Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry.
Limited data are available on the characteristics, clinical management, and outcomes of patients with atrial fibrillation at risk of stroke, from a worldwide perspective. The aim of this study was to describe the baseline characteristics and initial therapeutic management of patients with non-valvular atrial fibrillation across the spectrum of sites at which these patients are treated. The Global Anticoagulant Registry in the FIELD (GARFIELD) is an observational study of patients newly diagnosed with non-valvular atrial fibrillation. Enrollment into Cohort 1 (of 5) took place between December 2009 and October 2011 at 540 sites in 19 countries in Europe, Asia-Pacific, Central/South America, and Canada. Investigator sites are representative of the distribution of atrial fibrillation care settings in each country. Cohort 1 comprised 10,614 adults (≥18 years) diagnosed with non-valvular atrial fibrillation within the previous 6 weeks, with ≥1 investigator-defined stroke risk factor (not limited to those in existing risk-stratification schemes), and regardless of therapy. Data collected at baseline included demographics, medical history, care setting, nature of atrial fibrillation, and treatments initiated at diagnosis. The mean (SD) age of the population was 70.2 (11.2) years; 43.2% were women. Mean±SD CHADS2 score was 1.9±1.2, and 57.2% had a score ≥2. Mean CHA2DS2-VASc score was 3.2±1.6, and 8,957 (84.4%) had a score ≥2. Overall, 38.0% of patients with a CHADS2 score ≥2 did not receive anticoagulant therapy, whereas 42.5% of those at low risk (score 0) received anticoagulant therapy. These contemporary observational worldwide data on non-valvular atrial fibrillation, collected at the end of the vitamin K antagonist-only era, indicate that these drugs are frequently not being used according to stroke risk scores and guidelines, with overuse in patients at low risk and underuse in those at high risk of stroke. ClinicalTrials.gov TRI08888.


High antibody-dependent cellular cytotoxicity responses are correlated with strong CD8 T cell viral suppressive activity but not with B57 status in HIV-1 elite controllers.
The role of Antibody-dependent cellular cytotoxicity (ADCC) responses in HIV-1 controllers is still unclear due to the heterogeneity of these patients. We analyzed 67 HIV-1 controllers and found significantly higher levels of ADCC antibodies in controllers versus viremic subjects (p = 0.017). Moreover, multivariate analysis revealed significantly higher ADCC titers in HLA B57- controllers compared to HLA-B57+ ones (p = 0.0086). These data suggest a role for ADCC in immune control of HIV, especially in HLA B57 negative controllers.


Perioperative bridging therapy with unfractionated heparin or low-molecular-weight heparin in patients with mechanical prosthetic heart valves on long-term oral anticoagulants (from the REGIMEN Registry).
Patients with mechanical prosthetic heart valves require long-term oral anticoagulant therapy (OAT). During the temporary interruption of OAT, bridging anticoagulant therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is recommended. This prespecified subgroup analysis from REGIMEN-a large, prospective, multicenter registry-compared UFH (n = 73) and LMWH (n = 172) as bridging anticoagulation in patients with mechanical heart valves on long-term OAT. Patient demographics and co-morbidities were generally similar between groups. There were more bileaflet valves in the LMWH group (67.4% vs 43.8%, p = 0.0005), but no differences in valve positions between groups. The LMWH group was less likely to undergo major surgery (33.7% vs 58.9%, p = 0.0002) and cardiothoracic surgery (7.6% vs 19.2%, p = 0.008), and to receive intraprocedural anticoagulants or thrombolytics (4.1% vs 13.7%, p = 0.007). Major adverse event rates (5.5% vs 10.3%, p = 0.23) and major bleeds (4.2% vs 8.8%, p = 0.17) were similar in the LMWH and UFH groups, respectively; 1 arterial thromboembolic event occurred in each group. More LMWH-bridged patients were treated as outpatients or discharged from the hospital in <24 hours (68.6% vs 6.8%, p <0.0001). Multivariate logistic analysis found no significant differences in major bleeds and major composite adverse events when adjusting for cardiothoracic or major surgery between groups. In conclusion, for patients with mechanical prosthetic heart valves on long-term OAT, mostly outpatient-based LMWH bridging therapy appears to be feasible for selected procedures, is as safe as UFH, and is associated with a low arterial thromboembolic rate.


Whole Transcriptome Analyses Reveal Differential mRNA and microRNA Expression Profiles in Primary Human Dermal Fibroblasts Infected with Clinical or Vaccine Strains of Varicella Zoster Virus.
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype (clinical) versus attenuated (vaccine-derived) VZV-mediated host cellular responses, we performed high-throughput next generation sequencing to quantify and compare the expression patterns of mRNAs and microRNAs (miRNAs) in primary human dermal fibroblasts (HDFs) infected with wildtype (YC01 low passage) and attenuated (YC01 high passage, SuduVax, and VarilRix) VZV strains. 3D-multidimensional scaling of the differentially expressed genes demonstrated the distinct grouping of wildtype and attenuated strains. In particular, we observed that HDFs infected with attenuated strains had more differentially expressed genes (DEGs) involved in the retinoic-acid inducible gene-I-like receptor and interferon-mediated signaling pathways compared with wildtype strains. Additionally, miRNA expression patterns were profiled following the infection of HDFs with VZV. Small RNA sequencing identified that several miRNAs were upregulated, including miR-146a-5p, which has been associated with other herpesvirus infections, whereas let-7a-3p was downregulated in both wildtype and attenuated VZV-infected cells. This study identified genes and miRNAs that may be essential in VZV pathogenesis.


A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury.
Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white). Collaborative meta-analysis. 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Available eGFR, ACR, and 50 or more AKI events. Age, sex, race, eGFR, urine ACR, and interactions. Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code. Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.


A double blind placebo controlled trial of medroxyprogesterone acetate (MPA) in cancer cachexia.
Patients with breast cancer treated with MPA often report an improvement in appetite. Similar appetite stimulation is seen in patients treated with some corticosteroids, but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect. MPA (100 mg tds orally) has therefore been compared with placebo in 60 patients with advanced malignant disease. Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy. Patients were treated for 6 weeks and were assessed at weeks 0, 3 and 6 for appetite, energy, mood and pain using visual analogue scales. Nutritional status was assessed by the measurement of serum proteins and anthropometrics. Karnofsky score was recorded as a measure of performance status. There was a significant improvement in appetite in the MPA group between weeks 0 (pre-study) and 3 (P = 0.0002) and 0 and 6 (P = 0.015). There was no significant improvement in appetite in the placebo group. Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 (P = 0.023 and P = 0.039 respectively). These two parameters showed no significant change in the placebo group. There was no change in anthropometric measurements, weight, performance status, energy, mood or pain in either group. These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status. However, this apparent increase in appetite did not result in improved weight, performance status, energy levels, mood or relief of pain. Further studies to investigate the effect of higher doses of MPA are indicated.


Molecular Validation of Chondrogenic Differentiation and Hypoxia Responsiveness of Platelet-Lysate Expanded Adipose Tissue-Derived Human Mesenchymal Stromal Cells.
To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue-derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems. Both AMSCs and primary human chondrocytes were cultured for 21 days in chondrogenic media under normoxic (21% oxygen) or hypoxic (2% oxygen) conditions using 2 distinct 3D culture methods (high-density pellets and poly-ε-caprolactone [PCL] scaffolds). Histologic analysis of chondro-pellets and the expression of chondrocyte-related genes as measured by reverse transcriptase quantitative polymerase chain reaction were used to evaluate the efficiency of differentiation. AMSCs are capable of expressing established cartilage markers including COL2A1, ACAN, and DCN when grown in chondrogenic differentiation media as determined by gene expression and histologic analysis of cartilage markers. Expression of several cartilage-related genes was enhanced by low oxygen tension, including ACAN and HAPLN1. The pellet culture environment also promoted the expression of hypoxia-inducible cartilage markers compared with cells grown on 3D scaffolds. Cell type-specific effects of low oxygen and 3D environments indicate that mesenchymal cell fate and differentiation potential is remarkably sensitive to oxygen. Genetic programming of AMSCs to a chondrocytic phenotype is effective under hypoxic conditions as evidenced by increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix. Lower local oxygen levels within cartilage pellets may be a significant driver of chondrogenic differentiation.


Susceptibility of Aotus trivirgatus to Leishmania braziliensis and L. mexicana.
Two Aotus trivirgatus (owl monkeys) were infected experimentally with Leishmania braziliensis and two with L. mexicana strains of Panamanian origin in a pilot study to determine the susceptibility and the course of infection of cutaneous leishmaniasis in this primate species. Montenegro skin tests performed on all animals prior to parasite inoculation were negative. A standardized inoculum of promastigotes was injected intradermally on the nose of each monkey. All of the animals developed infections which lasted from 3.5 to 8.5 months. Depigmentation developed at the site of the inoculation in all of the subjects. The severity of the resulting lesions was greater in the animals infected with L. braziliensis. Positive skin tests developed in three A. trivirgatus at days 62, 76, and 139 postinoculation, respectively. An explanation for the negative skin test in the fourth animal is discussed.


Protein functionalized carbon nanotubes-based smart lab-on-a-chip.
A label-free impedimetric lab on a chip (iLOC) is fabricated using protein (bovine serum albumin) and antiapolipoprotein B functionalized carbon nanotubes-nickel oxide (CNT-NiO) nanocomposite for low-density lipoprotein (LDL) detection. The antiapolipoprotein B (AAB) functionalized CNT-NiO microfluidic electrode is assembled with polydimethylsiloxane rectangular microchannels (cross section: 100 × 100 μm). Cytotoxicity of the synthesized CNTs, NiO nanoparticles, and CNT-NiO nanocomposite has been investigated in the presence of lung epithelial cancer A549 cell line using MTT assay. The CNT-NiO nanocomposite shows higher cell viability at a concentration of 6.5 μg/mL compared to those using individual CNTs. The cell viability and proliferation studies reveal that the toxicity increases with increasing CNTs concentration. The X-ray photoelectron spectroscopy studies have been used to quantify the functional groups present on the CNT-NiO electrode surface before and after proteins functionalization. The binding kinetic and electrochemical activities of CNT-NiO based iLOC have been conducted using chronocoulometry and impedance spectroscopic techniques. This iLOC shows excellent sensitivity of 5.37 kΩ (mg/dL)(-1) and a low detection limit of 0.63 mg/dL in a wide concentration range (5-120 mg/dL) of LDL. The binding kinetics of antigen-antibody interaction of LDL molecules reveal a high association rate constant (8.13 M(-1) s(-1)). Thus, this smart nanocomposite (CNT-NiO) based iLOC has improved stability and reproducibility and has implications toward in vivo diagnostics.


Interstitial 14q24.3 to q31.3 deletion in a 6-year-old boy with a non-specific dysmorphic phenotype.
Few patients with interstitial deletions in the distal long arm of chromosome 14 have been reported, and these patients showed rather indistinct features, including growth and mental retardation and phenotypic alterations. We describe a de novo 14q interstitial deletion in a 6-year-old boy with dysmorphic facial traits such as hypertelorism, short and narrow palpebral fissures, broad nose with anteverted nostrils, long philtrum, thin upper lip with cupid's bow, prominent and everted lower lip, mildly low-set ears, as well as moderate developmental delay and mild mental retardation. Array-CGH mapped the deletion to the region 14q24.3 to 14q31.3, including 13.11 Mb, proximal to the imprinted genomic region of 14q32. This mild phenotypic presentation suggests that the deleted segment does not contain essential genes for early organ development. Twenty-two genes with known functions, including Neurexin III (NRXN3, OMIM 600567), map to the region deleted in the propositus.


The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila.
Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.


Assessing the understanding of biobank participants.
Biobanks have been developed as a tool to better understand the genetic basis of disease by linking DNA samples to corresponding medical information. The broad scope of such projects presents a challenge to informed consent and participant understanding. To address this, 200 telephone interviews were conducted with participants in the NUgene Project, Northwestern University's biobank. Interviews included a modified version of the "quality of informed consent measure" (QuIC) and semi-structured questions which were analyzed thematically for 109 of the interviews. The QuIC, originally applied to cancer clinical trials, objectively assessed some of the components of informed consent for a biobank, and interview questions provided rich data to assist in interpreting participant understanding. The best understood domains included: the nature of the study, benefit to future patients, and the voluntary nature of participation. Lower knowledge scores included: potential risks and discomforts, experimental nature of the research, procedures in the event of study-related injury, and confidentiality issues. Qualitatively, confidentiality protections of the study were described as good by most (>50%). Although some cited concerns with employer (12%) or insurance discrimination (25%), most considered the risks to privacy low (25%) or none (approximately 60%). Only 10% of participants explicitly stated they had no expectation for personal benefit, and when asked whether they expected to be contacted with study results, respondents were split between having no expectation (39%), being hopeful for results (37%) and expecting to be contacted with results (12%). These findings are informative to those establishing and implementing biobanks, and to the IRBs reviewing such studies.


Comparison of Cone Beam Computed Tomography and ultrasonography with two types of probes in the detection of opaque and non-opaque foreign bodies.
The aim of this study was to compare the diagnostic accuracy of intra-oral and extra-oral ultrasonographic (US) examinations performed with linear and convex probes in the detection of opaque and non-opaque foreign bodies (FBs) located in the maxillofacial area. Thirteen different type of FBs were inserted into a sheep's head: a) on the external bone surface of mandible (between the mandibular corpus and masseter muscle), b) in the intrinsic muscular tissue (in the dorsum of the tongue) and c) in the hollow structures (into the maxillary sinus of the sheep's head). The FBs in muscle tissue were scanned intra-orally whereas FBs in bone external bone surface of mandible and in maxillary sinus were scanned both intra-orally and extra-orally. The sensitivity of cone beam computed tomography (CBCT) and US imaging methods in detection of FBs were compared for FBs on the bone surface and in the muscular tissue. The intra-observer kappa coefficients provided identical values of 0.236 for the extra-oral convex probe, 0.461 for the intra-oral linear probe for overall FBs detection, which indicated notably poor to fair intra-observer agreement. The inter-observer agreement showed a poor agreement for the extra-oral use of linear probe (0.341 and 0.393) and extra-oral use of convex probe (0.319 and 0.335), However, a fair agreement was determined for use of probe intra-orally (0.530 and 0.534). Overall, the diagnostic accuracy of the CBCT was higher than the US regarding the visualization of FBs in the bone tissue. US with a linear probe should be the first choice for the detection of the low-radiodensity FBs, which are entrapped in the soft tissue. However, CBCT is a more sensitive technique for the visualization of FBs in air and bone tissue compared to the US, particularly for the diagnosis of high-radiodensity FBs.


[Infections of the breast].
The authors present their experiences of 45 female patients under the treatment of an acute purulent mastitis in five years period. From 45 treated female patients 8 (17.7%) were treated clinically, and 37 (82.2%) in the outpatient department. At the age to 35 years old, there were 87% of female patients from which 79.2% who bore the first child, and 21.7% of those who bore more than one child. From an acute lactic mastitis were treated 39 (86.6%) from which 2 (4.4%) were young girls, and 4 (8.8%) patients with already finished period of reproduction. Right-side localization of the pathological process was in 22 (48.8%) cases, left-side in 19 (42.2%) cases, and both-sides in 4 (8.8%) cases. In 15 (33.3%) female patients we have followed an immunological status. It is characteristic an immunological disbalance in acute phase. Following the immunological status, it can be useful for estimating and prognosis in treatment. In literature, there are quotation details of purulent diseases, among which breast infection takes a considerable place from 1.6 to 18%, and the death-rate is described in high percentage from 9.6 to 1.7%. Our attitude in the treatment of breast infection, especially when purulent process is present, as first we have to evacuate the suppuration, then to make good breast drainage, and separately to infiltrate the tissue because there are small abscesses in it, which bring to dissemination of pus within the breast. According to all mentioned above, we also give an antibiotic therapy.


A heuristic model of stone comminution in shock wave lithotripsy.
A heuristic model is presented to describe the overall progression of stone comminution in shock wave lithotripsy (SWL), accounting for the effects of shock wave dose and the average peak pressure, P+(avg), incident on the stone during the treatment. The model is developed through adaptation of the Weibull theory for brittle fracture, incorporating threshold values in dose and P+(avg) that are required to initiate fragmentation. The model is validated against experimental data of stone comminution from two stone types (hard and soft BegoStone) obtained at various positions in lithotripter fields produced by two shock wave sources of different beam width and pulse profile both in water and in 1,3-butanediol (which suppresses cavitation). Subsequently, the model is used to assess the performance of a newly developed acoustic lens for electromagnetic lithotripters in comparison with its original counterpart both under static and simulated respiratory motion. The results have demonstrated the predictive value of this heuristic model in elucidating the physical basis for improved performance of the new lens. The model also provides a rationale for the selection of SWL treatment protocols to achieve effective stone comminution without elevating the risk of tissue injury.


Regulatory mechanisms that modulate signalling by G-protein-coupled receptors.
The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neuro-transmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and down-regulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from G-proteins. Agonist-induced receptor endocytosis also contributes to desensitization by depleting the cell surface of high-affinity receptors, and recycling of internalized receptors contributes to resensitization of cellular responses. Receptor down-regulation is a form of desensitization that occurs during continuous, long-term exposure of cells to receptor agonists. Down-regulation, which may occur during the development of drug tolerance, is characterized by depletion of the cellular receptor content, and is probably mediated by alterations in the rates of receptor degradation and synthesis. These regulatory mechanisms are important, as they govern the ability of cells to respond to agonists. A greater understanding of the mechanisms that modulate signalling may lead to the development of new therapies and may help to explain the mechanism of drug tolerance.


Distinct cytokine/chemokine network in semen and blood characterize different stages of HIV infection.
The cytokine/chemokine network is used by the innate and adaptive immune system to orchestrate effective immune responses. Here, we describe the cross-sectional association between cytokine levels and stage of HIV infection to gain novel insights into HIV-1 immunopathogenesis and identify novel therapeutic targets. Concentrations of 31 cytokine/chemokines were retrospectively measured in blood and seminal plasma collected from 252 individuals enrolled in four well characterized cohorts: HIV-uninfected, untreated HIV-infected in early phase of infection, untreated HIV-infected in late phase of infection, and HIV-infected on antiretroviral therapy with undetectable HIV RNA levels in blood (<50 copies/ml). Cytokine/chemokine levels were measured by multiplex-bead array. Comparisons between groups were performed by Mann-Whitney U-test and P values were adjusted for multiple comparisons using the Benjamini-Hochberg method. Presence of HIV-infection skewed the cytokine/chemokine network towards a pro-inflammatory response in both blood and semen compared to HIV-uninfected controls. Such changes emerged within the first weeks of infection and were maintained thereafter: Among untreated HIV-infected individuals, none of the 31 measured cytokines were significantly different between early and later stages of infection. Suppression of plasma HIV RNA with ART did not result in normalization of the levels of pro-inflammatory cytokines in blood. In semen, several pro-inflammatory cytokines were even further upregulated in ART-treated compared with HIV-uninfected and HIV-untreated individuals. A profound disruption in the cytokine/chemokine network is evident in blood and semen from the earliest stage of HIV infection shortly after the first detection of systemic viremia. These changes are maintained throughout the chronic phase of the infection and do not normalize despite ART and suppression of plasma HIV RNA.


Tip-apex distance of intramedullary devices as a predictor of cut-out failure in the treatment of peritrochanteric elderly hip fractures.
A tip-apex distance (TAD) of greater than 25 mm has been shown to be an accurate predictor of lag screw cut-out when sliding hip screws (SHS) are used to treat peritrochanteric (PT) hip fractures. The purpose of this study was to determine which factors, including TAD, correlated with successful clinical outcomes of PT hip fractures surgically treated with intramedullary (IM) devices. A total of 192 patients were included in this retrospective study. The TAD values of this cohort were radiographically analysed at a mean follow-up of 13 months. This was correlated with limited functional status and the rate of revision for implant failure or inability to achieve fracture union. Only 82 patients had adequate follow-up to fracture union or definitive failure. There were 46 intertrochanteric (IT) hip fractures and 36 subtrochanteric (ST) fractures. Overall, seven patients (8.5%) went on to experience lag screw cut-out. The average TAD of the patients who did not cut-out was 18 mm, compared to 38 mm for those who did (p = 0.012). All patients who cut-out had IT fractures (p = 0.017). The percentage of cut-outs correlated directly to both the severity of IT fractures and the TAD. Using a cutoff of 25 mm there was a statistically significant difference in the incidence of lag screw cut-out (p < 0.001). As in sliding hip screws, surgeons should strive for a TAD less than 25 mm when using IM devices in the treatment of PT hip fractures to help avoid lag screw cut-out.


In vitro effectiveness of triterpenoids and their synergistic effect with antibiotics against Staphylococcus aureus strains.
The aim of this study is to evaluate the effect of four triterpenoids such as oleanolic acid, ursolic acid, cycloastragenol, and beta-boswellic acid alone and in combination with antibiotics against Staphylococcus aureus strains. Sixteen clinical strains of S. aureus from infected wounds were isolated. Eight were methicillin-sensitive S. aureus (MSSA), and the other eight were methicillin-resistant S. aureus (MRSA). The activity was also seen in reference S. aureus American Type Culture Collection™ strains. The activity of all the triterpenoids and antibiotics against S. aureus was evaluated by broth microdilution method. The effectiveness was judged by comparing the minimum inhibitory concentrations (MICs) of the compounds with antibiotics. The combination of antibiotics with compounds was evaluated by their fractional inhibitory concentrations (FIC). Against both clinical and reference MSSA strains, none of the compounds exhibited comparable activity to antibiotics vancomycin or cefradine except for ursolic acid (MIC 7.8 μg/ml). Against MRSA, all compounds (MIC 16-128 μg/ml) showed lesser activity than vancomycin (MIC 5.8 μg/ml). Among triterpenoid-antibiotic combinations, the most effective were ursolic acid and vancomycin against clinical strain MSSA (FICS 0.17). However, overall, different combinations between triterpenoids and antibiotics showed 95%-46% (P < 0.05) reduction in MICs of antibiotics compared to when antibiotics were used alone. Cefradine, a drug not suitable for treating MRSA (MIC = 45 μg/ml), showed a remarkable decrease in its MIC (87% P< 0.01) when it was used in combination with oleanolic acid or ursolic acid in both clinical and reference strains. The tested triterpenoids are relatively weaker than antibiotics. However, when used in combination with antibiotics, they showed remarkable synergistic effect and thus can help in prolonging the viability of these antibiotics against S. aureus infections. Furthermore, reduction in MIC of cefradine with oleanolic acid indicates their potential use against MRSA.


Comprehensive medical rehabilitation in the 1990s: the community integration rehabilitation model.
The development of new models of understanding the disabling process, the changing system of financing health care in the United States, and the increasing incidence of disability is challenging rehabilitation to define new models of care delivery. Current models of comprehensive medical rehabilitation include multidisciplinary therapy in inpatient, outpatient, home and community settings. Managed care and the development of capitated funding systems for health care financing will challenge rehabilitation to prevent disability in a population. This article proposes a model system for comprehensive rehabilitation in managed care: the Community Integration Rehabilitation Model. This system advocates the development of a continuum of services including a strong community-based rehabilitation system, that is, a shift in emphasis to expanding opportunities for independent and productive community living as well as management of disease and impairment for individuals with disabilities, and the forging of partnerships between institution-based rehabilitation and its community. Comprehensive rehabilitation is redefined as a continuum of disability prevention and treatment across the lifespan of a population.


Barriers and Facilitators for Generalizing Cycling Skills Learned at Camp to Home.
Many children with disabling conditions do not acquire the skills to successfully ride a 2-wheeled bicycle. The aim was to describe cycling patterns before and after an innovative learn-to-ride bike camp and factors that facilitate or hinder the generalization of skills developed at camp to home. Parents and children participated in semistructured interviews 3-4 mo postcamp. Transcripts were examined deductively for participation and contextual influences using a template of codes approach. None of the children were successfully riding a 2-wheeled bicycle before camp. Two patterns of participation were evident from narrative descriptions of postcamp riding: "riders" and "not there yet." Major facilitating factors were the camp itself, the interaction between the camp and the health service, and continued parent involvement. The program transferred well to home for children who were riding independently on the last day of camp. Ongoing support is needed for children "not there yet."


Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project.
Hip fractures are associated with diminished quality of life and survival especially amongst the elderly. All-cause mortality after hip fracture was investigated to assess its magnitude. A total of 122 808 participants from eight cohorts in Europe and the USA were followed up for a mean of 12.6 years, accumulating 4273 incident hip fractures and 27 999 deaths. Incident hip fractures were assessed through telephone interviews/questionnaires or national inpatient/fracture registries, and causes of death were verified with death certificates. Cox proportional hazards models and the time-dependent variable methodology were used to assess the association between hip fracture and mortality and its magnitude at different time intervals after the injury in each cohort. We obtained the effect estimates through a random-effects meta-analysis. Hip fracture was positively associated with increased all-cause mortality; the hazard ratio (HR) in the fully adjusted model was 2.12, 95% confidence interval (CI) 1.76-2.57, after adjusting for potential confounders. This association was stronger amongst men [HR: 2.39, 95% CI: 1.72-3.31] than amongst women [HR: 1.92, 95% CI: 1.54-2.39], although this difference was not significant. Mortality was higher during the first year after the hip fracture [HR: 2.78, 95% CI: 2.12-3.64], but it remained elevated without major fluctuations after longer time since hip fracture [HR (95% CI): 1.89 (1.50-2.37) after 1-4 years; 2.15 (1.81-2.55) after 4-8 years; 1.79 (1.57-2.05) after 8 or more years]. In this large population-based sample of older persons across eight cohorts, hip fracture was associated with excess short- and long-term all-cause mortality in both sexes.


Retinopathy, neuropathy and nephropathy in non-insulin-dependent diabetic patients.
In 1978, an epidemiological survey for adult diabetes was conducted in Taipei City. A total of 219 Chinese non-insulin-dependent diabetic patients were discovered and 217 of them were examined for retinopathy, neuropathy and nephropathy. Among the 110 men and 107 women studied, 63.1% were free of complications and the prevalences for retinopathy, nephropathy and neuropathy were 24.0%, 12.9% and 23.5%, respectively. The clinical and biochemical data of the patients were compared. For those with and those without complications, the diabetic duration (8.2 +/- 6.7 vs 4.1 +/- 2.7, years), percentage of insulin treatment (8.8% +/- 0.7%), percentage of hypertension (42.5% vs 26.3%), and the fasting plasma glucose (182.8 +/- 63.6 vs 135.0 +/- 44.6, mg/dl) were significantly different. Diabetic duration and glycemic control consistently correlated with retinopathy, nephropathy and neuropathy. Hypertension and insulin treatment were also associated positively with the complications. The more complications the diabetic patients had, the poorer the glycemic control, the longer the diabetic duration, a higher percentage of insulin treatment and hypertension were found.


NaHS Protects Cochlear Hair Cells from Gentamicin-Induced Ototoxicity by Inhibiting the Mitochondrial Apoptosis Pathway.
Aminoglycoside antibiotics such as gentamicin could cause ototoxicity in mammalians, by inducing oxidative stress and apoptosis in sensory hair cells of the cochlea. Sodium hydrosulfide (NaHS) is reported to alleviate oxidative stress and apoptosis, but its role in protecting aminoglycoside-induced hearing loss is unclear. In this study, we investigated the anti-oxidant and anti-apoptosis effect of NaHS in in vitro cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and isolated mouse cochlea. Results from cultured HEI-OC1 cells and cochlea consistently indicated that NaHS exhibited protective effects from gentamicin-induced ototoxicity, evident by maintained cell viability, hair cell number and cochlear morphology, reduced reactive oxygen species production and mitochondrial depolarization, as well as apoptosis activation of the intrinsic pathway. Moreover, in the isolated cochlear culture, NaHS was also demonstrated to protect the explant from gentamicin-induced mechanotransduction loss. Our study using multiple in vitro models revealed for the first time, the potential of NaHS as a therapeutic agent in protecting against aminoglycoside-induced hearing loss.


Phenological sensitivity to climate across taxa and trophic levels.
Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5-2.9 days earlier on average), with substantial taxonomic variation (1.1-14.8 days earlier on average).


Influenza vaccination in patients with end-stage renal disease: systematic review and assessment of quality of evidence related to vaccine efficacy, effectiveness, and safety.
Vaccination against influenza is recommended in patients with end-stage renal disease (ESRD). However, so far, no systematic review has summarized the available evidence on the effectiveness and safety of influenza vaccination in this patient group. We conducted a systematic review and meta-analysis and assessed the quality of evidence using the GRADE methodology. We searched MEDLINE, EMBASE, Cochrane Library databases, ClinicalTrials.gov, and reference lists for studies on efficacy, effectiveness, and/or safety of seasonal influenza vaccination in patients with ESRD receiving dialysis. All reported clinical outcomes were considered, including all-cause mortality, cardiac death, infectious death, all-cause hospitalization, hospitalization due to influenza or pneumonia, hospitalization due to bacteremia, viremia, or septicemia, hospitalization due to respiratory infection, ICU admission, and influenza-like illness. Five observational studies and no randomized-controlled trial were identified. In four studies, risk of bias was high regarding all reported outcomes. Strong residual confounding was likely to be present in one study reporting on three outcomes, as indicated by significant protective effects of vaccination outside influenza seasons. Therefore, the statistically significant protective effects on all-cause mortality (vaccine effectiveness (VE), 32%; 95% CI, 24-39%), cardiac death (VE, 16%; 95% CI, 1-29%), hospitalization due to influenza or pneumonia (VE, 14%; 95% CI, 7-20%), ICU admission (VE, 81%; 95% CI, 63-86%), and influenza-like illness (VE, 12%; 95% CI, 10-14%) have to be taken with caution. According to GRADE, the quality of the body of evidence was considered very low for all outcomes. No study reported on laboratory-confirmed influenza virus infections or on safety endpoints. Evidence on the protective effects of influenza vaccination in patients with ESRD is limited and of very low quality. Since VE estimates in the available literature are prone to unmeasured confounding, studies using randomization or quasi-experimental designs are needed to determine the extent by which vaccination prevents influenza and related clinical outcomes in this at-risk population. However, given the high rates of health-endangering events in these patients, even a low VE can be considered as sufficient to recommend annual influenza vaccination.


Application of a label-free, gel-free quantitative proteomics method for ecotoxicological studies of small fish species.
Although two-dimensional electrophoresis (2D-GE) remains the basis for many ecotoxicoproteomic analyses, newer non-gel-based methods are beginning to be applied to overcome throughput and coverage limitations of 2D-GE. The overall objective of our research was to apply a comprehensive, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic approach to identify and quantify differentially expressed hepatic proteins from female fathead minnows exposed to fadrozole, a potent inhibitor of estrogen synthesis. Female fathead minnows were exposed to 0 (control), 0.04, and 1.0 μg of fadrozole/L of water for 4 days, and proteomic analysis was performed. Proteins were extracted and digested, and proteolytic peptides were separated via high-resolution one- or two-dimensional (1-D or 2-D) ultrapressure liquid chromatography (UPLC) and analyzed by tandem mass spectrometry. Mass spectra were searched against the National Center for Biotechnology Information (NCBI) ray-finned fish ( Actinopterygii ) database, resulting in identification of 782 unique proteins by single-dimension UPLC. When multidimensional LC analysis (2-D) was performed, an average increase of 1.9× in the number of identified proteins was observed. Differentially expressed proteins in fadrozole exposures were consistent with changes in liver function, including a decline in concentrations of vitellogenin as well as other proteins associated with endocrine function and cholesterol synthesis. Overall, these results demonstrate that a gel-free, label-free proteomic analysis method can successfully be utilized to determine differentially expressed proteins in small fish species after toxicant exposure.


Hormone activities and the cell cycle machinery in immunity-triggered growth inhibition.
Biotic stress and diseases caused by pathogen attack pose threats in crop production and significantly reduce crop yields. Enhancing immunity against pathogens is therefore of outstanding importance in crop breeding. However, this must be balanced, as immune activation inhibits plant growth. This immunity-coupled growth trade-off does not support resistance but is postulated to reflect the reallocation of resources to drive immunity. There is, however, increasing evidence that growth-immunity trade-offs are based on the reconfiguration of hormone pathways, shared by growth and immunity signalling. Studies in roots revealed the role of hormones in orchestrating growth across different cell types, with some hormones showing a defined cell type-specific activity. This is apparently highly relevant for the regulation of the cell cycle machinery and might be part of the growth-immunity cross-talk. Since plants are constantly exposed to Immuno-activating microbes under agricultural conditions, the transition from a growth to an immunity operating mode can significantly reduce crop yield and can conflict our efforts to generate next-generation crops with improved yield under climate change conditions. By focusing on roots, we outline the current knowledge of hormone signalling on the cell cycle machinery to explain growth trade-offs induced by immunity. By referring to abiotic stress studies, we further introduce how root cell type-specific hormone activities might contribute to growth under immunity and discuss the feasibility of uncoupling the growth-immunity cross-talk.


Diversity among blaKPC-containing plasmids in Escherichia coli and other bacterial species isolated from the same patients.
Carbapenem resistant Enterobacteriaceae are a significant public health concern, and genes encoding the Klebsiella pneumoniae carbapenemase (KPC) have contributed to the global spread of carbapenem resistance. In the current study, we used whole-genome sequencing to investigate the diversity of blaKPC-containing plasmids and antimicrobial resistance mechanisms among 26 blaKPC-containing Escherichia coli, and 13 blaKPC-containing Enterobacter asburiae, Enterobacter hormaechei, K. pneumoniae, Klebsiella variicola, Klebsiella michiganensis, and Serratia marcescens strains, which were isolated from the same patients as the blaKPC-containing E. coli. A blaKPC-containing IncN and/or IncFIIK plasmid was identified in 77% (30/39) of the E. coli and other bacterial species analyzed. Complete genome sequencing and comparative analysis of a blaKPC-containing IncN plasmid from one of the E. coli strains demonstrated that this plasmid is present in the K. pneumoniae and S. marcescens strains from this patient, and is conserved among 13 of the E. coli and other bacterial species analyzed. Interestingly, while both IncFIIK and IncN plasmids were prevalent among the strains analyzed, the IncN plasmids were more often identified in multiple bacterial species from the same patients, demonstrating a contribution of this IncN plasmid to the inter-genera dissemination of the blaKPC genes between the E. coli and other bacterial species analyzed.


Review of performance-based incentives in community-based family planning programmes.
One strategy for improving family planning (FP) uptake at the community level is the use of performance-based incentives (PBIs), which offer community distributors financial incentives to recruit more users of FP. This article examines the use of PBIs in community-based FP programmes via a literature search of the peer-reviewed and grey literature conducted in April 2013. A total of 28 community-based FP programmes in 21 countries were identified as having used PBIs. The most common approach was a sales commission model where distributors received commission for FP products sold, while a referral payment model for long-term methods was also used extensively. Six evaluations were identified that specifically examined the impact of the PBI in community-based FP programmes. Overall, the results of the evaluations are mixed and more research is needed; however, the findings suggest that easy-to-understand PBIs can be successful in increasing the use of FP at the community level. For future use of PBIs in community-based FP programmes it is important to consider the ethics of incentivising FP and ensuring that PBIs are non-coercive and choice-enhancing.


A methionine-restricted diet and endurance exercise decrease bone mass and extrinsic strength but increase intrinsic strength in growing male rats.
Dietary methionine restriction (MR) has been suggested to be comparable to endurance exercise with respect to its beneficial effects on health. To further investigate the effects of MR and endurance exercise on growing bone, 7-wk-old male Sprague-Dawley rats were fed different l-methionine (Met)-containing diets with or without endurance exercise intervention (Ex; 0.86% Met, 0.52% Met, 0.17% Met, 0.86% Met-Ex, 0.52% Met-Ex, and 0.17% Met-Ex groups). After an 8-wk intervention period, exercise-trained rats had a 9.2% lower body weight (BW) than did sedentary rats (P < 0.05). Additionally, 0.17% Met-fed rats had 32% lower BW when compared with rats fed the other 2 diets (P < 0.05). Serum osteocalcin was lower in the 0.17% Met-Ex group compared with the other 2 exercise groups and the 0.17% Met group (P < 0.05). Serum concentrations of C-terminal telopeptide of type 1 collagen were lower in exercise-trained and 0.17% Met-fed rats than in sedentary rats and rats fed the other 2 diets (P < 0.05 for both). Rats fed the 0.17% Met diet had lower trabecular bone volume, bone mineralization activities, and bone mineral content (BMC; e.g., total, cortical, and spongy BMC) and bone mineral density (BMD; e.g., total and spongy BMD) indices compared with rats fed the other 2 diets (P < 0.05). Exercise-trained rats also had lower bone mineralization activity, trabecular osteoclast density, total BMC, cortical BMC, and total BMD compared with sedentary rats (P < 0.05). In total BMD, only the 0.17% Met-Ex group had values lower than the other 2 exercise groups and the 0.17% Met group (P < 0.05). Compared with rats fed the other 2 diets and sedentary rats, the femora of 0.17% Met-fed and exercise-trained rats, respectively, had smaller size and/or lower extrinsic strength but enhanced intrinsic biomechanical properties (P < 0.05). The results indicate that MR and endurance exercise caused lower whole bone mass, size, and/or strength but might enhance intrinsic bone strength.


Comparison of cancer-cell seeding, viability and deformation in the lung, muscle and liver, visualized by subcellular real-time imaging in the live mouse.
The comparison of cancer cell seeding, deformation and viability in the lung, muscle and liver of nude mice in real-time is reported here. The mice were intubated to support ventilation with positive end-respiratory pressure (PEEP) for imaging on the lung. Human fibrosarcoma cells with green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm (dual-color HT-1080 cells) were injected into the tail vein for lung imaging, the portal vein for liver imaging or the abdominal aorta for muscle imaging which was performed with an Olympus OV100 Small Animal Imaging System. The length of the cytoplasm and nuclei in 20 seeded cancer cells were measured. A large number of cells initially arrested in the lung capillaries and many cells formed aggregates. The cell number decreased rapidly at 6 and 24 h. There was no significant difference in cancer cell survival when immunocompetent C57BL/6 mice were used in place of the nude mice, suggesting that T cell reaction is not very important in the first 24 h after seeding of cancer cells in the lung. In the lung and liver, little cancer cell deformation occurred. In contrast in the muscle, the cytoplasm and nuclei of the seeded cells were highly deformed and many fragmented cells were observed. The rate of cancer cell death was highest in the lung and lowest in the muscle. In each organ, single disseminated cells tended to die earlier than aggregated cells. The results of this study suggest that the early steps of metastasis are different in the lung, liver and muscle.


Comparison of mammographic density assessed as volumes and areas among women undergoing diagnostic image-guided breast biopsy.
Mammographic density (MD), the area of non-fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy. Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm(3)) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm(2)) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression. Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated. Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI. Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques.


The best of both worlds: A combined approach for analyzing microalgal diversity via metabarcoding and morphology-based methods.
An increasing number of studies use next generation sequencing (NGS) to analyze complex communities, but is the method sensitive enough when it comes to identification and quantification of species? We compared NGS with morphology-based identification methods in an analysis of microalgal (periphyton) communities. We conducted a mesocosm experiment in which we allowed two benthic grazer species to feed upon benthic biofilms, which resulted in altered periphyton communities. Morphology-based identification and 454 (Roche) pyrosequencing of the V4 region in the small ribosomal unit (18S) rDNA gene were used to investigate the community change caused by grazing. Both the NGS-based data and the morphology-based method detected a marked shift in the biofilm composition, though the two methods varied strongly in their abilities to detect and quantify specific taxa, and neither method was able to detect all species in the biofilms. For quantitative analysis, we therefore recommend using both metabarcoding and microscopic identification when assessing the community composition of eukaryotic microorganisms.


Angiographic demonstration of neoangiogenesis after intra-arterial infusion of autologous bone marrow mononuclear cells in diabetic patients with critical limb ischemia.
Critical limb ischemia in diabetic patients is associated with high rates of morbidity and mortality. Suboptimal responses to the available medical and surgical treatments are common in these patients, who also demonstrate limited vascular homeostasis. Neovasculogenesis induced by stem cell therapy could be a useful approach for these patients. Neovasculogenesis and clinical improvement were compared at baseline and at 3 and 12 months after autologous bone marrow-derived mononuclear cell (BMMNC) transplantation in diabetic patients with peripheral artery disease. We conducted a prospective study to evaluate the safety and efficacy of intra-arterial administration of autologous BMMNCs (100-400 × 10(6) cells) in 20 diabetic patients with severe below-the-knee arterial ischemia. Although the time course of clinical effects differed among patients, after 12 months of follow-up all patients presented a notable improvement in the Rutherford-Becker classification, the University of Texas diabetic wound scales, and the Ankle-Brachial Index in the target limb. The clinical outcome was consistent with neovasculogenesis, which was assessed at 3 months by digital subtraction angiography and quantified by MetaMorph software. Unfortunately, local cell therapy in the target limb had no beneficial effect on the high mortality rate in these patients. In diabetic patients with critical limb ischemia, intra-arterial perfusion of BMMNCs is a safe procedure that generates a significant increase in the vascular network in ischemic areas and promotes remarkable clinical improvement.


The Ebola Crisis and the Corresponding Public Behavior: A System Dynamics Approach.
The interaction of several sociocultural and environmental factors during an epidemic crisis leads to behavioral responses that consequently make the crisis control a complex problem. The system dynamics approach has been adopted to study the relationships between spread of disease, public attention, situational awareness, and community's response to the Ebola epidemic. In developing different simulation models to capture the trend of death and incidence data from the World Health Organization for the Ebola outbreak, the final model has the best fit to the historical trends. Results demonstrate that the increase of quarantining rate over time due to increase in situational awareness and performing safe burials had a significant impact on the control of epidemic. However, public attention did not play a significant role. The best fit to historical data are achieved when behavioral factors specific to West Africa like studying the Situational Awareness and Public Attention are included in the model. However, by ignoring the sociocultural factors, the model is not able to represent the reality; therefore, in the case of any epidemics, it is necessary that all the parties and community members find the most significant behavioral factors that can curb the epidemic.


Personalising Management of Behavioural and Psychological Symptoms of Dementia in Nursing Homes: Exploring the Synergy of Quantitative and Qualitative Data.
Researchers have been exploring how to manage Behavioural and Psychological Symptoms of Dementia (BPSD) in a personalised way, meanwhile, assistive technologies have been developed to collect a variety of personal data. This urges more research in investigating the combination of: data collected by the care team, which are mainly qualitative; and data collected by assistive technologies, the majority of which are quantitative. Previous studies, however, have yet to explore if and how a combination of quantitative and qualitative data could facilitate the care team to better understand each resident with dementia in the nursing home context for personalised BPSD management. Guided by a Research through Design approach, a prototype for collecting and visualising the quantitative and qualitative data towards personalised BPSD management was developed together with the care team. Via developing this prototype, knowledge was gained in what types of data could be combined for personalised BPSD management in nursing homes, what are their values, how to collect and present them, and how to introduce them in the working routine of the care team for analysis. The main findings suggest that the types of data to be collected could be unique for each resident with dementia; the quantitative and qualitative data are of value to each other during data collection and analysis; data collection should be quick and standardised yet flexible for the care team; the overview page is vital for data presentation; and user scenarios could be created to nudge the care team to analyse the data at certain points of their working routine. In general, a combination of qualitative data and quantitative data could help the care team to discover more insights about each resident with dementia and thus improve the current practice of personalised BPSD management.


Two-level approach to efficient visualization of protein dynamics.
Proteins are highly flexible and large amplitude deformations of their structure, also called slow dynamics, are often decisive to their function. We present a two-level rendering approach that enables visualization of slow dynamics of large protein assemblies. Our approach is aligned with a hierarchical model of large scale molecules. Instead of constantly updating positions of large amounts of atoms, we update the position and rotation of residues, i.e., higher level building blocks of a protein. Residues are represented by one vertex only indicating its position and additional information defining the rotation. The atoms in the residues are generated on-the-fly on the GPU, exploiting the new graphics hardware geometry shader capabilities. Moreover, we represent the atoms by billboards instead of tessellated spheres. Our representation is then significantly faster and pixel precise. We demonstrate the usefulness of our new approach in the context of our collaborative bioinformatics project.


A literature review of interprofessional working and intermediate care in the UK.
This systematic literature review aimed at addressing two questions: first, what evidence exists regarding intermediate care in the UK; and what interventions have been used to develop interprofessional working in intermediate care in the UK? A systematic review of the literature from 2000-2006 resulted in a total of 104 full-text articles describing research into intermediate care in the UK. The review was the first stage of a large, national project evaluating and developing interprofessional working among health and social care staff, particularly in relation to the intermediate care of older people. Systematic literature review. All the literature was reviewed by one reviewer, and a second review was carried out by a team of reviewers to ensure each article was reviewed twice, independently. One article was reviewed by all the reviewers to ensure inter-rater reliability; finally, all the reviews were amalgamated, which resulted in one summary per article. The main findings drawn from this systematic literature review are that research carried out on intermediate care in the UK has a diverse set of aims, for example economic evaluations, delivery of intermediate care and exploring the views and perceptions of those involved in intermediate care. Although several articles include discussions about the importance of interprofessional working in intermediate care, no article specifically focused on the interprofessional focus of intermediate care, and there was no research about interventions used to develop interprofessional working. Intermediate care as a policy has been interpreted very differently across the four countries of the UK; there is no one preferred or consistent interpretation to its delivery.


Comprehensive identification of native medium-sized and short bioactive peptides in sea bass muscle.
Native peptides from sea bass muscle were analyzed by two different approaches: medium-sized peptides by peptidomics analysis, whereas short peptides by suspect screening analysis employing an inclusion list of exact m/z values of all possible amino acid combinations (from 2 up to 4). The method was also extended to common post-translational modifications potentially interesting in food analysis, as well as non-proteolytic aminoacyl derivatives, which are well-known taste-active building blocks in pseudo-peptides. The medium-sized peptides were identified by de novo and combination of de novo and spectra matching to a protein sequence database, with up to 4077 peptides (2725 modified) identified by database search and 2665 peptides (223 modified) identified by de novo only; 102 short peptide sequences were identified (with 12 modified ones), and most of them had multiple reported bioactivities. The method can be extended to any peptide mixture, either endogenous or by protein hydrolysis, from other food matrices.


Eectrophysiological observations in pateints with rate dependent bundle branch block.
Electrophysiological studies were conducted in 15 patients with tachycardic rate dependent bundle branch block (RDBBB): ten with left, and five with right. No bradycardic RDBBB was observed, despite occurrence of cycle lengths (CL) longer than 1200 msec in over half the patients studied. Onset of RDBBB was abrupt in 13 patients, and gradual in two. In three patients, the CL allowing reversion to normal conduction (once RDBBB was initiated) was 50, 55, and 190 msec longer, respectively, than the CL inducing RDBBB. Bundle brance refractory periods (RP) were measured with atrial extrastimulus technique in five patients. All RP (except one) were prolonged at all tested CL when compared to patients without conduction disease. The expected decrease in RP with shortening of CL did not occur in four of the five patients. The electrophysiological abnormality in patients with DBBB thus appeared to be an increase in refractoriness in the affected bundle branch, along with a loss of the normal decrease in refractoriness with decrease in CL. Similar findings might be demonstrable in patients with early bundle branch disease.


Biased feedback in brain-computer interfaces.
Even though feedback is considered to play an important role in learning how to operate a brain-computer interface (BCI), to date no significant influence of feedback design on BCI-performance has been reported in literature. In this work, we adapt a standard motor-imagery BCI-paradigm to study how BCI-performance is affected by biasing the belief subjects have on their level of control over the BCI system. Our findings indicate that subjects already capable of operating a BCI are impeded by inaccurate feedback, while subjects normally performing on or close to chance level may actually benefit from an incorrect belief on their performance level. Our results imply that optimal feedback design in BCIs should take into account a subject's current skill level.


T-cell migration into allografts.
The ability of T and B lymphocytes to migrate into skin allografts undergoing rejection was studied in mice. Spleen cells from CBA/J mice sensitized to transplantation antigens of A/J or C57BL/6 mice were separated on immunabsorbent columns into purified populations of T and B cells, labeled in vitro with 3H-uridine and injected intravenously into CBA/J mice with 7-day old skin iso and allografts (A/J or C57BL/6). The mice were sacrificed 24 h later and studied by autoradiography. After transfer of either unfractionated spleen cells or T cells, large numbers of labeled cells were found in the cellular infiltrate of allografts, whereas extremely few were seen in isografts. In contrast, after transfer of B cells, almost no labeled cells were detected either in the allografts or the isografts, although they, like T cells, homed normally to lymphoid tissue.


Histological reclassification, histochemical characterization and c-kit immunoexpression in renal cell carcinoma.
Renal cell carcinoma is the most lethal of all urologic malignancies. Several parameters such as histological subtype, nuclear grade and TNM staging help in determining the prognosis and treatment options. A newer therapeutic modality has been suggested based on expression of c-kit antigen by the tumor cells. This study was designed to evaluate various histological parameters and correlate them with c-kit expression. The study was done on 40 consecutive cases of renal epithelial tumors. Histological sections were reviewed and reclassified according to WHO (2004) classification and nuclear grade assessed. Hale's colloidal iron stain was done to identify the chromophobe variant. Immunostaining with c-kit was done and its expression was studied. The results were correlated and statistical significance was assessed. The age range was 31-81 years, with a male to female ratio of 2:1. Seventy per cent of the cases were clear cell RCC (ClRCC), 17.5% were chromophobe type, 7.5% were papillary RCCs and 5% cases were oncocytomas. Fuhrman nuclear grading revealed 60.5% cases to be of low grade and 39.5% high grade. Hale's colloidal iron staining was positive in chromophobe RCC and oncocytomas, while it was negative in ClRCC. Immunostaining with c-kit was positive only in oncocytomas. Clear cell RCC was the most common histological subtype of RCC. Clear cell RCC known to have a poor prognosis, showed a statistically significant higher nuclear grade than chromophobe and papillary RCCs which have a better prognosis. Hale's colloidal iron staining was extremely useful in distinguishing chromophobe RCC and oncocytoma from the granular cell variant of clear RCC. Our study revealed c-kit negativity in all RCC. As Imatinib could be ineffective in such tumors, its clinical activity has to be carefully assessed in such tumors through further studies.


Melatonin in the oral cavity: physiological and pathological implications.
The purpose of this article was to summarize what is known about the function of melatonin in the oral cavity. Databases were searched for the relevant published literature to 30 November, 2013. The following search items were used in various combinations: melatonin, gingiva, periodontium, inflammation, herpes, alveolar bone, periodontal ligament, dental implants, xerostomia, methacrylate, chlorhexidine, cancer. The literature uncovered is summarized herein. Salivary melatonin levels exhibit a circadian rhythm with highest values at night. Melatonin has both receptor-mediated and receptor-independent actions in cells of the oral cavity. Melatonin is released into the saliva by the acinar cells of the major salivary glands and via the gingival fluid. Functions of melatonin in the oral cavity are likely to relate primarily to its anti-inflammatory and antioxidant activities. These actions may suppress inflammation of the gingiva and periodontium, reduce alveolar bone loss, abrogate herpes lesions, enhance osteointegration of dental implants, limit oral cancer, and suppress disorders that have a free radical component. Sublingual melatonin tablets or oral melatonin sprays and topical melatonin-containing gel, if used on a regular basis, may improve overall oral health and reduce mucosal lesions. Collectively, the results indicate that endogenously-produced and exogenously-applied melatonin are beneficial to the oral cavity.


Simple mechanisms organise orientation of escape swimming in embryos and hatchling tadpoles of Xenopus laevis.
Many amphibian tadpoles hatch and swim before their inner ears and sense of spatial orientation differentiate. We describe upward and downward swimming responses in hatchling Xenopus laevis tadpoles from stages 32 to 37/38 in which the body rotates about its longitudinal axis. Tadpoles are heavier than water and, if touched while lying on the substratum, they reliably swim upwards, often in a tight spiral. This response has been observed using stroboscopic photography and high-speed video recordings. The sense of the spiral is not fixed for individual tadpoles. In 'more horizontal swimming' (i.e. in directions within +/-30 degrees of the horizontal), the tadpoles usually swim belly-down, but this position is not a prerequisite for subsequent upward spiral swimming. Newly hatched tadpoles spend 99 % of their time hanging tail-down from mucus secreted by a cement gland on the head. When suspended in mid-water by a mucus strand, tadpoles from stage 31 to 37/38 tend to swim spirally down when touched on the head and up when touched on the tail. The three-dimensional swimming paths of stage 33/34 tadpoles were plotted using simultaneous video images recorded from the side and from above. Tadpoles spiralled for 70 % of the swimming time, and the probability of spiralling increased to 1 as swim path angles became more vertical. Tadpoles were neutrally buoyant in Percoll/water mixtures at 1.05 g cm(-)(3), in which anaesthetised tadpoles floated belly-down and head-up at 30 degrees. In water, their centre of mass was ventral to the muscles in the yolk mass. A simple mathematical model suggests that the orientation of tadpoles during swimming is governed by the action of two torques, one of which raises the head (i.e. increases the pitch) and the other rotates (rolls) the body. Consequently, tadpoles (i) swim belly-down when the body is approximately horizontal because the body is ballasted by dense yolk, and (ii) swim spirally at more vertical orientations when the ballasting no longer stabilises orientation. Measurements in tethered tadpoles show that dorsal body flexion, which could produce a dorsal pitch torque, is present during swimming and increases with tailbeat frequency. We discuss how much of the tadpole's behaviour can be explained by our mathematical model and suggest that, at this stage of development, oriented swimming responses may depend on simple touch reflexes, the organisation of the muscles and physical features of the body, rather than on vestibular reflexes.


Physical function improvements and relief from fatigue and pain are associated with increased productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol.
To evaluate the association between improvements in physical function, fatigue and pain and improvements in productivity at work and at home in patients treated with certolizumab pegol (CZP) in combination with MTX. Physical function, fatigue and pain were assessed in two CZP clinical trials (Rheumatoid Arthritis PreventIon of structural Damage 1 and 2) using the HAQ-Disability Index (HAQ-DI), Fatigue Assessment Scale (FAS) and Patient Assessment of Pain, with minimal clinically important differences (MCIDs) defined as ≥ 0.22, ≥ 1 and ≥ 10 points, respectively. Work and home productivity were evaluated using the RA-specific Work Productivity Survey (WPS-RA). The odds of achieving an HAQ-DI, FAS or pain 'response' at Week 12, defined as improvements ≥ MCID, were compared between CZP and control groups. Improvements in productivity at Week 12 were compared between CZP-treated HAQ-DI, FAS or pain responders and non-responders. The odds of achieving improvements ≥ MCID were five times higher for pain, and two to three times higher for physical function and fatigue, in patients receiving CZP vs control. Per month, responders reported significantly greater improvements in productivity at work and reduced interference of RA with their work productivity than non-responders. Responders also reported significantly greater improvements in productivity at home and participation in family, social and leisure activities. This study demonstrated a clear association between patient-reported improvements in physical function, fatigue and pain, and improvements in productivity both at work and home.


Effects of drinking patterns on the relationship between alcohol an coronary occlusion.
Previous reports have described an inverse relationship between alcohol consumption and the prevalence of myocardial infarction or the extent of coronary artery occlusion. The study reported here explored the relationship between patterns of alcohol intake and coronary occlusion in 526 patients who have had coronary arteriography. Patients were characterized as regular drinkers, occasional drinkers and non-drinkers. Regular drinkers were further characterized as drinking relatively consistent amounts or variable amounts. The inverse correlation between amounts of alcohol consumed and coronary occlusion found in previous studies was reaffirmed. It was also observed that the pattern of alcohol intake was related to the degree of occlusion. Higher levels of occlusion were found among non-drinkers, occasional drinkers, and regular drinkers with patterns of variable intake, while significantly lower levels of occlusion were observed for regular drinkers who drank relatively consistent amounts (P = 0.014). Furthermore, while occlusion scores were inversely correlated with amounts consumed by regular drinkers with consistent intake (P = 0.019), drinkers with variable drinking patterns had higher occlusion scores regardless of amounts consumed. Analyses of serum lipids according to drinking patterns showed a significant association between the total/HDL cholesterol ratio and drinking patterns. These findings suggest that whatever attenuating effect alcohol consumption might exert on coronary occlusion, it appears to be reversed by a variable or sporadic pattern of alcohol intake.


The Effect of Intrathecal Morphine Dose on Outcomes After Elective Cesarean Delivery: A Meta-Analysis.
The intrathecal morphine dose achieving optimal analgesia for cesarean delivery while minimizing side effects has not yet been deduced. In this meta-analysis, our objective was to determine whether low- or high-dose intrathecal morphine provides acceptable duration and intensity of analgesia with fewer side effects. A literature search (PubMed, EMBASE, MEDLINE, Scopus, Web of Science, and CINAHL) was performed to identify randomized controlled trials involving patients undergoing elective cesarean delivery under spinal anesthesia comparing low-dose (LD; 50-100 μg) morphine with higher dose (HD; >100-250 μg). The primary outcome was the time for first request for supplemental analgesia. The secondary outcomes included pain scores, morphine use, maternal side effects (vomiting and pruritus), and Apgar scores. Mean differences (MDs) and odds ratios (ORs) were calculated using random effects modeling with 95% confidence intervals (CIs). Eleven articles met our inclusion criteria. Four hundred eighty patients were recruited in all study groups (233 patients in the HD and 247 in the LD groups). The mean time to first analgesic request was longer (MD, 4.49 hours [95% CI, 1.85-7.13]; P = 0.0008) in the HD group compared with the LD group. Pain scores (0-100 scale) at 12 hours (MD, 2.54 [95% CI, -2.55 to 7.63]; P = 0.33) as well as morphine consumption at 24 hours (MD, 1.31 mg [95% CI, -3.06 to 7.31]; P = 0.42) were not significantly different. The incidence of nausea or vomiting (OR, 0.44 [95% CI, 0.27-0.73]; P = 0.002) and pruritus (OR, 0.34 [95% CI, 0.20-0.59]; P = 0.0001) was lower in the LD group. The incidence of Apgar scores <7 at 1 minute was not different between groups (OR, 1.11 [95% CI, 0.06-20.49]; P = 0.94). This meta-analysis shows that HDs of intrathecal morphine prolong analgesia after cesarean delivery compared with lower doses. The MD of 4.5 hours (95% CI, 1.9-7.1 and 99% CI, 1.0-8.2 hours) of pain relief must be balanced against the increased risk of maternal pruritus and vomiting. Results from this study can be used by clinicians to weigh the benefits and potential side effects of using HDs of intrathecal morphine for cesarean delivery.


Association of pain ratings with the prediction of early physical recovery after general and orthopaedic surgery-A quantitative study with repeated measures.
To compare different levels of self-rated pain and determine if they predict anticipated early physical recovery in patients undergoing general and orthopaedic surgery. Previous research has indicated that average self-rated pain reflects patients' ability to recover the same day. However, there is a knowledge gap about the feasibility of using average pain ratings to predict patients' physical recovery for the next day. Descriptive, quantitative repeated measures. General and orthopaedic inpatients (n = 479) completed a questionnaire (October 2012-January 2015) about pain and recovery. Average pain intensity at rest and during activity was based on the Numeric Rating Scale and divided into three levels (0-3, 4-6, 7-10). Three out of five dimensions from the tool "Postoperative Recovery Profile" were used. Because few suffered severe pain, general and orthopaedic patients were analysed together. Binary logistic regression analysis showed that average pain intensity postoperative day 1 significantly predicted the impact on recovery day 2, except nausea, gastrointestinal function and bladder function when pain at rest and also nausea, appetite changes, and bladder function when pain during activity. High pain ratings (NRS 7-10) demonstrated to be a better predictor for recovery compared with moderate ratings (NRS 4-6), day 2, as it significantly predicted more items in recovery. Pain intensity reflected general and orthopaedic patients' physical recovery postoperative day 1 and predicted recovery for day 2. By monitoring patients' pain and impact on recovery, patients' need for support becomes visible which is valuable during hospital stays.


AinS and a new family of autoinducer synthesis proteins.
In Vibrio fischeri, the autoinducer N-3-oxohexanoyl-L-homoserine lactone (AI-1) governs the cell density-dependent induction of the luminescence operon via the LuxR transcriptional activator. The synthesis of AI-1 from bacterial metabolic intermediates is dependent on luxI. Recently, we found a second V. fischeri autoinducer molecule, N-octanoyl-L-homoserine lactone (AI-2), that in E. coli also activates the luminescence operon via LuxR. A locus independent of luxI was identified as being required for AI-2 synthesis. This 2.7-kb ain (autoinducer) locus was characterized by transposon insertion mutagenesis, deletion and complementation analysis, and DNA sequencing. A single 1,185-bp gene, ainS, was found to be the sole exogenous gene necessary for the synthesis of AI-2 in Escherichia coli. In addition, a V. fischeri ainS mutant produced AI-1 but not AI-2, confirming that in its native species ainS is specific for the synthesis of AI-2. ainS is predicted to encode a 45,580-Da protein which exhibits no similarity to LuxI or to any of the LuxI homologs responsible for the synthesis of N-acyl-L-homoserine lactones in a variety of other bacteria. The existence of two different and unrelated autoinducer synthesis genes suggests the occurrence of convergent evolution in the synthesis of homoserine lactone signaling molecules. The C-terminal half of AinS shows homology to a putative protein in Vibrio harveyi, LuxM, which is required for the synthesis of a V. harveyi bioluminescence autoinducer. Together, AinS and LuxM define a new family of autoinducer synthesis proteins. Furthermore, the predicted product of another gene, ainR, encoded immediately downstream of ainS, shows homology to LuxN, which is similarly encoded downstream of luxM in V. harveyi and proposed to have sensor/regulator functions in the bioluminescence response to the V. harveyi auto inducer. This similarity presents the possibility that AI-2, besides interacting with LuxR, also interacts with AinR under presently unknown conditions.


Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma.
Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma. We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 × 10(6) GM-K562 cells or 1 × 10(7) GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation. Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4(+) cells and PD-1 and 4-1BB by CD8(+) cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4(+) T lymphocytes. Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885-96. ©2016 AACR.


The quality of colonoscopy services--responsibilities of referring clinicians: a consensus statement of the Quality Assurance Task Group, National Colorectal Cancer Roundtable.
Primary care clinicians initiate and oversee colorectal screening for their patients, but colonoscopy, a central component of screening programs, is usually performed by consultants. The accuracy and safety of colonoscopy varies among endoscopists, even those with mainstream training and certification. Therefore, it is a primary care responsibility to choose the best available colonoscopy services. A working group of the National Colorectal Cancer Roundtable identified a set of indicators that primary care clinicians can use to assess the quality of colonoscopy services. Quality measures are of actual performance, not training, specialty, or experience alone. The main elements of quality are a complete report, technical competence, and a safe setting for the procedure. We provide explicit criteria that primary care physicians can use when choosing a colonoscopist. Information on quality indicators will be increasingly available with quality improvement efforts within the colonoscopy community and growth in the use of electronic medical records.


Abrupt transitions to tumor extinction: a phenotypic quasispecies model.
The dynamics of heterogeneous tumor cell populations competing with healthy cells is an important topic in cancer research with deep implications in biomedicine. Multitude of theoretical and computational models have addressed this issue, especially focusing on the nature of the transitions governing tumor clearance as some relevant model parameters are tuned. In this contribution, we analyze a mathematical model of unstable tumor progression using the quasispecies framework. Our aim is to define a minimal model incorporating the dynamics of competition between healthy cells and a heterogeneous population of cancer cell phenotypes involving changes in replication-related genes (i.e., proto-oncogenes and tumor suppressor genes), in genes responsible for genomic stability, and in house-keeping genes. Such mutations or loss of genes result into different phenotypes with increased proliferation rates and/or increased genomic instabilities. Despite bifurcations in the classical deterministic quasispecies model are typically given by smooth, continuous shifts (i.e., transcritical bifurcations), we here identify a novel type of bifurcation causing an abrupt transition to tumor extinction. Such a bifurcation, named as trans-heteroclinic, is characterized by the exchange of stability between two distant fixed points (that do not collide) involving tumor persistence and tumor clearance. The increase of mutation and/or the decrease of the replication rate of tumor cells involves this catastrophic shift of tumor cell populations. The transient times near bifurcation thresholds are also characterized, showing a power law dependence of exponent [Formula: see text] of the transients as mutation is changed near the bifurcation value. These results are discussed in the context of targeted cancer therapy as a possible therapeutic strategy to force a catastrophic shift by simultaneously delivering mutagenic and cytotoxic drugs inside tumor cells.


Cytogenetic and phenotypic analysis of a human colon carcinoma cell line resistant to mitoxantrone.
A human colon carcinoma cell line selected for a 21-fold resistance to mitoxantrone was cross-resistant to the anthracycline, doxorubicin, but not to the anthracene, bisantrene. A 2-fold resistance was observed with vinblastine, another drug associated with multidrug resistance. Net intracellular mitoxantrone and doxorubicin accumulation were decreased at 1 h for all dose levels in the resistant cell line compared to the sensitive cell line. Although the resistant cells were more resistant to mitoxantrone than doxorubicin, the net accumulation of mitoxantrone was only 19% less than the sensitive cell line; whereas doxorubicin accumulation was decreased by 49%. No significant difference between the sensitive and resistant cell lines was observed in the initial accumulation of mitoxantrone; however, the efflux of mitoxantrone was increased in the resistant cell line. Verapamil did not overcome the resistance to mitoxantrone and did not increase the net accumulation of drug. No alterations in the electrophoretic mobility of membrane proteins were observed. Using immunoblotting techniques, the resistant cell line did not express P-glycoprotein which is frequently observed for cells resistant to anthracycline antibiotics. Cytogenetic analysis showed a putative homogenously staining region on the short arm of chromosome 7 in the resistant cell line. The limited cross-resistant phenotype, lack of verapamil reversal, nondetection of P-glycoprotein, and cytogenetic evidence of gene amplification suggests the involvement of a novel drug-resistant gene associated with resistance to mitoxantrone.


HE3286 reduces axonal loss and preserves retinal ganglion cell function in experimental optic neuritis.
Optic nerve inflammation, demyelination, and axonal loss are all prominent features of optic neuritis. While corticosteroids hasten visual recovery in optic neuritis, no treatment improves final visual outcomes. HE3286 (17α-ethynyl-5-androstene-3β,7β,17β-triol), a synthetic derivative of a natural steroid, β-AET (5-androstene-3β,7β,17β-triol), exerts anti-inflammatory effects in several disease models and has purported neuroprotective effects as well. HE3286's ability to suppress optic neuritis was examined in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Experimental autoimmune encephalomyelitis was induced in C57/BL6 mice. Mice were treated daily with intraperitoneal vehicle or 40 mg/kg HE3286. Visual function was assessed by optokinetic responses (OKR) at baseline and every 10 days until euthanasia at 40 days post immunization. Retinas and optic nerves were isolated. Inflammation (hematoxylin and eosin and Iba1 staining), demyelination (Luxol fast blue staining), and axonal loss (neurofilament staining) were assessed in optic nerve sections. Retinal ganglion cells (RGCs) were immunolabeled with Brn3a antibodies to quantify RGC survival. Progressive decreases in OKR occurred in vehicle-treated EAE mice, and HE3286 treatment reduced the level of this vision loss. HE3286 also attenuated the degree of inflammation, demyelination, and axonal loss in EAE optic nerves as compared to nerves from vehicle-treated EAE mice. Retinal ganglion cell loss that occurred in both vehicle- and HE3286-treated EAE mice was reduced in the temporal retinal quadrant of HE3286-treated mice. HE3286 suppresses inflammation, reduces demyelination and axonal loss, and promotes RGC survival during experimental optic neuritis. Importantly, HE3286 treatment also preserves some RGC function. Results suggest that HE3286 is a potential novel treatment for optic neuritis.


The role of metal oxide interactions: revisiting Pt growth on the TiO2 surface in the process of impregnation method.
First-principles calculations and experiments with PtOx on TiO2 surfaces were performed together to understand the interactions of metal oxides during the calcination process and their influence on the growth pattern of Pt on the TiO2 surface. Our calculations indicate that PtOx with a high concentration of oxygen binds more strongly to rutile than to anatase, indicating the formation of stronger interactions between Pt oxide and the rutile surface compared with anatase during the calcination stage under an oxidative atmosphere. X-ray photoelectron spectra quantification analysis illustrates that higher amounts of Pt oxide are obtained when impregnation is performed with a rutile support after calcination in comparison with that of anatase. After reduction, the stronger interaction between PtOx and rutile leads to a larger amount of partially charged and highly dispersed Pt nanoclusters on the surface, while the weaker interaction between PtOx and anatase illustrates the dispersion and sintering of higher amounts of metal nanoparticles on the anatase surface. Furthermore, the photocatalytic oxygen evolution test highlights the importance of understanding the interaction between the metal oxide and anatase/rutile for targeted synthesis of the supported catalyst.


The fate of neuroradiologic abstracts presented at national meetings in 1993: rate of subsequent publication in peer-reviewed, indexed journals.
Abstract presentations are a valuable means of rapidly conveying new information; however, abstracts that fail to eventually become published are of little use to the general medical community. Our goals were to determine the publication rate of neuroradiologic papers originally presented at national meetings in 1993 and to assess publication rate as a function of neuroradiologic subspecialty and study design. Proceedings from the 1993 ASNR and RSNA meetings were reviewed. A MEDLINE search encompassing 1993-1997 was performed cross-referencing lead author and at least one text word based on the abstract title. All ASNR and RSNA neuroradiologic abstracts were included. Study type, subspecialty classification, and sample size were tabulated. Publication rate, based on study design and neuroradiologic subspecialty, was compared with overall publication rate. Median duration from meeting presentation to publication was calculated, and the journals of publication were noted. Thirty-seven percent of ASNR abstracts and 33% of RSNA neuroradiologic abstracts were published as articles in indexed medical journals. Publication rates among neuroradiologic subspecialty types were not significantly different. Prospective studies presented at the ASNR were published at a higher rate than were retrospective studies. There was no difference between the publication rate of experimental versus clinical studies. Neuroradiologic abstracts were published less frequently than were abstracts within other medical specialties. Median time between abstract presentation and publication was 15 months. Approximately one third of neuroradiologic abstracts presented at national meetings in 1993 were published in indexed journals. This rate is lower than that of abstracts from medical specialties other than radiology.


Examining the formulation of emulsion electrospinning for improving the release of bioactive proteins from electrospun fibers.
Emulsion electrospinning has been sought as a method to prepare fibrous materials/scaffolds for growth factor delivery. Emulsion conditions, specifically sonication and the addition of a surfactant, were evaluated to determine their effect on the release and bioactivity of proteins from electrospun scaffolds. Polycaprolactone (PCL) and poly(ethylene oxide) (PEO/PCL) blends were evaluated where PEO, a hydrophilic polymer, was shown to enhance the incorporation of proteins. Electrospun scaffolds prepared with the addition of the nonionic surfactant Span® 80 at a concentration greater than the critical micelle concentration followed by mild sonication (10% amplitude) released lysozyme, the model protein, with a higher level of bioactivity as compared with other surfactant and sonication conditions. These conditions were then used to prepare emulsions of platelet-derived growth factor-BB (PDGF-BB) in PEO/PCL blends. Electrospun mats prepared by emulsions consisting of PDGF-BB incorporated with Span® 80 and sonicated at 10% amplitude exhibited a controlled release of PDGF-BB over 96 h as compared with a more rapid release from solutions that were not emulsified (Direct Addition) or emulsions that did not receive Span® 80 or sonication. Bioactive PDGF-BB incorporated in electrospun scaffolds enhanced the osteogenic differentiation of human mesenchymal stem cells as evidenced by increased alkaline phosphatase activity, improved cell attachment and reorganized cytoskeletal filaments. The findings in this study provide improved methods for achieving controlled release of bioactive proteins from electrospun materials.


Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials.
Acute respiratory distress syndrome (ARDS) is a potentially fatal disease with high mortality. Our aim was to summarize the current evidence for use of neuromuscular blocking agents (NMBA) in the early phase of ARDS. Systematic review and meta-analysis of publications between 1966 and 2012. The Medline and CENTRAL databases were searched for studies on NMBA in patients with ARDS. The meta-analysis was limited to: 1) randomized controlled trials; 02) adult human patients with ARDS or acute lung injury; and 03) use of any NMBA in one arm of the study compared with another arm without NMBA. The outcomes assessed were: overall mortality, ventilator-free days, time of mechanical ventilation, adverse events, changes in gas exchange, in ventilator settings, and in respiratory mechanics. Three randomized controlled trials covering 431 participants were included. Patients treated with NMBA showed less mortality (Risk ratio, 0.71 [95 % CI, 0.55 - 0.90]; number needed to treat, 1 - 7), more ventilator free days at day 28 (p = 0.020), higher PaO2 to FiO2 ratios (p = 0.004), and less barotraumas (p = 0.030). The incidence of critical illness neuromyopathy was similar (p = 0.540). The use of NMBA in the early phase of ARDS improves outcome.