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Introduction Apomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. Methods Sixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. Results After injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. Conclusion These results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

OBJECTIVES: To evaluate the prevalence of diarrhea and its association with drug use in elderly outpatients. METHODS: The study was carried out by 133 general practitioners (GPs) who referred to 24 geriatric units in Italy. The demographic data, disability, gastrointestinal symptoms, and current medications were evaluated using a structured interview, including the evaluation of the activities of daily living (ADL), the instrumental activities of daily living (IADL), and the gastrointestinal symptoms rating scale (GSRS). RESULTS: The study included 5,387 elderly subjects who regularly completed the structured interview. In total, 488 patients (9.1% of the whole population, 210 men and 278 women, mean age 75.6 6.2 yr, range 65–100 yr) reported diarrhea, that is, items 11 and 12 of the GSRS, during the 7-day period before the interview. The prevalence of diarrhea significantly increased with older age (P= 0.025), the severity of ADL (P < 0.0001) and IADL disability (P < 0.0001), and the number of drugs taken (P= 0.0002). A multivariate analysis demonstrated that the presence of diarrhea was significantly associated with the use of antibiotics (odds ratio [OR] 4.58, 95% confidence interval [CI] 1.95–10.73), proton pump inhibitors (OR 2.97, 95% CI 2.03–4.35), allopurinol (OR 2.19, 95% CI 1.26–3.81), psycholeptics (OR 1.82, 95% CI 1.26–2.61), selective serotonin reuptake inhibitors (OR 1.71, 95% CI 1.01–2.89), and angiotensin II receptor blockers (OR 1.46, 95% CI 1.08–1.99), also accounting for sex, age, and the use of antidiarrheal agents and drugs for functional gastrointestinal disorders. CONCLUSION: Diarrhea is a common problem in elderly outpatients. Its prevalence increases with old age, the severity of disability, and the number of drugs. Monitoring the presence of diarrhea and its complications in elderly patients who need treatments with drugs significantly associated with diarrhea may be clinically useful.

OBJECTIVE: This study aimed to evaluate the surgical treatment of acute pancreatitis in Italy and to assess compliance with international guidelines. METHODS: A series of 1173 patients in 56 hospitals were prospectively enrolled and their data analysed. RESULTS: Twenty-nine patients with severe pancreatitis underwent surgical intervention. Necrosectomy was performed in 26 patients, associated with postoperative lavage in 70% of cases. A feeding jejunostomy was added in 37% of cases. Mortality was 21%. Of the patients with mild pancreatitis, 714 patients with a biliary aetiology were evaluated. Prophylactic treatment of relapses was carried out in 212 patients (36%) by cholecystectomy and in 161 using a laparoscopic approach. Preoperative endoscopic retrograde cholangiopancreatography was associated with cholecystectomy in 83 patients (39%). Forty-seven patients (22%) were treated at a second admission, with a median delay of 31 days from the onset of pancreatitis. Eighteen patients with severe pancreatitis underwent cholecystectomy 37.9 days after the first admission. There were no deaths. DISCUSSION: The results indicate poor compliance with published guidelines. In severe pancreatitis, early surgical intervention is frequently performed and enteral feeding is seldom used. Only a small number of patients with mild biliary pancreatitis undergo definitive treatment (i.e. cholecystectomy) within 4 weeks of the onset of pancreatitis.

Dichrostachys cinerea is a thorny, acacia-like, fast-growing woody bush which invades fields, wasteland, road sides and other disturbed areas. This gregarious species has become a very aggressive invasive weed in Cuba, where no native predators or pathogens are found. It often encroaches in fallows, overgrazed areas and mismanaged veld. D. cinerea is a very difficult weed to eliminate because of its active suckering, and is liable to produce dense thickets which are quite impenetrable on account of the density and abundance of its long, stiff, sharp thorns. In the Valle de los Ingenios area (Cuba Central), the tree is unchecked and forms veritable forests in areas on which cane growing has been discontinued. Physical management by cutting and burning the plants is not a very efficient control method, since the seeds survive in the soil, and they grow very fast. Therefore, chemical methods via the use of herbicides are often necessary to eradicate this weed. A preliminary study using glyphosate and auxin-like herbicides (2,4-D + picloram, MCPA, and MCPA + 2,4-D) plus adjuvants has been carried out in order to elucidate the best mixtures rendering maximum weed control with minimum herbicide rate and environmental stress. None of the herbicides used except glyphosate and 2,4-D + picloram showed acceptable mortality rates (75-80%) at the recommended doses tested. In the failed herbicide treatments, only the use of double herbicide rates succeeded in controlling marabou. The herbicide mixture of 2,4-D + picloram formulated with either a non-ionic surfactant or a mixture of fatty acid esters was the best option to control D. cinerea in terms of maximum effectiveness and minimum environmental stress, as the reduction in active ingredients applied to the environment was x3 in these two adjuvant-amended formulations compared to 2,4-D + picloram alone.

In this study we show that SV-IV, a major immunomodulatory, anti-inflammatory, and sperm immunoprotective protein secreted from the rat seminal vesicle epithelium, acts in vitro as a substrate of protein kinase C (PKC) competing efficiently with H1 histone, a very well known PKC substrate. Electrospray mass spectrometry (ES-MS) analysis demonstrated that approximately 10% of the native SV-IV molecules were phosphorylated by PKC and that such a modification involved only a single serine residue (Ser58) out of the 22 occurring in the protein. Interestingly, this modification produced a substantial enhancement (approximately 50%) of the native SV-IV's ability to stimulate the activity of both horseradish peroxidase (POD) and selenium-dependent glutathione peroxidase (GPX), an enzyme that is known to protect the mammalian spermatozoa from oxidative stress and loss of motility in the female genital tract following ejaculation. In contrast, the phosphorylation of SV-IV on Ser58 did not produce any effect on the anti-inflammatory properties of SV-IV, as measured by its ability to inhibit the phospholipase A2.

The leader peptide of a recombinant MnSOD (rMnSOD-Lp) constitutes the carrier that allows rMnSOD to penetrate tumor cells. A synthetic preparation of rMnSOD-Lp was (68)Ga labelled (rMnSOD-Lp-(68)Ga) and injected into animals bearing spontaneous mammary cancers, followed by PET examinations which demonstrated unambiguously the tumor sites in all the animals, suggesting that if rMnSOD-Lp was able to transport the radioisotope into tumor cells, it would also be able to deliver cytotoxic molecules. The rMnSOD-Lp was therefore conjugated to cisplatin (rMnSOD-Lp-CC) and added to cultured tumor cells. Equal concentrations of cisplatin were used for the tests. After treating the ovarian cancer cells with 11.1 mug of cisplatin alone, analysis by atomic absorbance spectrophotometry was able to detect only 6 ng of platinum, whereas when the same cells were treated with the same amount of cisplatin conjugated to leader peptide rMnSOD, 387 ng of platinum were detected, i.e. an amount 80 times greater. Only the tumor cells died following treatment with rMnSOD-Lp-CC; molecular analysis revealed that its addition generated an increasing expression of Erk-2 and Bax products which could be inhibited only by a selective MAP/ERK kinase inhibitor (PD98059), revealing that rMnSOD-Lp-CC has an apoptotic function, exactly as occurs when using the cisplatin alone. Data are statistically significant and indicate that by using rMnSOD-Lp-CC, the cisplatin can be transformed from an agent with antireplicative activity into a specific and selective antitumor molecule, increasing its therapeutic index. We think that rMnSOD-Lp-CC deserves to be considered as a new antitumor agent. (c) 2010 UICC

A retrospective analysis of 462 consecutive liver transplantations has been carried out, These were divided into two groups, according to whether they failed within 90 days (Group I) or survived longer than 90 days (Group II). Twenty-five donor and recipient variables were analyzed, In the univariate analysis, the only donor variable that was significantly different between the two groups was age (45.3 +/- 16.9 years in Group I vs 37.9 +/- 15.4 years in Group II, p < 0.001), There were five recipient variables significantly associated with early graft failure: history of previous liver transplantations (p < 0.0001), United Network for Organ Sharing 4 status (p = 0.003), primary diagnosis (p = 0.001), preoperative serum creatinine (1.97 +/- 1.5 mg/dL, in Group I vs 1.46 +/- 1.2 mg/dL, in Group II, p = 0.005), and preoperative total serum bilirubin (13.5 +/- 14.4 mg/dL in Group I vs 8.4 +/- 11.4 mg/dL in Group II, p = 0.003), In the multivariate analysis, only three variables were independently associated with outcome: donor age greater than 45 years, abnormal (> 1.5 mg/dL) recipient preoperative creatinine, and a history of previous liver transplantation.

Seminal vesicle protein IV (SV-IV) is a secretory anti-inflammatory, procoagulant, and immunomodulatory protein produced in large amounts by the seminal vesicle epithelium of the rat under the strict transcriptional control of androgen. In particular, this protein was shown to possess the ability to markedly inhibit in vivo the humoral and cell-mediated immune responses of mice to nonbacterial cellular antigens (sheep erythrocytes and spermatozoa). We report data that demonstrate that in mice treated with SV-IV and infected with Salmonella enterica serovar Typhimurium, SV-IV is able to downregulate some important immunological and biochemical parameters that serovar Typhimurium normally upregulates in these animals. This event did not correlate with a lower bacterial burden but was associated with a markedly increased one (300%). Furthermore, the treatment of mice with SV-IV alone also produced a significant increase in the rate of mortality among serovar Typhimurium-infected animals. The mechanism underlying these phenomena was investigated, and the strong immunosuppression produced by SV-IV in serovar Typhimurium-infected mice was suggested to be the basis for the increased rate of mortality. The SV-IV-mediated immunosuppression was characterized by a decrease in the humoral and cell-mediated immune responses, altered lymphocyte-macrophage interaction, downregulation of cytokine and inducible nitric oxide synthase gene expression, inhibition of macrophage phagocytosis and intracellular killing activities, and absence of apoptosis in the splenocyte population of SV-IV- and serovar Typhimurium-treated mice. The immunosuppressive activity of SV-IV was specific and was not due to aspecific cytotoxic effects. SV-IV-specific receptors (K(d) = 10(-8) M) occurring on the macrophage and lymphocyte plasma membranes may be involved in the molecular mechanism underlying the SV-IV-mediated immunosuppression. Some results obtained by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay also revealed a functional impairment of mitochondria (a decrease in mitochondrial dehydrogenase activity), thus indicating the possible implication of these organelles in the immunosuppressive process.

Tensioning of the tendons of the semitendinosus and the gracilis used to reconstruct the anterior cruciate ligament (ACL) of the knee is one of the main factors to take into consideration during surgery that aims at obtaining good postoperative joint stability. Some authors have shown in vitro that the viscoelastic nature of the patellar tendon is responsible for its gradual release (loss of tension). It is the purpose of this study to verify in vivo the biomechanical behavior of the semitendinosus and gracilis tendons. A total of 40 consecutive patients were submitted to reconstruction of the ACL with flexor tendons of the knee using a method that allows for the gradual tensioning of the doubled semitendinosus and gracilis tendons using the Swing Bridge method. Patients were divided into 2 groups: in the first 20 patients (group I), after adequate manual pretensioning and tibial and femoral stabilization, the tendons were twisted using a dynamometer to measure torsion forces until tensioning equal to 2.5 N was achieved. The control group (group II) was made up of the successive 20 patients in whom tensioning of the tendons at 2.5 N was carried out in many phases. Five minutes after initial tensioning at 2.5 N the decrease in tension was recorded that returned to initial values. A similar procedure was carried out after 5 more minutes. The patients in both groups were evaluated using a KT-1000 arthrometer one year after surgery. The patients in group II showed a decrease in torsion equal to 37.2% after the first 5 minutes, and a further 26.8% after 5 more minutes, and measurement by means of KT-1000 revealed mean values for S/S 30 lb. and S/S MM of 1.3 mm and 1.7 mm, respectively, that proved to have a statistically significant difference (p0.05) as compared to the patients in group I (S/S 30 lb.: 2.0 mm; S/S MM: 2.4 mm). Although these data do not provide indications on the amount and duration of pretensioning and definitive tensioning to be applied to the transplant, they do clearly show the viscoelastic properties of the tendons. These properties require a more in-depth study to better determine the exact tensioning of the neoligament.

The Valdes Peninsula is a high-natural value area, located on the east coast of Argentine Patagonia. The aim of the reported research was to analyze the community of breeding passerine birds of the inland areas, with the purpose to identify the species that characterize each community, determining the main environmental typologies frequented, in order to study the relationships between bird richness and abundance, and environmental structure. During the breeding season 2011, 107 point counts were performed. 869 birds belonging to 23 passerine species were contacted and analyzed through a cluster analysis using the Indicator Value method. Results revealed the existence of two different communities: one that essentially refers to the grassy steppe where the characteristic species are Shortbilled Pipit (Anthus furcatus) and Common Miner (Geositta cunicularia), and the other one, which occupies the shrub-steppe consisting of more characteristic species, starting from the Rufous-collared Sparrow (Zonotrichia capensis), the most widespread species. These results update previous results on the community of passerines living in the study area and provide some useful insights for management purposes. La Península de Valdes es un area de gran riqueza natural, localizada en la costa Este de la Pa- tagonia Argentina. El propósito de este trabajo fue analizar la comunidad de aves Passeriformes de las areas internas de la región, con el proposito de identificar las especies que caracterizan cada comuni- dad, determinando las principales tipologias ambientales frecuentadas, para poder estudiar las rela- ciones entre la riqueza y abundancia de aves y la estructura del ambiente. Se realizaron 107 puntos de conteo durante la temporada reproductiva de 2011, en donde se detectaron 869 aves pertenecientes a 23 especies de Passeriformes. Para los análisis se usó el método de agrupamiento por el método del Indicator Value. Los resultados evidencian la existencia de dos diferentes comunidades: una asociada exclusivamente a la estepa herbácea y caracterizada por las especies Cachirla uña corta (Anthus furca- tus) y Minero común (Geositta cunicularia); mientras que la otra, asociada a la estepa arbustiva, es car- acterizada por diferentes especies típicas, como el Chingolo (Zonotrichia capensis), que es la especie de mayor distribución. Estos resultados constituyen una actualización al conocimiento de la fauna de la Península de Valdés, los cuales pueden ser útiles para el manejo y conservación de la avifauna de la región. Fil: Pruscini, Fabio. Università Di Urbino; Italia Fil: Morelli, Federico. Università Di Urbino; Italia Fil: Sisti, Davide. Università Di Urbino; Italia Fil: Perna, Paolo. Universita Degli Di Camerino. Scuola Di Scienze Ambientale; Italia Fil: Catorci, Andrea. Universita Degli Di Camerino. Scuola Di Scienze Ambientale; Italia Fil: Bertellotti, Nestor Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagónico; Argentina Fil: Rocchi, Marco Bruno Luigi. Università Di Urbino; Italia Fil: Santolini, Ricardo. Università Di Urbino; Italia

Stability and Ductility of Steel Structures 2019 : Proceedings of the International Colloquia on Stability and Ductility of Steel Structures, Prague, Czech Republic, September 11-13, 2019 / Editors: Frantiček Wald & Michal Jandera, Czech Technial University in Prague, Czech Republic International Colloquia on Stability and Ductility of Steel Structures, SDSS, Prague, Czech Republic, 11 Sep 2019 - 13 Sep 2019; Leiden : CRC Press/Balkema 329-336 (2019). doi:10.18154/RWTH-2020-07900, Published by CRC Press/Balkema, Leiden

A 34-year-old patient underwent liver transplantation for progressive hepatic failure in the setting of congenital hepatic fibrosis. In past medical history, the patient had undergone splenectomy with proximal Linton’s splenorenal surgical shunt creation for symptomatic portal hypertension with hypersplenism. The patient developed an early allograft dysfunction, with radiologic evidence of a reduced portal flow associated to portal steal from the patent surgical shunt. The patient was successfully treated through endovascular placement of a 30 mm Amplatzer cardiac plug at the origin of the splenic vein.

Background Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. Objective To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. Design, setting, and participants Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. Outcome measurements and statistical analysis Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. Results and limitations Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37–0.72; p p 50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p Conclusions Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. Patient summary We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

The Emilia, May–July 2012, earthquake hit a highly industrialized area, where some tens thousands industrial buldings, mainly single storey precast structures, are located. Due to the likelihood of strong after shocks and the high vulnerability of these structures, the authorities first asked for a generalized seismic retrofit after the strong shakings of May 20th. In order to accelerate community recovery, this requirement was later loosened, leaving out the buildings which had undergone a strong enough shaking without any damage; the strong enough shaking was defined with reference to the ultimate limit state design earthquake. To the authors’ knowledge, it is the first time that the information on the earthquake intensity and structural damage is used for such a large scale post earthquake simplified safety assessment. In short, the earthquake was used as large experimental test. This paper shows the details of the models and computations made to identify the industrial buildings which have been considered earthquake tested and therefore not compelled to mandatory seismic retrofit. Since earthquake indirect (e.g. due to economic halt) costs may be as large the direct ones, or even larger, it is believed that this method may considerably lower the earthquake total costs and speed up the social and economic recovery of a community.

Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1a (HIF-1a) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1a regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1α (HIF-1α) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1α regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. © 2011 Società Italiana di Nefrologia.

The major toxic components in the outer membranes of gram-negative bacteria are lipopolysaccharides (LPS) (endotoxins) and porins. The latter are hydrophobic proteins (mass, about 35,000 Da) that account for more than 50% (18, 35) of the total membrane proteins and that are named porins for their ability to form transmembrane channels for the passive diffusion of small molecules across the cell membrane (26, 27). Purified porins possess immunomodulatory and procoagulant activities and are considered pathogenicity determinants. Depending on the dose, LPS and porins are either frankly toxic to a number of target cells or significantly alter normal cell functions (10, 45). By acting on human polymorphonuclear leukocytes (PMNs), subtoxic concentrations of porins, for example, inhibit phagocytosis and intracellular killing of Salmonella typhimurium (45), decrease oxidative burst and cell hydrophobicity, and cause significant morphological changes in the target cells (46). Subcutaneous injection of porins in rat hind paws causes local inflammation without complement activation (12, 13), a process that is known to be triggered in vitro by these proteins. Finally, it has recently been demonstrated that nontoxic concentrations of porins stimulate the synthesis and release of platelet-activating factor from different types of human cells (PMNs and mesangial and endothelial cells) (6, 41, 42) and promote proinflammatory and immunomodulatory cytokine release from immunocompetent cells or other cellular sources (11). Porins from different microorganisms have similar effects (8, 23, 43, 44). The cell damage from severe infections by gram-negative bacteria comes mainly from exotoxins and enterotoxins, even though the occurrence of LPS and porins in the bacterial microenvironment contributes significantly. Exposure of target cells to high concentrations of these substances leads to a rapid lytic death of the cells (1, 5, 10, 34, 45). In contrast, lower concentrations of LPS produce a less dramatic type of death: programmed cell death (PCD), or apoptosis (49). Classic morphological and biochemical signs of apoptosis in the toxin-injured cells are cell shrinkage, extensive blebbing of the cell surface, disappearance of microvilli, chromatin condensation, internucleosomal DNA fragmentation, presence of large intracytoplasmic vacuoles, increase of intracellular calcium ion and free radical levels, enhancement of endonuclease and protease activities, cell cycle arrest, and modified transcriptional activity of different apoptosis-linked genes (p53, bcl-2, c-myc, etc.) (2, 7). An increase in the expression of type II transglutaminase (tissue transglutaminase [tTGase]) has also been reported to be associated with apoptosis in several cell types, and an important role for tTGase in this process has been proposed (15). The ability of bacterial endotoxin to kill cells by necrosis and/or apoptosis has been found to play a key role in the pathogenesis of many alterations occurring in subjects with infections by gram-negative bacteria, including disseminated intravascular coagulation, septic shock, degenerative processes in different tissues, and reduced fertility or sterility (4, 10, 24, 48). The tissue lesions produced by Pseudomonas aeruginosa are of particular interest. P. aeruginosa is an opportunistic pathogen that commonly invades immunocompromised patients. The main targets of the LPS and porin released by this gram-negative rod during its lysis or active growth are the endothelial and epithelial cells present in many anatomical regions, including the skin, eyes, genitourinary tract, and heart valves. In particular, it has been reported that low levels of natural porin or LPS in patients with mild chronic infections severely damage the human spermatozoa in vitro and lead to reduced fertility or sterility (29). On the basis of these data and considerations, and taking into account the scarce information available on the cytotoxic effects of very low concentrations of LPS or porin on specific target cells, we were prompted to investigate the possible involvement of these substances in the induction of apoptosis in a cell line (SVC1) derived from the rat seminal vesicle secretory epithelium (36, 37, 49).

Rationale PSA responses have been associated with a survival benefit in patients treated with enzalutamide in retrospective analyses. Patient concerns However the prognostic value of PSA declines in highly pretreated patients receiving enzalutamide remains to be defined. Diagnoses and interventations Medical records of patients with documented mCRPC treated with enzalutamide between September 2011 and August 2016 were reviewed at multiple participating centers and assessed for overall survival (OS), PSA variations, and other variables of interest. Univariable and multivariable analyses were conducted. Outcomes A total of 129 patients received enzalutamide. PSA response rates (>50% PSA declines) were 58/119 (48.7%), 58/115 (50.4%), 54/110 (49.1%), and 47/91 (51.7%) at weeks 4, 8, 12, and 16, respectively. Having a PSA response was a statistically significant prognostic factor of improved OS at 8 and 12 weeks in univariable analysis, whereas it was significant at 12 weeks in the multivariable analysis. Patients treated with enzalutamide had a median OS of 7.8 months. Lessons Our study supports the prognostic value of PSA declines in heavily treated patients receiving enzalutamide.

The effect of nontoxic, low concentrations (10 −8 M) of retinoic acid (RA) for a relatively long time (28 days) on a Kirsten ras-virus transformed cell line (Ki-SVC1), derived from the rat seminal vesicle epithelium, was investigated. In these experimental conditions, the cell treatment with RA induced a decrease of the proliferation rate, apoptosis and a marked reduction of both anchorage-independent growth and tumorigenicity. These biological responses were either preceded or associated with important changes in adenylate cyclase/protein kinase C signaling pathways, the activation of important apoptosis-linked genes and a marked decrease of the v-Ki-ras p21 protein. The significance of these findings is discussed.

The aim of the study was to evaluate the effect of the protein Seminal Vesicle Protein No. 4 (SV-IV), a potent inhibitor of antithrombin III (antithrombin), on the coagulation of blood obtained from patients affected by hemophilia A. In the coagulating blood of these patients, the antithrombin/thrombin ratio was found to be markedly higher (about 44) than in normal individuals (about 4. 4). This high ratio was related to the low efficiency of thrombin-generating reactions induced by the factor VIII deficiency and to the high levels of free (not bound to serine proteases) antithrombin present in the hemophilic serum (antithrombin concentration was the same in normal and hemophilic plasma). The elevated concentration of free antithrombin in hemophiliacs was primarily a consequence of a reduced consumption caused by the scarce availability in the hemophilic serum of factors Xa and IIa, which are serine proteases possessing strong binding affinity for antithrombin. Addition of SV-IV to coagulating hemophilic blood reduced markedly the serum antithrombin and thrombin-antithrombin complexes, normalizing, as a consequence, the clotting time and other coagulation parameters. Similar results were obtained by using appropriate concentration of factor VIII.

Objective The authors determined the impact of a positive cytotoxic crossmatch on the outcome of liver transplantation. Summary Background Data Liver allografts rarely undergo hyperacute rejection, but transplants performed across a positive cytotoxic crossmatch tend to follow a different clinical course, with higher intraoperative blood use, postoperative graft dysfunction, and, in some cases, graft loss. How this affects overall graft survival has not been determined. Methods The authors provide a retrospective analysis of 1520 liver transplants performed between November 1989 and December 1993, with a minimum follow-up of 1 year. All cases had a cytotoxic crossmatch using serum pretreated with dithiothreitol. Results There were 1390 negative crossmatch and 130 positive crossmatch cases. There was no difference in overall graft survival, although early survival rates were lower in the positive crossmatch group, with the maximum difference at 6 months: 0.76 (95% confidence interval, 0.74-0.78) for a negative crossmatch versus 0.68 (95% confidence interval, 0.61-0.77) for a positive crossmatch. These differences become negligible by the 2-year mark. Using stepwise logistic regression, the authors identified seven variables independently associated with outcome: 1) donor age, 2) donor gender, 3) prior liver transplant, 4) medical urgency status, 5) ischemia time, 6) indication for transplantation, and 7) primary immunosuppressant. Conclusions The cytotoxic crossmatch is not statistically associated with overall graft survival after liver transplantation. However, early failure rates are higher in the positive crossmatch cases, a difference that disappears by the second year.

The involvement of brain deoxyribonucleic acid (DNA) synthesis in adaptive neural events was studied in the adult rat during long-term habituation (LTH) or potentiation (LTP) of the perforant path-granule cell synapse. Male Long-Evans rats were given 50 muCi [3H]thymidine intraventricularly under urethane anesthesia. Soon thereafter, field excitatory postsynaptic potential (EPSP) slope and population spike were monitored from the right dentate gyrus before and at various times (5, 10, 15, 60 min) following the delivery to the ipsilateral perforant bundle of a low frequency (LFS: 1.0 Hz, 160 s) or a high-frequency train (HFS: 400 Hz, 200 ms), repeated once after 5 min. Unstimulated implanted rats served as controls. DNA synthesis was evaluated by the incorporation of the radioactive precursor into DNA of several brain areas at the end of a 1 h incorporation period. In CA1, LTH and LTP increased DNA synthesis by 30% on the stimulated side. In the entorhinal cortex, LTH but not LTP increased DNA synthesis (by 30%) on the stimulated side. Conversely, in the frontal cortex, LTP but not LTH increased DNA synthesis (by 100%) on both sides. Long-lasting changes in synaptic efficacy covaried non-linearly with DNA synthesis in mono- and polysynaptically stimulated hippocampal regions, and in functionally associated neocortical areas. The co-variations of population spike amplitude were positive for LTH and negative for LTP in the dentate gyrus and frontal cortex of both sides, and in CA3/CA1 of the stimulated side, indicating higher DNA synthesis at lower values of LTH and LTP, and viceversa. Further, regional cross-correlation analyses revealed a high degree of synchronization among brain sites, following low- or high-frequency train pulses, indicating that (i) extra-target sites participate on the stimulated and on the contralateral side, and (ii) small distributed changes take place across the sampled neural networks. A modulatory role of information flow on brain DNA synthesis is inferred to take place in a diffuse, distributed manner.

Previous data showing an increase of receptor binding activity of [R16]VIP, a vasoactive intestinal peptide (VIP) structural analogue containing arginine at the position 16 of its amino acid sequence, have pointed out the importance of a positive charge at this site. Here, the functional characterization of three VIP polyaminated adducts (VIPDap, VIPSpd, and VIPSpm), obtained by a transglutaminase-catalysed reaction between the VIP Gln16 residue and 1,3-diaminopropane (Dap), spermidine (Spd), or spermine (Spm), is reported. Appropriate binding assays and adenylate cyclase enzymatic determinations have shown that these VIP adducts act as structural VIP agonists, both in vitro and in vivo. In particular, their IC50 and EC50 values of human and rat VIP/pituitary adenylate cyclase activating peptide (PACAP)1 and VIP/PACAP2 receptors indicate that VIPDap is a VIP agonist, with an affinity and a potency higher than that of VIP, while VIPSpd and VIPSpm are also agonists but with affinities lower than that of VIP. These findings suggest that the difference in adduct agonist activity reflects the differences in the positive charge and carbon chain length of the polyamine covalently linked with the VIP Gln16 residue. In addition, the data obtained strongly suggest that the length of polyamine carbon chain could be critical for the interaction of the agonist with its receptor, even though possible hydrophobic interaction cannot be ruled out. In vivo experiments on murine J774 macrophage cell cultures have shown the ability of these compounds to stimulate the inducible nitric oxide synthase activity at the transcriptional level.