Response of Osteoblasts on Amine-Based Nanocoatings Correlates with the Amino Group Density.

Increased life expectancy in industrialized countries is causing an increased incidence of osteoporosis and the need for bioactive bone implants. The integration of implants can be improved physically, but mainly by chemical modifications of the material surface. It was recognized that amino-group-containing coatings improved cell attachment and intracellular signaling. The aim of this study was to determine the role of the amino group density in this positive cell behavior by developing controlled amino-rich nanolayers. This work used covalent grafting of polymer-based nanocoatings with different amino group densities. Titanium coated with the positively-charged trimethoxysilylpropyl modified poly(ethyleneimine) (Ti-TMS-PEI), which mostly improved cell area after 30 min, possessed the highest amino group density with an N/C of 32%. Interestingly, changes in adhesion-related genes on Ti-TMS-PEI could be seen after 4 h. The mRNA microarray data showed a premature transition of the MG-63 cells into the beginning differentiation phase after 24 h indicating Ti-TMS-PEI as a supportive factor for osseointegration. This amino-rich nanolayer also induced higher bovine serum albumin protein adsorption and caused the cells to migrate slower on the surface after a more extended period of cell settlement as an indication of a better surface anchorage. In conclusion, the cell spreading on amine-based nanocoatings correlated well with the amino group density (N/C).

Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.

OBJECTIVES: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain. PATIENTS AND METHODS: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs. RESULTS: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003). CONCLUSIONS: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.

DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas.

BACKGROUND: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. METHODS: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. RESULTS: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. CONCLUSION: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors.

Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma.

BACKGROUND: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. RESULTS: High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). CONCLUSIONS: We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.

Survey of Anesthesia, Sedation, and Non-sedation Practices for Children Undergoing Repetitive Cranial or Craniospinal Radiotherapy.

Background Children undergoing cranial or craniospinal radiotherapy may require over 30 treatments within a six-week period. Facilitating these many treatments with the patient under anesthesia presents a significant challenge, and the most preferred anesthetic methods remain unknown. The primary goal of this study was to determine the most preferred anesthetic methods and agents for children undergoing daily cranial or craniospinal radiotherapy. Methods An 83-item web-based survey was developed. An introductory email was sent to 505 physicians and child-life specialists with expertise in pediatric anesthesia and/or affiliated with pediatric radiation oncology departments. Results The response rate was 128/505 (25%) and included specialists from Africa (5, 4%), Asia (18, 14%), Australia/Oceania (5, 4%), Europe (45, 35%), North America (50, 39%), and South America (5, 4%). The 128 respondents included 91 anesthesiologists (71%), 20 physicians who were not anesthesiologists (16%), 14 child life/social education specialists (11%), one radiotherapist, one pediatric radiation nurse, and one non-specified medical professional (all = 2%). Of the 128 respondents, 95 (74%) used anesthesia or sedation to facilitate repetitive cranial or craniospinal radiotherapy. Overall, total intravenous anesthesia without intubation was preferred by 67 of 95 (71%) specialists during one or more forms of radiotherapy. During photon-based radiotherapy, total intravenous anesthesia without intubation was the preferred anesthetic method with the patient in the supine (57/84, 68%) and prone positions (25/40, 63%). Propofol was the most used anesthetic agent for both supine (73/84, 87%) and prone positions (38/40, 95%). For proton radiotherapy, total intravenous anesthesia without intubation was the most preferred anesthetic method for the supine (32/42, 76%) and prone treatment positions (11/18, 61%), and propofol was the most used anesthetic (supine: 40/43, 93%; prone: 16/18, 89%). Conclusions In this survey of 95 specialists responsible for anesthesia or sedation of children undergoing repetitive cranial or craniospinal radiotherapy, propofol-based total intravenous anesthesia without intubation was the preferred anesthetic technique.

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.

Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele)=0.55; 95% confidence interval (CI)=0.34-0.89; P=0.014 and HR (per allele)=0.51; 95%CI=0.30-0.86; and P=0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele)=1.72; 95%CI=1.05-2.82; and P=0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR=1.64 (95% CI=1.26-2.14; P=0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

Cupric Oxide Nanostructures from Plasma Surface Modification of Copper.

Taking inspiration from the hydrophilic and superhydrophilic properties observed from the nanostructures present on the leaves of plants such as Alocasia odora, Calathea zebrina, and Ruelia devosiana, we were able to synthesize cupric oxide (CuO) nanostructures from the plasma surface modification of copper (Cu) that exhibits hydrophilic and superhydrophilic properties. The Cu sheets were exposed to oxygen plasma produced from the P300 plasma device (Alliance Concept, Cran-Gevrier, France) at varying power, irradiation times, gas flow rates, and pulsing duty cycles. The untreated and plasma-treated Cu sheets were characterized by contact angle measurements, scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) to determine the changes in the surface of Cu before and after plasma treatment. Results showed that plasma-treated Cu sheets exhibited enhanced wetting properties compared to untreated Cu. We attributed the decrease in the measured water contact angles after plasma treatment to increased surface roughness, formation of CuO nanostructures, and transformation of Cu to either CuO2 or Cu2O3. The presence of the CuO nanostructures on the surface of Cu is very useful in terms of its possible applications, such as: (1) in antimicrobial and anti-fouling tubing; (2) in the improvement of heat dissipation devices, such as microfluidic cooling systems and heat pipes; and (3) as an additional protection to Cu from further corrosion. This study also shows the possible mechanisms on how CuO, CuO2, and Cu2O3 were formed from Cu based on the varying the plasma parameters.

Viral monitoring and successful treatment of a ganciclovir-resistant cytomegalovirus infection in a heart transplant recipient.

We reported a ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection in a heart transplant recipient. Genotypic and phenotypic susceptibility assays demonstrated an A594V mutation in the UL97 phosphotransferase gene and GCV IC(50)>96 microM. Low GCV concentration exposure, immunosuppressive treatment, donor-positive/recipient-negative CMV serostatus, viral reactivations within antiviral prophylaxis or treatment, contributed to GCV-resistant strain selection.

Attention, in and Out: Scalp-Level and Intracranial EEG Correlates of Interoception and Exteroception.

Interoception, the monitoring of visceral signals, is often presumed to engage attentional mechanisms specifically devoted to inner bodily sensing. In fact, most standardized interoceptive tasks require directing attention to internal signals. However, most studies in the field have failed to compare attentional modulations between internally- and externally-driven processes, thus probing blind to the specificity of the former. Here we address this issue through a multidimensional approach combining behavioral measures, analyses of event-related potentials and functional connectivity via high-density electroencephalography, and intracranial recordings. In Study 1, 50 healthy volunteers performed a heartbeat detection task as we recorded modulations of the heartbeat-evoked potential (HEP) in three conditions: exteroception, basal interoception (also termed interoceptive accuracy), and post-feedback interoception (sometimes called interoceptive learning). In Study 2, to evaluate whether key interoceptive areas (posterior insula, inferior frontal gyrus, amygdala, and somatosensory cortex) were differentially modulated by externally- and internally-driven processes, we analyzed human intracranial recordings with depth electrodes in these regions. This unique technique provides a very fine grained spatio-temporal resolution compared to other techniques, such as EEG or fMRI. We found that both interoceptive conditions in Study 1 yielded greater HEP amplitudes than the exteroceptive one. In addition, connectivity analysis showed that post-feedback interoception, relative to basal interoception, involved enhanced long-distance connections linking frontal and posterior regions. Moreover, results from Study 2 showed a differentiation between oscillations during basal interoception (broadband: 35-110 Hz) and exteroception (1-35 Hz) in the insula, the amygdala, the somatosensory cortex, and the inferior frontal gyrus. In sum, this work provides convergent evidence for the specificity and dynamics of attentional mechanisms involved in interoception.

Efficacy and safety of valgancyclovir as preemptive therapy for the prevention of cytomegalovirus disease in solid organ transplant recipients.

We prospectively followed 70 CMV-seropositive solid organ transplant recipients to evaluate the efficacy and safety of valganciclovir (VGCV) as preemptive therapy based on antigenemia test to prevent cytomegalovirus (CMV) disease. From December 2003 to May 2004, 12 of 70 (17%) asymptomatic patients who showed an antigenemia value > or =25 positive cells per 2 x 10(5) polymorphonuclear (PMN) were treated with VGCV (900 mg twice a day adjusted to renal function) until resolution of CMV antigenemia, a minimum of 14 days. No patient developed CMV disease during follow-up. Only one who showed an asymptomatic relapse of the antigenemia test > or =25 positive cells was successfully treated with a repeated course of VGCV. Mean duration of VGCV therapy was 18 days (range, 14 to 28). Antigenemia was negative in 7 of 12 (58%) patients after 14 days and negative in all patients 4 weeks after the administration of VGCV. No significant side effects were associated with the use of VGCV therapy. Preemptive VGCV therapy is safe and effective in the prevention of CMV disease in seropositive solid organ transplant recipients.

Comparison of cytomegalovirus viral load measure by real-time PCR with pp65 antigenemia for the diagnosis of cytomegalovirus disease in solid organ transplant patients.

Cytomegalovirus (CMV) infection is the most frequent complication in solid organ transplant recipients. Currently, the antigenemia assay is widely used to detect this infection, although its success is being questioned to a great extent nowadays. The aim of our study is to compare a quantitative real time PCR to measure CMV DNA to the antigenemia assay, for the diagnosis to CMV disease. For our research, we prospectively processed 1198 samples (plasma and peripheral blood leukocytes [PBMC]), which belonged to 158 transplant recipients. In every sample the detection of the pp65 antigen in PBMC was carried out, as well as the quantification of CMV DNA by PCR (Light Cycler, LC-PCR). For this process, FRET probes, which detect a 254-bp fragment from the CMV gB gene, were used. The dynamic range of the LC-PCR was 500 to 5.10(7) copies/mL plasma and from 62 to 6.10(6) copies/10(6) PBMC. Twenty-three episodes of cytomegalovirus (CMV) disease occurred in 22 out of 158 patients and PCR displayed levels of sensitivity and specificity of 100% and 67%, respectively. The antigenemia assay obtained values of 91% and 57%. We established a cutoff value of 10(3) copies/mL plasma and 315 copies/10(6) cells. According to these cutoff values, PCR showed levels of sensitivity, specificity, VPN and VPP of 95.6%, 81.6%, 99%, and 53% respectively. Moreover, the LC-PCR assay anticipated the antigenemia assay in 10 patients out of 22 who developed CMV disease and the appearance of any clinical symptoms in 12 out of 22 patients. In conclusion, we believe that the quantification of CMV DNA by LC-PCR is a superior assay to pp65 antigenemia test regarding the early diagnosis of CMV disease in solid organ transplant recipients.

Irradiation of poly(tetrafluoroethylene) surfaces by CF4 plasma to achieve robust superhydrophobic and enhanced oleophilic properties for biological applications.

Poly(tetrafluoroethylene) (PTFE) was irradiated by CF4 plasma produced in the gas discharge ion source facility to produce stable and robust superhydrophobic surfaces and to enhance the materials' oleophilic property for biological applications. The characterizations employed on the samples are contact angle measurements, analysis of the surface morphology (scanning electron microscopy), surface roughness measurements (atomic force microscopy) and analysis of the surface chemistry (Fourier transform infrared spectroscopy). Superhydrophobic behavior with water contact angles as high as 156° was observed. The wettability of all the treated samples was found to be stable in time as evidenced by the statistically insignificant differences in the hysteresis contact angles. The level of enhanced hydrophobicity depended on the plasma energies (i.e. irradiation times, discharge current, and discharge voltage); higher plasma energies produced surfaces with high hydrophobicity. The plasma treatment also enhanced the oleophilic property of the materials' surface as evidenced by the decrease in the PDMS-oil contact angle from 33° to as low as 10°. The superhydrophobicity of the modified PTFE and the enhancement of its oleophilic property were due to (1) the changes in the roughness of the surface, (2) the formation of nanoparticles or nanostructures on the surface, and (3) the changes in the surface chemistry.

Kaolin and copper-based products applications: ecotoxicology on four natural enemies.

Lethal and sublethal effects of kaolin clays and two copper-based products on four natural enemies found in olive orchards Anthocoris nemoralis (F.) (Hem. Anthocoridae), Chelonus inanitus (L.) (Hym. Braconidae), Chilocorus nigritus (F.) (Col. Coccinellidae) and Scutellysta cyanea Motschulsky (Hym. Pteromalidae) are described. Both kaolin and copper can be applied for controlling the olive fruit fly and the olive moth, two important pests of this crop. The products did not increase the mortality of any of the insects studied, with the exception of A. nemoralis. The sublethal effects, however, differed depending on the parameter evaluated and the insect studied. Both kaolin and coppers slightly, but significantly, reduced the life span of C. inanitus and S. cyanea. Number of eggs laid by A. nemoralis females were reduced, but not significantly compared to the controls. In the behavioural experiments, clear preference for remaining on kaolin-untreated surfaces when insects were able to choose was observed. Despite having some negative effects, the negative impact on natural enemies was lower than the impact caused by products commonly applied in this crop against the pests stated above. Therefore, both kaolin and copper can be considered as alternative products to be applied in olive orchards if an effective resistance management programme is to be developed. Furthermore, both of them are allowed in organic farming, in which the number of products that can be applied is more restricted.

Limited impact of cytomegalovirus infection in the long-term outcome of renal and liver transplant.

BACKGROUND: The strength of the assumed association of CMV and long term deleterious events in solid organ transplant recipients (SOT) is controversial. OBJECTIVES: The aim of the present study was to evaluate whether viral replication dynamics during CMV infection or CMV disease may correlate not only with graft dysfunction and survival, but also with other potentially related late events in a long-term followed cohort of kidney (KT) and liver (LT) transplant recipients. STUDY DESIGN: 162 SOT (104 kidney, 58 liver) at our institution (2003-2005) with survival over 180 days and a median follow-up of 71 months (9-86) were analyzed. Using a Cox proportional hazard model, CMV infection (including area under the curve of DNAemia[AUC]) and CMV disease in the first 180 days were evaluated as potential predictors of the following late events (>180 days): mortality, graft dysfunction (GD), graft loss (GL), cardiovascular events (CVE), malignant tumors (MT). RESULTS: CMV infection occurred in 59% and CMV disease in 8%. Late death occurred in 17%, GD in 45.6%, GL in 14.2%, CVE in 10.5% and MT in 9.9%. We found no significant association between the intensity or duration of CMV viremia (AUC, persistent viremia or untreated CMV viremia) or CMV disease and the development of evaluated late events. According multivariate analysis neither CMV infection (hazard ratio [HR] 2.18 95% CI 0.949-5 p = 0.066) nor CMV disease (HR: 1.72; 95% CI 0.59-5 p = 0.31) were significantly correlated with late mortality. CONCLUSIONS: Our data do not support that CMV infection or CMV disease contribute significantly to long-term deleterious events in SOT.

Stability of the hydrophilic and superhydrophobic properties of oxygen plasma-treated poly(tetrafluoroethylene) surfaces.

Poly(tetrafluoroethylene) (PTFE) materials were exposed to low and high-energy oxygen plasma, and the stability of the materials' surface was evaluated using contact angle, surface roughness, and surface chemistry characterizations. Lower-energy oxygen plasma treatments exhibited hydrophilic behavior with contact angles as low as 87°, and the higher-energy oxygen plasma treatments exhibited superhydrophobic behavior with contact angles as high as 151°. The wettability of all the treated samples as stored in air and in water was found to be stable in time as evidenced by the statistically insignificant differences in the advancing, receding, and hysteresis contact angles. Low contact angle hysteresis (θH<5°) and low sliding angle (α≈4°) were exhibited by the superhydrophobic surface. The surface morphology was found to be responsible for the changes in the wettability of the PTFE samples since (1) there was an increase in the surface rms roughness as the plasma discharge energy was increased, and (2) there were no significant changes in the observed group frequencies of the FT-IR spectra of the treated PTFE from the untreated PTFE.

Hemodynamics and patient safety during pump-off studies of an axial-flow left ventricular assist device.

BACKGROUND: Axial-flow left ventricular assist devices (LVADs), when inactivated, may result in regurgitant blood flow. We assessed the effects of regurgitant pump flow with the intraventricular Jarvik 2000 Heart LVAD (Jarvik Heart, Inc., New York, NY) on hemodynamics and patient safety under pump-off conditions. METHODS: Thirty patients being supported by a Jarvik 2000 as a bridge to heart transplantation underwent pump-off studies. Hemodynamics, vital signs and cognitive function were monitored; Doppler echocardiographic studies were done with the pump turned off for 5 minutes if tolerated. Regurgitant flow was assessed in terms of the difference between left ventricular and right ventricular outflow tract cardiac output (LVOT CO - RVOT CO). RESULTS: During pump-off periods, the mean regurgitant flow was 0.42 +/- 0.41 liter/min, and the mean arterial blood pressure was 63.1 +/- 11.6 mm Hg. There was no regurgitant flow when the pump was on. Three patients did not tolerate the pump being off for periods of 5 minutes; in these tests, the mean regurgitant flow rate was 0.54 +/- 0.50 liter/min, the mean arterial blood pressure was 52.8 +/- 9.8 mm Hg, and the mean pump-off time was 3.1 +/- 1.1 minutes. All patients remained conscious during the pump-off period, and none showed lasting adverse effects. CONCLUSIONS: Our findings suggest that patients being supported with the axial-flow Jarvik 2000 Heart LVAD can generally tolerate pump-off times of 5 minutes.

Promoting library services to qualified nurses: towards a market-led approach.

This article summarizes a research project carried out with the nursing staff of South Buckinghamshire NHS Trust. A 'community profile' looked at nurses' use of library and information services for patient care purposes and found that only a small portion of all categories of qualified staff were library users. A postal questionnaire was used to investigate why nurses sought information, what they used it for, where they obtained it from and how valuable they perceived it to be. The results shown that personal and departmental collections were used quite frequently and the information was widely disseminated by the nurses to patients and their families, to colleagues and to students. The overall message from the survey was that the information obtained is valued highly and is used for various important purposes in health care delivery, such as educating patients and their families and revising treatment plans. However, nurses have difficulty in accessing libraries, which are judged to contain the most accurate, reliable and up-to-date information. The data from the community profile and questionnaire were further analysed using soft systems methodology, in order to identify problems in the traditional model of information delivery to nurses via conventional library and information service. These were then investigated further and a series of recommendations for action drawn up.