Role of Mitochondria in Tributyltin-Induced Interleukin-1α Production in Murine Keratinocytes

Tributyltin (TBT) salts are well known skin irritants in rodents and humans. TBT induced both the intracellular production of Interleukin-1α (IL-1α) and its release into culture medium in a murine keratinocyte cell line (HEL30). Here, we report that mitochondria are important for TBT-induced IL-1α production.Confluent cells were treated with increasing concentrations of TBT (0–2.5 μM) or dimethylsulfoxide as vehicle control. At different times thereafter (0–24 h), nuclear extracts were analyzed for nuclear factor-κB (NF-κB) binding activity by electrophoretic mobility shift assay, and the released and cell-associated IL-1α was measured by enzyme-linked immunosorbent assay. TBT induced a direct and concentration-related activation of NF-κB, which peaked at 2h and was blocked by pyrrolidinedithiocarbamate, a potent NF-κB inhibitor, and rotenone, an inhibitor of the electron entry from complex I to ubiquinone. Rotenone also induced a concentration-related inhibition of IL-1α synthesis induced by TBT, but rotenone did not completely abrogate TBT-induced IL-1α production, which suggests that other transcription factors may be involved in IL-1α production.Prolongod treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, was used to partially deplete cells of functional mitochondria. After 5 d of treatment, mitochondria conversion of tetrazolium bromide to formazan was reduced by 50%, and IL-1α release was decreased by 65%, whereas no induction of intracellular IL-1α was observed. This effect was not due to inhibition prot in synthesis because identical incorporation of [3H]leucine into protein in control and ethidium bromide–treated cells was identical. This impairment of mitochondrial metabolism inhibited NF-κB activation by TBT. These findings indicate that mitochondria may be the source of second messenger molecules important for TBT-induced IL-1α production

A Boundary Element Method for Motions and Added Resistance of Ships in Waves

The accurate prediction of ship resistance in waves is nowadays of increased importance since it greatly influences ship performance regarding sustainable service speed and fuel consumption in seaways. Added resistance is considered as the longitudinal component of the second order mean force acting on a ship in waves and can be calculated from the first order ship motions by integrating the corresponding second-order pressure on the body surface. The purpose of this paper is to present a methodology for the prediction of motions and added resistance by a three dimensional Rankine panel method and to discuss and validate its results by comparing them with experimental data. The prediction in the short wave range, where forces due to wave reflection dominate, has been made applying semi-empirical corrections proposed by Kuroda. Experimental data for the heave, pitch, and added resistance of an ITTC benchmark KRISO container ship have been compared with numerical ones, and the applicability of the proposed method is discussed

Role of SP-1 in SDS-Induced Adipose Differentiation Related Protein Synthesis in Human Keratinocytes

Skin irritation is a complex phenomenon, and keratinocytes play an important role in it. We have recently characterized the expression and protective role of adipose differentiation related protein (ADRP) in skin irritation. In particular, ADRP expression is induced to recover functional cell membrane following the cell damage caused by skin irritants

Reversible Holmes Tremor due to Middle Cerebral Artery Giant Aneurysm

A 40-year-old man presented with a 6-month history of mild but worsening tremor of variable intensity. The patient had a focal, irregular, rest and action tremor of middle amplitude and low frequency (about 4 Hz), limited to his right arm with oscillatory motion around the elbow. It was present inconsistently at rest, particularly during emotional activation, and enhanced by posture maintenance. It was evoked by various positions and tasks. Particularly, the tremor was present during fine motor skills such as writing, and it was increased by drinking and shaving, showing a minimal intentional component. The patient also reported slight loss in manual dexterity in his right hand

Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1β and NMDA stimulation

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin-1 receptor type I (IL-1RI) and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88) and the IL-1R accessory protein (IL-1RAcP). This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL-1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1β also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1β as a neuromodulator in physiological and pathological events relying on NMDA receptor activation

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.

Background: In this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC).Results: Patients were stratified into high SII (? 730) and low SII (< 730) groups. SII was associated with objective response, p < 0.0001. The median PFS was 6.3 months (95% CI 5.5–8.9) in patients with SII ? 730 and 18.7 months (95% CI 14.7–22.8) in those with SII < 730, p < 0.0001. The median OS was 43.6 months (95% CI 35.3–52.1) in patients with SII < 730, and 13.5 months (95% CI 9.8–18.5) in those with SII ? 730, p < 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively).Materials and Methods: We included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses.Conclusions: The SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC

Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients

WSTĘP. Celem badania była ocena wpływu przewlekłego doustnego stosowania L-argininy, działającej przez normalizację szlaku NO/cykliczny 3’,5’-guanozyno monofosforan (cGMP), na poprawę insulinowrażliwości obwodowej i wątrobowej u 12 szczupłych osób chorych na cukrzycę typu 2. MATERIAŁ I METODY. Badanie, przeprowadzone metodą podwójnie ślepej próby, trwało 3 miesiące. W pierwszym miesiącu chorych leczono typową dietą cukrzycową. Następnie losowo przydzielono ich do dwóch grup. W grupie 1 przez 2 miesiące stosowano typową dietę i placebo (doustnie 3 × d.). W grupie 2 pacjentów leczono przez miesiąc dietą i placebo (doustnie 3 × d.) i następnie przez miesiąc dietą i L-argininą (3 g 3 × d.). Po pierwszymi i drugim miesiącu wykonano badanie za pomocą klamry euglikemiczno-hiperinsulinemicznej z jednoczesnym wlewem dożylnym znakowanej izotopowo glukozy (glukoza 6,6- 2H2). Grupą kontrolną stanowiło 10 zdrowych osób, u których również wykonano badanie za pomocą klamry. WYNIKI. W grupie 1 w czasie badania nie zaobserwowano zmian podstawowego stężenia cGMP, skurczowego ciśnienia tętniczego, przepływu krwi w przedramieniu, wykorzystania glukozy i endogennej produkcji glukozy. W grupie 2 przyjmowanie L-argininy spowodowało normalizację podstawowego stężenia cGMP, poprawę przepływu w przedramieniu o 36%, oraz wykorzystania glukozy w badaniu metodą klamry metabolicznej o 34%, jak również obniżenie skurczowego ciśnienia tętniczego i endogennej produkcji glukozy odpowiednio o 14 i 29%. Pomimo tego w porównaniu z grupą kontrolną podawanie L-argininy nie normalizuje całkowicie metabolizmu glukozy. WNIOSKI. Podawanie L-argininy u chorych na cukrzycę typu 2 znacznie poprawia insulinowrażliwość obwodową i wątrobową, lecz nie normalizuje jej całkowicie.INTRODUCTION. The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine- 3’,5’-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. MATERIAL AND METHODS. A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-2H2] glucose infusion. A total of 10 normal subjects underwent the same test as control subjects. RESULTS. In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure, and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. CONCLUSIONS. L-arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients

An open day for children: The Bambineide in Arcetri

We briefly review the outreach activities at the Arcetri Astrophysical Observatory, and in particular the annual open day for children called Bambineide

The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study

Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era

Railway Systems and the 'Universal Good of the State': Technologies of Government in the 19th-Century Papal State

Informed by Foucault’s concept of governmentality, the paper focuses on nineteenth-century General Commissariat for the Railroad Industry in the Papal State. Unlike in liberal States, where government intervention in the affairs of railway companies was limited, the pressing need to reinforce the Pope’s pastoral power, strengthen the bond between the believers and the Holy See and ensure equity and the efficiency of the new infrastructure meant that the Commissariat acted as a governmental centre of calculation. Accounting technologies in the form of budgets, cost accounting systems and penetrating audits enabled the government to intervene in the operations of private railway companies. The study analyses the role of accounting and auditing practices in the pursuit of non-liberal goals in an industry which is traditionally perceived as critical to the development of a liberal economy, one in which accounting was traditionally used to maintain investors’ confidence in the capitalist system