue and for providing double-blind peer review for the submissions.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A major problem in cancer treatment is the progressive desensitization of the cancer cells to chemotherapeutic drugs. Several hypotheses have been advanced to explain this property of neoplastic cells. In recent years, some calcium-channel blockers have successfully been used to restore drug-sensitivity in previously resistant tumors. The presence of a correlation between ion channels and membrane fluidity is well known. In the ambit of our studies on the activity of several chemotherapeutic drugs on tumors, we have studied the variations in mem brane depolarization and fluidity in some leukemic cells as a result of polychemotherapeutic treatments. Our results demonstrate that the membrane fluidity and K+ induced depolarization of some types of leukemic cells in patients untreated and treated with some chemotherapeutic agents, are altered significantly as compared to those of normal leukocytes.

Autosomal dominant polycystic kidney disease (ADPKD) affects millions of people worldwide. Vasopressin promotes disease progression.A randomized controlled trial with equal (1:1) allocation.This trial examined the effect of combining a low-osmolar (low-sodium [1,500 mg/d], low-protein [0.8 g per kilogram of body weight]) diet and adjusted water intake on vasopressin secretion in 34 patients with ADPKD.Participants were randomly assigned to receive a low-osmolar diet followed by adjusted water intake to achieve urine osmolality ≤ 280 mOsm/kg water versus no intervention for 2 weeks.The primary outcome of the study was change (delta) in copeptin levels and urine osmolality between the intervention and control groups from baseline to 2 weeks.Fasting plasma copeptin level, 24-hour urine osmolality, and total solute intake.Baseline characteristics of the 2 groups were similar. Mean plasma copeptin levels and urine osmolality declined from 6.2 ± 3.05 (SD) to 5.3 ± 2.5 pmol/L (P = 0.02) and from 426 ± 193 to 258 ± 117 mOsm/kg water (P = 0.01), respectively, in the intervention group compared to a nonsignificant change in the control group (from 4.7 ± 3.6 to 5.07 ± 4 pmol/L [P = 0.2] and 329 ± 159 to 349 ± 139 mOsm/kg water [P = 0.3], respectively). The change in copeptin levels (primary outcome) and urine osmolality was statistically significant between the intervention and control groups (delta copeptin, −0.86 ± 1.3 vs +0.39 ± 1.2 pmol/L [P = 0.009]; delta urine osmolality, −167 ± 264 vs +20 ± 80 mOsm/kg water [P = 0.007], respectively). Total urinary solute decreased in only the intervention group and significantly differed between groups at week 1 (P = 0.03), reducing mean water prescription from 3.2 to 2.6 L/d.Small sample size and short follow-up.We developed a stepwise dietary intervention that led to a significant reduction in vasopressin secretion in patients with ADPKD. Furthermore, this intervention led to a reduction in water required for vasopressin reduction.

Constituting an integral part of a heme's porphyrin ring, iron is essential for supplying cells and tissues with oxygen. Given tight links between oxygen delivery and iron availability, it is not surprising that iron deprivation and oxygen deprivation (hypoxia) have very similar consequences at the molecular level. Under hypoxia, the expression of major iron homeostasis genes including transferrin, transferrin receptor, ceruloplasmin, and heme oxygenase-1 is activated by hypoxia-inducible factors to provide increased iron availability for erythropoiesis in an attempt to enhance oxygen uptake and delivery to hypoxic cells. Iron-response proteins (IRP1 and IRP2) and “cap-n-collar” bZIP transcriptional factors (NE-F2 p45; Nrf1, 2, and 3; Bach1 and 2) also control gene and protein expression of the key iron homeostasis proteins. In this article, we give an overview of the mechanisms by which iron pathways are regulated by hypoxia at multiple levels. In addition, potential clinical benefits of manipulating iron pathways in the hypoxia-related conditions anemia and ischemia are discussed.

Gonadotropin-releasing-hormone (GnRH) analogues are synthetic compounds derived from decapeptide neurohormones (LHRH; LH/FSH-RH). They have a key role in hormone dependent cancer, particularly breast and prostate cancer. GnRH analogues produce an efficient inhibition of gonadotropins and sex steroid hormones. Their use in cancer therapy result in a, pharmacological castration (i.e. ovariectomy and orchiectomy), providing an androgen and estrogen ablation. GnRH exert an inhibitory action on the growth of hormone-dependent human and canine mammary tumor. Mammary tumors can produce growth factor that potentially could modulate their own proliferation in an autocrine fashion (i.e. TGF-&alpha; and TGF-&beta; or with a paracrine mechanism (i.e. EGF, IGF, FGF). The expression of EGF receptors is related in mammary tissues to the action of oestrogen and progesteron and to the presence of functional receptors for oestrogen (ER) and progesteron (PR). The present review elucidate the role of GnRH receptors in cancer and their connection with steroid hormones. Besides we showed the link between GnRH and signal transductions pathways: Estrogen-receptors, GnRH-receptors, EGF-receptors signal transduction pathways. A very tight link exists between steroid hormones and GnRH analogues both on central pituitary gonadal axis and on tumor receptors peripherically. This last mechanism could be explained either locally activating GnRH receptors or locally interacting with EGF receptor-Intracellular NitricOxide system.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Source of materialThe title compound was synthesized according to [1] by treatment of optically active a-lithiated 2-alkyl-2-oxazoline with N-cumyl nitrone followed by acidic hydrolysis with trifluoroacetic acid.To apre-cooled (-78 °C) solution of alkyloxazoline (1.2 mmol) in 10 ml of THF under N 2 was added s-BuLi (hexane solution 1.4 M, 1.2 mmol).The resulting orange mixture was stirred for 20 min at this temperature before adding slowly as olution of Ncumyl-a-phenylnitrone (THF, 5ml, 1.0 mmol).Then, the reaction mixture was warmed up to room temperature, quenched with sat.aq.NH 4 Cl, poured into 20 ml of saturated brine, extracted with Et 2O(30 ml), dried (Na2SO4)and the solvent evaporated under reduced pressure.The crude mixture was flash-chromatographed (silica gel; petroleum ether :AcOEt =7:3)togive an in-

Article Crystal structure of (2R*,3R*)-3-amino-2-ethyl-N-(2-hydroxy-1,1- dimethylethyl)-3-p-methoxyphenylpropanamide, C17H28N2O3 was published on December 1, 2008 in the journal Zeitschrift für Kristallographie - New Crystal Structures (volume 223, issue 4).

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.