Effectiveness of topical administration of Anethum graveolens essential oil on MRSA-infected wounds.
Medicinal plants are conventionally used for wound healing, but their action mechanisms are still unknown. The present study evaluated the effect of topical administration of ointment containing dill (Anethum graveolens) essential oil (DEO) in the management of apoptosis and cell proliferation during MRSA-infected experimentally induced wound healing process in BALB/c mice model. The GC-FID and GC-MS techniques were used to analyze chemical composition of the essential oil. The mice were randomly divided into four treatment groups including negative control (sham), 2% and 4% DEO and mupirocin®-treated animals. The full-thickness excisional wounds were inoculated by 5 × 107 colony-forming units of MRSA. In order to assess the effect of different concentrations of DEO on wounds infection, wound area, bacterial count, histopathological, immunohistochemical and RT-PCR analysis were evaluated. The GC-MS analysis identified α-phellandrene (47.3%), p-cymene (18.5%) and carvone (14.1%) as the main compounds of the essential oil tested here. Administration of DEO prevented bacterial growth and also reduced wound area in comparison to the control group. Topical administration of DEO significantly reduced the inflammatory phase and accelerated re-epithelialization, angiogenesis, fibroblast and collagen deposition. Moreover, the DEO-treated animals exhibited higher expressions of Bcl-2, p53 caspase-3, VEGF and FGF-2 in comparison to the control and mupirocin®-treated groups (P < 0.05). Topical administration of DEO decreases the inflammatory phase by increasing p53 and caspases-3 expression. It triggers the proliferative phase by up-regulation of the Bcl-2, VEGF and FGF-2 expression and also up-regulates the collagen biosynthesis by enhancing the ERα expression level. Thus, ointment prepared from dill essential oil, in Iran, with its major compounds such as α-phellandrene, p-cymene and carvone can be used as an agent for accelerating the infected wound healing.


Rational design of coaxial structured carbon nanotube-manganese oxide (CNT-MnO2) for energy storage application.
Recently, there has been great research interest in the development of composites (core-shell structures) of carbon nanotubes (CNTs) with metal oxides for improved electrochemical energy storage, photonics, electronics, catalysis, etc. Currently, the synthetic strategies for metal oxides/hydroxides are well established, but the development of core-shell structures by robust, cost-effective chemical methods is still a challenge. The main drawbacks for obtaining such electrodes are the very complex synthesis methods which ultimately result in high production costs. Alternatively, the solution based method offers the advantages of simple and cost effective synthesis, as well as being easy to scale up. Here, we report on the development of multi-walled carbon nanotube-manganese oxide (CNT-MnO2) core-shell structures. These samples were directly utilized for asymmetric supercapacitor (ASC) applications, where the CNT-MnO2 composite was used as the positive electrode and ZIF-8 (zeolitic imidazolate framework, ZIF) derived nanoporous carbon was used as the negative electrode. This unconventional ASC shows a high energy density of 20.44 W h kg(-1) and high power density of 16 kW kg(-1). The results demonstrate that these are efficient electrodes for supercapacitor application.


A Rapid and Chemical-free Hemoglobin Assay with Photothermal Angular Light Scattering.
Photo-thermal angular light scattering (PT-AS) is a novel optical method for measuring the hemoglobin concentration ([Hb]) of blood samples. On the basis of the intrinsic photothermal response of hemoglobin molecules, the sensor enables high-sensitivity, chemical-free measurement of [Hb]. [Hb] detection capability with a limit of 0.12 g/dl over the range of 0.35 - 17.9 g/dl has been demonstrated previously. The method can be readily implemented using inexpensive consumer electronic devices such as a laser pointer and a webcam. The use of a micro-capillary tube as a blood container also enables the hemoglobin assay with a nanoliter-scale blood volume and a low operating cost. Here, detailed instructions for the PT-AS optical setup and signal processing procedures are presented. Experimental protocols and representative results for blood samples in anemic conditions ([Hb] = 5.3, 7.5, and 9.9 g/dl) are also provided, and the measurements are compared with those from a hematology analyzer. Its simplicity in implementation and operation should enable its wide adoption in clinical laboratories and resource-limited settings.


Systematic improvement of a chemically-defined protein-free medium for hybridoma growth and monoclonal antibody production.
A chemically-defined protein-free medium (FMX-Turbodoma) has been improved for the production of monoclonal IgA antibodies by hybridoma cells, using a systematic method. Cell growth rate, IgA production, activity and molecular weight pattern have been used as optimization criteria. Of potentially important supplements, glucose, glutamine, Pluronic acid F-68 as well as several amino acids had significant beneficial effects. A determination of amino acids profiles via HPLC analysis allowed the formulation of a balanced medium. Unbalanced supplementations of amino acids were found undesirable because of the toxicity of some amino acids at high concentration. Compared with the basal medium, the maximum viable cell and final IgA concentrations in the final version of the protein-free medium were increased by 130% and 700%, respectively, whereas the IgA molecular weight pattern and in vitro activity were not affected. The IgA production was even higher than in a serum-containing medium (RPMI 1640 + 10% FCS) and the price of the protein-free medium is about 20% of this serum-containing medium. This makes such a protein-free medium very convenient for laboratory and large-scale production.


Protein secondary structural types are differentially coded on messenger RNA.
Tricodon regions on messenger RNAs corresponding to a set of proteins from Escherichia coli were scrutinized for their translation speed. The fractional frequency values of the individual codons as they occur in mRNAs of highly expressed genes from Escherichia coli were taken as an indicative measure of the translation speed. The tricodons were classified by the sum of the frequency values of the constituent codons. Examination of the conformation of the encoded amino acid residues in the corresponding protein tertiary structures revealed a correlation between codon usage in mRNA and topological features of the encoded proteins. Alpha helices on proteins tend to be preferentially coded by translationally fast mRNA regions while the slow segments often code for beta strands and coil regions. Fast regions correspondingly avoid coding for beta strands and coil regions while the slow regions similarly move away from encoding alpha helices. Structural and mechanistic aspects of the ribosome peptide channel support the relevance of sequence fragment translation and subsequent conformation. A discussion is presented relating the observation to the reported kinetic data on the formation and stabilization of protein secondary structural types during protein folding. The observed absence of such strong positive selection for codons in non-highly expressed genes is compatible with existing theories that mutation pressure may well dominate codon selection in non-highly expressed genes.


Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines.
The lysis of infected host cells by virus-specific cytolytic T lymphocytes (CTL) is an important factor in host resistance to viral infection. An optimal vaccine against human immunodeficiency virus type 1 (HIV-1) would elicit virus-specific CTL as well as neutralizing antibodies. The induction by a vaccine of HIV-1-specific CD8+ CTL in humans has not been previously reported. In this study, CTL responses were evaluated in HIV-1-seronegative human volunteers participating in a phase I acquired immune deficiency syndrome (AIDS) vaccine trial involving a novel vaccine regimen. Volunteers received an initial immunization with a live recombinant vaccinia virus vector carrying the HIV-1 env gene and a subsequent boost with purified env protein. An exceptionally strong env-specific CTL response was detected in one of two vaccine recipients, while modest but significant env-specific CTL activity was present in the second vaccinee. Cloning of the responding CTL gave both CD4+ and CD8+ env-specific CTL clones, permitting a detailed comparison of critical functional properties of these two types of CTL. In particular, the potential antiviral effects of these CTL were evaluated in an in vitro system involving HIV-1 infection of cultures of normal autologous CD4+ lymphoblasts. At extremely low effector-to-target ratios, vaccine-induced CD8+ CTL clones lysed productively infected cells present within these cultures. When tested for lytic activity against target cells expressing the HIV-1 env gene, CD8+ CTL were 3-10-fold more active on a per cell basis than CD4+ CTL. However, when tested against autologous CD4+ lymphoblasts acutely infected with HIV-1, CD4+ clones lysed a much higher fraction of the target cell population than did CD8+ CTL. CD4+ CTL were shown to recognize not only the infected cells within these acutely infected cultures but also noninfected CD4+ T cells that had passively taken up gp120 shed from infected cells and/or free virions. These results were confirmed in studies in which CD4+ lymphoblasts were exposed to recombinant gp120 and used as targets for gp120-specific CD4+ and CD8+ CTL clones. gp120-pulsed, noninfected targets were lysed in an antigen-specific fashion by CD4+ but not CD8+ CTL clones. Taken together, these observations demonstrate that in an in vitro HIV-1 infection, sufficient amounts of gp120 antigen are produced and shed by infected cells to enable uptake by cells that are not yet infected, resulting in the lysis of these noninfected cells by gp120-specific, CD4+ CTL.(ABSTRACT TRUNCATED AT 400 WORDS)


A multicenter prospective cohort study to develop frailty-based prognostic criteria in heart failure patients (FLAGSHIP): rationale and design.
Heart failure (HF) and frailty often co-exist, and frailty in HF results in a poor prognosis. However, in Asian populations, prognostic criteria are needed to examine the effect of frailty on HF. Therefore, we conducted a nationwide cohort study to develop frailty-based prognostic criteria in HF patients (FLAGSHIP). FLAGSHIP mainly aims to 1) develop the frailty criteria based on HF-specific outcomes, 2) propose a hypothesis of the potential mechanisms of frailty manifestations in HF, and 3) examine the effects of outpatient cardiac rehabilitation on frailty. In this prospective study, we consecutively enroll ambulatory patients admitted because of acute HF or exacerbation of HF and elderly patients admitted for acute myocardial infarction (age ≥ 70 years). They will be followed up for 2 years to assess frailty and hard clinical events. The primary endpoints of FLAGSHIP are cardiac events including cardiac mortality and HF-related readmission after discharge. Secondary endpoints are readmissions because of fracture or pneumonia and all-cause mortality. We used clinical data, including the items related to the frailty phenotype to develop diagnostic criteria for frailty and known prognostic factors of HF. Cognitive function, depression, and anorexia are also considered as potential components of frailty. As of March 2018, 2650 patients (85% was patients admitted for HF) have been registered from 30 collaborating hospitals nationwide in Japan. FLAGSHIP provides diagnostic criteria and fundamental information on frailty manifestations to develop the best practices for the long-term management of HF. Diagnostic criteria on frailty developed by FLAGSHIP is expected to become a novel indicator for the stratification of patients at risk to functional decline after medical or surgical treatment, and in turn to contribute to the best practices in the long-term management of HF.


Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism.
Maternal immune activation (MIA) can affect fetal brain development and thus behavior of young and adult offspring. Reports have shown that increased Interleukin-6 (IL-6) in the maternal serum plays a key role in altering fetal brain development, and may impair social behaviors in the offspring. Interestingly, these effects could be attenuated by blocking IL-6. The current study investigated the effects of luteolin, a citrus bioflavonoid, and its structural analog, diosmin, on IL-6 induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) phosphorylation and signaling as well as behavioral phenotypes of MIA offspring. Luteolin and diosmin inhibited neuronal JAK2/STAT3 phosphorylation both in vitro and in vivo following IL-6 challenge as well as significantly diminishing behavioral deficits in social interaction. Importantly, our results showed that diosmin (10mg/kgday) was able to block the STAT3 signal pathway; significantly opposing MIA-induced abnormal behavior and neuropathological abnormalities in MIA/adult offspring. Diosmin's molecular inhibition of JAK2/STAT3 pathway may underlie the attenuation of abnormal social interaction in IL-6/MIA adult offspring.


In vivo evaluation of the biocompatibility of implanted biomaterials: morphology of the implant-tissue interactions.
Electron microscopic observations were made from tissues apposing titanium and ceramic root form and blade implants. The tissue was serially sectioned from the most coronal epithelium, through the gingival connective tissue, to the osseous support tissues, and directly to the most apical tissue support. Of the thousands of sections analyzed for each implant, 500 micrographs were routinely viewed for each of the implants analyzed by this study. Of the 120 total implants placed in 30 adult dogs, 60 were used for electron microscopy. Osseointegrated implants were often apposed by a mineralized matrix of collagenous fibers. The dense mineralized collagen matrix was often separated from the implant by only a ruthenium positive electron dense deposit 20 to 50 nanometers thick. Areas of the same implant were also apposed by an unmineralized collagen fiber stroma, which ranged in thickness, that contained osteoblasts. Interaction of the osteoblasts and the unmineralized collagen fibers resulted in the mineralization events of osteogenesis. Also apposing other areas of the same integrated implants were lacunar areas containing osteoclasts and vessels. These zones were similar to Howship's Lacunae. These results demonstrated that a normal homeostasis of catabolic osteoclastic activity and metabolic osteoblastic activity resulted in a dynamic implant-tissue interface. This biocompatible and dynamic support complex provides a construct for the long-term clinical serviceability of osseointegrated implants.


First Report of Downy Mildew Caused by Peronospora belbahrii on Basil (Ocimum spp.) in Ontario.
Basil (Ocimum spp.) is one of the most commercially significant fresh culinary herb crops worldwide. In Ontario, basil is grown both in the field and in the greenhouse. In the summer of 2011, basil plants grown in a research field at the Simcoe Research Station in Norfolk County, Ontario, Canada (44°15'N, 77°35'W), were infected with downy mildew. Infected leaves exhibited interveinal chlorotic lesions on the upper surface and clear to black sporulation on the abaxial leaf surfaces. Leaf senescence and defoliation occurred at high disease severity, which reduced marketable yield. Basil downy mildew symptoms were severe on leaves of cultivars Genovese and Sweet Basil, with 40 to 100% disease incidence. Based on morphological characteristics, the basil downy mildew causal agent was identified as Peronospora belbahrii Thines (4). Infected leaves were collected and microscopic observations of the sporulating lesions were carried out and the structures measured. Sporangiophores (n = 20) were hyaline with relatively long, straight trunks and were monopodially branched, with a length of 150 to 360 μm (average 285 μm). Sporangiophores ended with two slightly curved branchlets, the longer one measuring 15 to 27 μm (average 19 μm) and the shorter one 5 to 15 μm (average 9 μm). Sporangia (n = 50) were round, or slightly ovoid, olive to brown in color, and measured 29 × 25 μm (25 to 35 × 20 to 30 μm). Genomic DNA was extracted from 10 isolates and the nuclear ribosomal internal transcribed spacer (ITS) region was amplified with ITS4 and ITS5 primers and sequenced. The sequences of the 10 isolates were nearly identical. A BLAST search of the NCBI database with the ITS sequences (GenBank Accession No. KC756923) revealed a 98 to 100% similarity to the sequences of P. belbahrii (HQ730979, FJ436024, and HQ702191) isolated from sweet basil in Florida (3), California (1), and Hungary (2), respectively. To confirm pathogenicity, 5-week-old 'Genovese' seedlings were sprayed with a suspension of 1 × 105 sporangia/ml. Plants were kept in a growth chamber maintained at 23/18°C, 60 to 85% relative humidity, and 12/12 h light/dark. Non-inoculated plants served as controls. Basil downy mildew symptoms developed after 8 days on the inoculated plants and the pathogen was identified in association with symptoms consistent with downy mildew. The non-inoculated controls remained healthy. In North America, the occurrence of basil downy mildew has been reported since 2007 (3) and the disease has spread into several U.S. states. To our knowledge, this is the first report of downy mildew on sweet basil in Canada. References: (1) C. L. Blomquist et al. Plant Dis. 93:968, 2009. (2) G. Nagy and A. Horvath. Plant Dis. 95:1034, 2011. (3) P. D. Roberts et al. Plant Dis. 98:199, 2009. (4) M. Thines et al. Mycol. Res. 113:532, 2009.


Surveillance of molecular markers for antimalarial resistance in Zambia: Polymorphism of Pfkelch 13, Pfmdr1 and Pfdhfr/Pfdhps genes.
Antimalarial resistance is an inevitable feature of control efforts and a key threat to achieving malaria elimination. Plasmodium falciparum, the deadliest of several species causing human malaria, has developed resistance to essentially all antimalarials. This study sought to investigate the prevalence of molecular markers associated with resistance to sulfadoxine-pyrimethamine (SP) and artemether-lumefantrine (AL) in Southern and Western provinces in Zambia. SP is used primarily for intermittent preventive treatment during pregnancy, while AL is the first-line antimalarial for uncomplicated malaria in Zambia. Blood samples were collected from household members of all ages in a cross-sectional survey conducted during peak malaria transmission, April to May of 2017, and amplified by polymerase chain reaction (PCR). Amplicons were then analysed by high-resolution melt following PCR to identify mutations associated with SP resistance in the P. falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps) genes and lumefantrine resistance in the P. falciparum multi-drug resistance 1 (Pfmdr1) gene. Finally, artemether resistance was assessed in the P. falciparum Kelch 13 (PfK13) gene using nested PCR followed by amplicon sequencing. The results showed a high frequency of genotypic-resistant Pfdhps A437G (93.2%) and Pfdhfr C59R (86.7%), N51I (80.9%), and S108N (80.8%) of which a high proportion (82.4%) were quadruple mutants (Pfdhfr N51I, C59R, S108N +Pfdhps A437G). Pfmrd1 N86Y, Y186F, and D1246Y - NFD mutant haplotypes were observed in 41.9% of isolates. The high prevalence of quadruple dhps/dhfr mutants indicates strong antifolate drug pressure from SP or other drugs (e.g., co-trimoxazole). Three samples contained PfK13 mutations, two synonymous (T478 and V666) and one non-synonymous (A578S), none of which have been associated with delayed clearance. This suggests that artemisinin remains efficacious in Zambia, however, the moderately high prevalence of approximately 40% Pfmdr1 NFD mutations calls for close monitoring of AL.


Successful management of severe hemolytic disease of the fetus due to anti-Jsb using intrauterine transfusions with serial maternal blood donations: a case report and a review of the literature.
The management of pregnant women with anti-Jsb is challenging due to the paucity of antigen-negative blood for fetal and neonatal transfusion. A 29-year-old woman with anti-Jsb was referred for assessment of recurrent fetal losses. With the presence of the sister as a historically matched donor, she was planned for active surveillance for fetal anemia during pregnancy. The fetus remained well until 21 weeks of gestation when signs of fetal anemia and early hydrops fetalis were noted. Anti-Jsb titer was at 128. The sister's red blood cells (RBCs) were cross-match incompatible. Urgent intrauterine transfusion (IUT) was performed with washed irradiated maternal RBCs, donated after cessation of heparin. The mother was given intravenous iron (IV-Fe) and continued on weekly recombinant human erythropoietin (rHu-EPO). Repeated IUTs were needed every 1 to 3 weeks. Throughout a 7-week period, three maternal donations were performed with total donated whole blood volume of 1250 mL, supporting four IUTs. At 29 weeks of gestation, the procedure was complicated by umbilical cord hematoma necessitating urgent cesarean section. A male newborn was delivered, transfused at birth, and subsequently treated with phototherapy and five top-up transfusions. This case represents a successful example of managing hemolytic disease of the fetus due to a rare antibody using maternal blood. It also supports previous data on safety of maternal donations during pregnancy and the use of combination of rHu-EPO and IV-Fe as a supportive measure.


Race, punishment, and the Michael Vick experience.
Objective. The relationship between race and crime has been contentious, focusing primarily on offending and incarceration patterns among minorities. There has been some limited work on public perceptions of criminal punishment, and findings show that while minorities believe in the role and rule of law, they simultaneously perceive the justice system as acting in a biased and/or unfair manner. Two limitations have stalled this literature. First, research has focused mainly on criminal punishments to the neglect of noncriminal punishments. Second, most studies have not examined whether race remains salient after considering other demographic variables or discrimination and legitimacy attitudes.Methods. Using data from 400 adults, we examine how race affects perceptions of criminal punishment and subsequent reinstatement into the National Football League in the case of Michael Vick, a star professional quarterback who pled guilty to charges of operating an illegal dog-fighting ring.Results. Findings show that whites are more likely to view Vick's punishment as too soft and that he should not be reinstated, while nonwhites had the opposite views. Race remained significant after controlling for other variables believed to be related to punishment perceptions.Conclusion. Attitudes toward both criminal punishment and NFL reinstatement vary across race such that there exists important divides in how individuals perceive the system meting out punishment and subsequently reintegrating offenders back into society. These results underscore that white and nonwhites perceive the law and its administration differently.


New insights into the role of mitochondria in aging: mitochondrial dynamics and more.
A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders. A deeper understanding of the intricate nature of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in several key pathologies associated with aging. Indeed, a recent wave of studies has demonstrated the pleiotropic role of fusion and fission proteins in numerous cellular processes, including mitochondrial metabolism, redox signaling, the maintenance of mitochondrial DNA and cell death. Additionally, mitochondrial fusion and fission, together with autophagy, have been proposed to form a quality-maintenance mechanism that facilitates the removal of damaged mitochondria from the cell, a process that is particularly important to forestall aging. Thus, dysfunctional regulation of mitochondrial dynamics might be one of the intrinsic causes of mitochondrial dysfunction, which contributes to oxidative stress and cell death during the aging process. In this Commentary, we discuss recent studies that have converged at a consensus regarding the involvement of mitochondrial dynamics in key cellular processes, and introduce a possible link between abnormal mitochondrial dynamics and aging.


Multichip free-space global optical interconnection demonstration with integrated arrays of vertical-cavity surface-emitting lasers and photodetectors.
The experimental optical interconnection module of the Free-Space Accelerator for Switching Terabit Networks (FAST-Net) project is described and characterized. Four two-dimensional (2-D) arrays of monolithically integrated vertical-cavity surface-emitting lasers (VCSEL's) and photodetectors (PD's) were designed, fabricated, and incorporated into a folded optical system that links a 10 cm x 10 cm multichip smart pixel plane to itself in a global point-to-point pattern. The optical system effects a fully connected network in which each chip is connected to all others with a multichannel bidirectional data path. VCSEL's and detectors are arranged in clusters on the chips with an interelement spacing of 140 microm. Calculations based on measurements of resolution and registration tolerances showed that the square 50-microm detector in a typical interchip link captures approximately 85% of incident light from its associated VCSEL. The measured optical transmission efficiency was 38%, with the losses primarily due to reflections at the surfaces of the multielement lenses, which were not antireflection coated for the VCSEL wavelength. The overall efficiency for this demonstration is therefore 32%. With the measured optical confinement, an optical system that is optimized for transmission at the VCSEL wavelength will achieve an overall efficiency of greater than 80%. These results suggest that, as high-density VCSEL-based smart pixel technology matures, the FAST-Net optical interconnection concept will provide a low-loss, compact, global interconnection approach for high bisection-bandwidth multiprocessor applications in switching, signal processing, and image processing.


Nano- and microstructured materials for in vitro studies of the physiology of vascular cells.
The extracellular environment of vascular cells in vivo is complex in its chemical composition, physical properties, and architecture. Consequently, it has been a great challenge to study vascular cell responses in vitro, either to understand their interaction with their native environment or to investigate their interaction with artificial structures such as implant surfaces. New procedures and techniques from materials science to fabricate bio-scaffolds and surfaces have enabled novel studies of vascular cell responses under well-defined, controllable culture conditions. These advancements are paving the way for a deeper understanding of vascular cell biology and materials-cell interaction. Here, we review previous work focusing on the interaction of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) with materials having micro- and nanostructured surfaces. We summarize fabrication techniques for surface topographies, materials, geometries, biochemical functionalization, and mechanical properties of such materials. Furthermore, various studies on vascular cell behavior and their biological responses to micro- and nanostructured surfaces are reviewed. Emphasis is given to studies of cell morphology and motility, cell proliferation, the cytoskeleton and cell-matrix adhesions, and signal transduction pathways of vascular cells. We finalize with a short outlook on potential interesting future studies.


Selecting lung cancer screenees using risk prediction models-where do we go from here.
The National Lung Screening Trial (NLST) demonstrated that low dose computed tomography (LDCT) screening could reduce lung cancer mortality by 20% in high-risk individuals. The United States Preventive Services Task Force (USPSTF) and Centers for Medicare and Medicaid Services (CMS) approved lung cancer screening. The NLST, USPSTF and CMS define high risk as smoking ≥30 pack-years, smoking within the past 15 years, and being ages 55-74, 55-80 or 55-77. Retrospective studies demonstrated selection using model-estimated risk is superior to NLST-like criteria: higher sensitivity and positive predictive value (PPV), more deaths averted and higher cost-effectiveness. Projects are underway that may additionally support use of risk to determine eligibility. Firstly, the International Lung Screen Trial (ILST) is prospectively enrolling 4,000 individuals for screening if individuals have PLCOm2012 model risk ≥1.5% or are USPSTF+ve. Six-year follow-up will allow comparisons. Interim results support the risk approach. Secondly, Cancer Care Ontario started the Lung Cancer Screening Pilot for People at High Risk in order to find optimal design for province-wide programmatic screening. They are enrolling 3,000 individuals to screening based on PLCOm2012 risk ≥2%. Some hesitation to recommend screening selection based on model risk comes from the observation that selected individuals are older, have more comorbidities, are expected to have fewer life years and quality-adjusted life years (QALY) and are more likely to die from competing causes. We show that 25.6% of NLST eligible smokers are at low risk (6-year lung cancer incidence proportion =0.008). This group will not benefit from screening but has lower age, fewer comorbidities and fewer competing causes of death. When they are excluded from the NLST+ve group, age, comorbidity count and competing causes of death are similar to those in the PLCOm2012+ve group. In some jurisdictions, model-based lung cancer screening selection needs to take into consideration the elevated risk in blacks and indigenous peoples.


Stability and diversity at three trophic levels in terrestrial successional ecosystems.
An ecosystem perturbation experiment in which inorganic fertilizer was added to two successional old fields of different ages indicated that stability, expressed as resistance to modification by enrichment, increased during succession only at the primary trophic level. The perturbation was propagated throughout the arthropod herbivores and carnivores. Both herbivores and carnivores were less stable in the older field. In contrast to current ecological theory, greater diversity at a trophic level was accompanied by lower stability at the next higher level.


A mixed community of actinomycetes produce multiple antibiotics for the fungus farming ant Acromyrmex octospinosus.
Attine ants live in an intensely studied tripartite mutualism with the fungus Leucoagaricus gongylophorus, which provides food to the ants, and with antibiotic-producing actinomycete bacteria. One hypothesis suggests that bacteria from the genus Pseudonocardia are the sole, co-evolved mutualists of attine ants and are transmitted vertically by the queens. A recent study identified a Pseudonocardia-produced antifungal, named dentigerumycin, associated with the lower attine Apterostigma dentigerum consistent with the idea that co-evolved Pseudonocardia make novel antibiotics. An alternative possibility is that attine ants sample actinomycete bacteria from the soil, selecting and maintaining those species that make useful antibiotics. Consistent with this idea, a Streptomyces species associated with the higher attine Acromyrmex octospinosus was recently shown to produce the well-known antifungal candicidin. Candicidin production is widespread in environmental isolates of Streptomyces, so this could either be an environmental contaminant or evidence of recruitment of useful actinomycetes from the environment. It should be noted that the two possibilities for actinomycete acquisition are not necessarily mutually exclusive. In order to test these possibilities we isolated bacteria from a geographically distinct population of A. octospinosus and identified a candicidin-producing Streptomyces species, which suggests that they are common mutualists of attine ants, most probably recruited from the environment. We also identified a Pseudonocardia species in the same ant colony that produces an unusual polyene antifungal, providing evidence for co-evolution of Pseudonocardia with A. octospinosus. Our results show that a combination of co-evolution and environmental sampling results in the diversity of actinomycete symbionts and antibiotics associated with attine ants.


Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells.
Nucleostemin is a nucleolus residing GTPase that is considered to be an important cancer stem/progenitor cell marker protein due to its high expression levels in breast cancer stem cells and its role in tumor-initiation of human mammary tumor cells. It has been proposed that nucleostemin may represent a valuable therapeutic target for breast cancer; however, to date evidence supporting the cellular mechanism has not been elucidated. Expression of exogenous HER2, a member of the EGF receptor gene family, in the human MCF-10AT preneoplastic mammary epithelial cell line formed a new breast cancer cell line, 10AT-Her2, which is highly enriched in cells with stem/progenitor cell-like character. 10AT-Her2 cells display a CD44+/CD24-/low phenotype with high levels of the cancer stem/progenitor cell marker proteins nucleostemin, and active aldehyde dehydrogenase-1. The overall expression pattern of HER2 protein and the stem/progenitor cell marker proteins in the 10AT-Her2 cell population is similar to that of the luminal HER2+ SKBR3 human breast cancer cell line, whereas, both MCF-7 and MDA-MB-231 cells display reduced levels of nucleostemin and no detectable expression of ALDH-1. Importantly, in contrast to the other well-established human breast cancer cell lines, 10AT-Her2 cells efficiently form tumorspheres in suspension cultures and initiate tumor xenograft formation in athymic mice at low cell numbers. Furthermore, 10AT-Her2 cells are highly sensitive to the anti-proliferative apoptotic effects of indole-3-carbinol (I3C), a natural anti-cancer indolecarbinol from cruciferous vegetables of the Brassica genus such as broccoli and cabbage. I3C promotes the interaction of nucleostemin with MDM2 (Murine Double Mutant 2), an inhibitor of the p53 tumor suppressor, and disrupts the MDM2 interaction with p53. I3C also induced nucleostemin to sequester MDM2 in a nucleolus compartment, thereby freeing p53 to mediate its apoptotic activity. siRNA knockdown of nucleostemin functionally documented that nucleostemin is required for I3C to trigger its cellular anti-proliferative responses, inhibit tumorsphere formation, and disrupt MDM2-p53 protein-protein interactions. Furthermore, expression of an I3C-resistant form of elastase, the only known target protein for I3C, prevented I3C anti-proliferative responses in cells and in tumor xenografts in vivo, as well as disrupt the I3C stimulated nucleostemin-MDM2 interactions. Our results provide the first evidence that a natural anti-cancer compound mediates its cellular and in vivo tumor anti-proliferative responses by selectively stimulating cellular interactions of the stem/progenitor cell marker nucleostemin with MDM2, which frees p53 to trigger its apoptotic response. Furthermore, our study provides a new mechanistic template that can be potentially exploited for the development of cancer stem/progenitor cell targeted therapeutic strategies.


On the Frontlines: Perspectives of Providers Working With Homeless Women.
Homeless service providers (HSPs) are on the frontlines of caring for the most vulnerable populations to help them navigate out of homelessness and access health and social services. The purpose of this qualitative study was to understand, from the perspectives of HSPs ( N = 19; age range, 27-58 years; SD = 10.37), their account and experiences in working with homeless women (HW), and opportunities for intervention development and integration. Five focus groups were conducted with HSPs in Central City East, Los Angeles. Five main themes emerged which included (a) seeking to establish a therapeutic relationship, (b) internal and external drivers of change, (c) navigating systems, (d) targeted outreach, and (e) program design recommendations. Within these themes, individual- and structural-level characteristics emerged. To better equip HW, HSPs' perspectives need to be considered in future interventions to aid women traverse homelessness.


Development of a questionnaire to evaluate practitioners' confidence and knowledge in primary care in managing chronic kidney disease.
In the UK, chronic disease, including chronic kidney disease (CKD) is largely managed in primary care. We developed a tool to assess practitioner confidence and knowledge in managing CKD compared to other chronic diseases. This questionnaire was part of a cluster randomised quality improvement interventions in chronic kidney disease (QICKD; ISRCTN56023731). The questionnaire was developed by family physicians, primary care nurses, academics and renal specialists. We conducted three focus groups (n=7, 6, and 8) to refine the questionnaire using groups of general practitioners, practice nurses and trainees in general practice. We used paper based versions to develop the questionnaire and online surveys to test it. Practitioners in a group of volunteer, trial practices received the questionnaire twice. We measured its reliability using Cohen's Kappa (K). The practitioners in the focus groups reached a consensus as to the key elements to include in the instrument. We achieved a 73.1% (n=57/78) initial response rate for our questionnaire; of these 57, 54 completed the questionnaire a second time. Family physicians made up the largest single group of respondents (47.4%, n=27). Initial response showed more female (64.9%, n=37) than male (35.1%, n=20) respondents. The reliability results from retesting showed that there was moderate agreement (k>0.4) on all questions; with many showing substantial agreement (k>0.6). There was substantial agreement in the questions about loop diuretics (k=0.608, CI 0.432-0.784, p<0.001), confidence in managing hypertension (k=0.628, 95%CI 0.452-0.804, p<0.001), diastolic blood pressure treatment thresholds in CKD (k=0.608, 95%CI 0.436-0.780, p<0.001) and the rate of decline of eGFR that would prompt referral (k=0.764, 95%CI 0.603-0.925, p<0.001). The QICKD-CCQ is a reliable instrument for measuring confidence and knowledge among primary care practitioners on CKD management in the context of UK primary care.


Using Neuroscience to Inform Tobacco Control Policy.
Techniques employed in the field of neuroscience, such as eye tracking, electroencephalography, and functional magnetic resonance imaging, have been important in informing our understanding of the cognitive mechanisms underlying tobacco smoking. These techniques are now increasingly being used to investigate the likely impact of tobacco control policies. In this narrative review, we outline the value of these methodological approaches in answering policy-relevant tobacco control research questions, with a particular focus on their use in examining the impact of standardized cigarette packaging and health warnings. We also examine the limitations of these methodologies and provide examples of how they can be used to answer other policy-relevant questions. We argue that neuroscience techniques can provide more objective evidence of the impacts of policy measures, allow investigation where it is not possible to conduct behavioral manipulations, and facilitate a deeper understanding of the cognitive mechanisms underlying the impacts of tobacco control policies such as standardized packaging, health warnings, point-of-sale displays, and mass media campaigns. Rather than replacing more traditional methods of examining tobacco control measures, such as observational experiments, surveys, and questionnaires, neuroscience techniques can complement and extend these methods. Neuroscience techniques facilitate objective examination of the mechanisms underlying the impacts of tobacco control measures. These techniques can therefore complement and extend other methodologies typically used in this field, such as observational experiments, surveys, and questionnaires.


Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.


Free radical-derived quinone methide mediates skin tumor promotion by butylated hydroxytoluene hydroperoxide: expanded role for electrophiles in multistage carcinogenesis.
Free radical derivatives of peroxides, hydroperoxides, and anthrones are thought to mediate tumor promotion by these compounds. Further, the promoting activity of phorbol esters is attributed, in part, to their ability to stimulate the cellular generation of oxygen radicals. A hydroperoxide metabolite of butylated hydroxytoluene, 2,6-di-tert-butyl-4-hydroperoxyl-4-methyl-2,5-cyclohexadienone (BHTOOH), has previously been shown to be a tumor promoter in mouse skin. BHTOOH is extensively metabolized by murine keratinocytes to several radical species. The primary radical generated from BHTOOH is a phenoxyl radical that can disproportionate to form butylated hydroxytoluene quinone methide, a reactive electrophile. Since electrophilic species have not been previously postulated to mediate tumor promotion, the present study was undertaken to examine the role of this electrophile in the promoting activity of BHTOOH. The biological activities of two chemical analogs of BHTOOH, 4-trideuteromethyl-BHTOOH and 4-tert-butyl-BHTOOH, were compared with that of the parent compound. 4-Trideuteromethyl-BHTOOH and 4-tert-butyl-BHTOOH have a reduced ability or inability, respectively, to form a quinone methide; however, like the parent compound, they both generate a phenoxyl radical when incubated with keratinocyte cytosol. The potency of BHTOOH, 4-trideuteromethyl-BHTOOH, and 4-tert-butyl-BHTOOH as inducers of ornithine decarboxylase, a marker of tumor promotion, was commensurate with their capacity for generating butylated hydroxytoluene quinone methide. These initial results were confirmed in a two-stage tumor promotion protocol in female SENCAR mice. Together, these data indicate that a quinone methide is mediating tumor promotion by BHTOOH, providing direct evidence that an electrophilic intermediate can elicit this stage of carcinogenesis.


Audit of geriatric hip fracture care - a Slovenian trauma center analysis.
The aim was to describe an audit of hip fracture patient care and outcomes in a Slovenian healthcare setting prior to the implementation of the Geriatric Fracture Center (GFC) model of care. The Fragility Fracture Network (FFN) hip fracture audit database was used to collect data on hip fracture care in elderly patients. Epidemiological data were submitted as well as fracture type, prefracture residence and mobility prior to the fracture. The timeline of events and acute care data were also collected. Follow-up after 30 days included hip-related readmission, mobility, residence and life status. Included were 495 patients with a mean age of 81 years of which 20% were preoperatively seen by a physician or geriatrician, 93.1% had surgical repair, 58.5% of them within 48 h of admission. The mortality rate in hospital was 5.4% and 10.1% at follow-up, 61.8% patients were able to return to prefracture residency and 23% could walk with minor assistance. This comprehensive and detailed audit report provides baseline data on case-mix, care and outcomes following hip fractures in Slovenia, in advance of planned quality improvement work in geriatric fracture care and provides a strong basis for the assessment of the impact of the GFC model of care.


Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.
Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo. There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia.


[A proposal for the creation of a system to monitor cases of malignant mesothelioma in Curitiba, Paraná, Brazil].
The study proposes the creation of a system to monitor cases of malignant mesothelioma in the municipality of Curitiba, Paraná State, Brazil, based on the Italian model. This diagnosis-type action-research project featured exploratory and planning phases conducted from July 2015 to May 2017. The following search tools were used: Hospital-Based Cancer Registries Integrator with specific morphologies for mesothelioma; Hospital-Based Cancer Registry with codes C38.4 and C45 of the International Classification of Diseases, 10th revision, and/or records coded by the ICD-O with topographies C38 and C48; Population-Based Cancer Registry of the Curitiba Municipal Health Department, with the same codes. The study also identified, analyzed, and adapted to the Brazilian reality the model, questionnaires, and registry software for mesothelioma from Lombardy, Italy. Fifteen cases of mesothelioma were recorded in the Hospital-Based Cancer Registries Integrator. Two cases were recorded in the University Hospital-Based Cancer Registry and 16 in the Cancer Hospital. There were 317 cases recorded in the Population-Based Cancer Registry during the same period. Although some information was complete, data were lacking on patients' occupational history, thereby preventing the determination of a causal nexus. Given a predicted increase in cases of mesothelioma in the coming decades and the response to court cases, the implementation of registries has become essential to facilitate knowledge and follow-up on the determination of the causal link and specific sources of asbestos exposure in the country.


Immunization Coverage of Children in Care of the Child Welfare System in High-Income Countries: A Systematic Review.
Children in care of the child welfare system tend to underutilize preventive health services compared with other children. The purpose of this systematic review was to assess current knowledge regarding immunization coverage levels for children in the child welfare system and to determine barriers and supports to them utilizing immunization services. Articles published in Medline, Embase, Cochrane Library, CINAHL, SocINDEX, and ERIC from January 1, 2000 to October 13, 2017 were searched. Thesis and conference databases and relevant websites were also examined. Studies were included if written in English, from high-income countries, and addressed immunizations for children in the child welfare system. Independent dual screening, extraction, and quality appraisal were conducted between October 2016 and December 2017, followed by narrative synthesis. Of 2,906 records identified, 33 met inclusion criteria: 21 studied coverage, two studied barriers/supports, and ten studied both. Nineteen studies were moderate or high quality and thus included in the narrative synthesis; 15 studied coverage, one studied barriers/supports, and three studied both. Most studies found lower coverage among children in child welfare. The few studies that explicitly studied barriers/supports to immunization identified that a collaborative and coordinated approach between health and social services was key to service delivery to this population. This review highlights that children in care of the child welfare system are at risk of poor immunization coverage. There is a need for high-quality studies on this issue, with a focus on assessing supports/barriers to immunization in this population.


Bacillus aciditolerans sp. nov., isolated from paddy soil.
A Gram-stain-positive, motile, rod-shaped bacterial strain, YN-1T, was isolated from a rice field in the town of Jietou, Yunnan Province, PR China. Colonies were circular, 1-2 mm in diameter, creamy white, with slightly irregular margins. The isolate grew optimally at 37 °C, pH 7.0 and with 1.0 % (w/v) NaCl. On the basis of the results of 16S rRNA gene sequence similarity comparisons, YN-1T clustered together with other species of the genus Bacillus and showed highest similarities with Bacillus onubensis 0911MAR22V3T (98.0 %), Bacillus humi LMG22167T (97.5 %), 'Bacillus timonensis' 10403023 (97.4 %) and 'Bacillussinesaloumensis' P3516 (97.1 %). However, the DNA-DNA hybridization values between YN-1T and closely related strains of species of the genus Bacillus were well below 47 %, indicating that they represent different taxa. The average nucleotide identity and the Genome-to-Genome Distance Calculator also revealed low relatedness (below 95 and 70 %, respectively) between YN-1T and type strains of closely related species of the genus Bacillus. The DNA G+C content of the strain was 40 mol%. The major cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, and C16 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified phospholipids, three unidentified aminophospholipids and two other unidentified lipids. Physiological and biochemical test results were also different from those of the most closely related species. On the basis of the phenotypic, genetic and chemotaxonomic data, strain YN-1T is considered to represent a novel species of the genus Bacillus, for which the name Bacillusaciditolerans sp. nov. is proposed, with strain YN-1T (=CCTCC AB 2017280T=JCM 32973T) as the type strain.


Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study.
While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (∼30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging. The present study is a preliminary post-mortem histological analysis of the effects of CR on brain health, and further studies using molecular and biochemical techniques are warranted to elucidate underlying mechanisms.


Deep Learning Deformation Initialization for Rapid Groupwise Registration of Inhomogeneous Image Populations.
Groupwise image registration tackles biases that can potentially arise from inappropriate template selection. It typically involves simultaneous registration of a cohort of images to a common space that is not specified a priori. Existing groupwise registration methods are computationally complex and are only effective for image populations without large anatomical variations. In this paper, we propose a deep learning framework to rapidly estimate large deformations between images to significantly reduce structural variability. Specifically, we employ a multi-level graph coarsening method to agglomerate similar images into clusters, each represented by an exemplar image. We then use a deep learning framework to predict the initial deformations between images. Warping with the estimated deformations brings the images closer in the image manifold and their alignment can be further refined using conventional groupwise registration algorithms. We evaluated the effectiveness of our method in groupwise registration of MR brain images and compared it against state-of-the-art groupwise registration methods. Experimental results indicate that deformation initialization enables groupwise registration to converge significantly faster with competitive accuracy, therefore facilitates large-scale imaging studies.


Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.
Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an in vitro model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.-Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.


Nitrazepam in patients with sleep apnoea: a double-blind placebo-controlled study.
We wanted to assess whether benzodiazepines worsen sleep apnoea, since their use in such patients has been controversial. Fourteen male patients with mild to moderate obstructive sleep apnoea were investigated in a placebo-controlled, double-blind study evaluating the influence of nitrazepam (NIT) on apnoea frequency and severity. Each patient was given oral nitrazepam 5 or 10 mg, or corresponding placebo, in a randomized order on three separate nights. Wash-out time was one week. A complete sleep study was undertaken at each study night. Eleven patients completed the study. Although there were individuals with marked variability in apnoea index between the three study nights, there was no significant change in apnoea index or minimum arterial oxygen saturation with any of the two nitrazepam dosages studied. Only 3 out of 11 patients had a higher apnoea index after both nitrazepam doses compared to placebo, and in these patients the increase in sleep-disordered breathing was of marginal clinical significance. Nitrazepam caused a modest increase in total sleep time and a decrease in rapid eye movement (REM) sleep. These results demonstrate that nitrazepam does not worsen sleep apnoea in patients with mild to moderate sleep apnoea. The previously reported sleep apnoea promoting effects of benzodiazepines may be restricted to a small subgroup of patients with sleep-disordered breathing.


Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function.
The purpose of this paper is to provide an integrative review and offer novel insights regarding human research with classic psychedelics (classic hallucinogens), which are serotonin 2A receptor (5-HT2AR) agonists such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Classic psychedelics have been administered as sacraments since ancient times. They were of prominent interest within psychiatry and neuroscience in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular neuroscience. Promising results were reported for treatment of both end-of-life psychological distress and addiction, and classic psychedelics served as tools for studying the neurobiological bases of psychological disorders. Moreover, classic psychedelics were shown to occasion mystical experiences, which are subjective experiences reported throughout different cultures and religions involving a strong sense of unity, among other characteristics. However, the recreational use of classic psychedelics and their association with the counterculture prompted an end to human research with classic psychedelics in the early 1970s. We provide the most comprehensive review of epidemiological studies of classic psychedelics to date. Notable among these are a number of studies that have suggested the possibility that nonmedical naturalistic (non-laboratory) use of classic psychedelics is associated with positive mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic psychedelics in non-supervised settings. We then review recent therapeutic studies suggesting efficacy in treating psychological distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol addictions. We also describe the construct of mystical experience, and provide a comprehensive review of modern studies investigating classic psychedelic-occasioned mystical experiences and their consequences. These studies have shown classic psychedelics to fairly reliably occasion mystical experiences. Moreover, classic-psychedelic-occasioned mystical experiences are associated with improved psychological outcomes in both healthy volunteer and patient populations. Finally, we review neuroimaging studies that suggest neurobiological mechanisms of classic psychedelics. These studies have also broadened our understanding of the brain, the serotonin system, and the neurobiological basis of consciousness. Overall, these various lines of research suggest that classic psychedelics might hold strong potential as therapeutics, and as tools for experimentally investigating mystical experiences and behavioral-brain function more generally.


Emergence and genetic variation of neuraminidase stalk deletions in avian influenza viruses.
When avian influenza viruses (AIVs) are transmitted from their reservoir hosts (wild waterfowl and shorebirds) to domestic bird species, they undergo genetic changes that have been linked to higher virulence and broader host range. Common genetic AIV modifications in viral proteins of poultry isolates are deletions in the stalk region of the neuraminidase (NA) and additions of glycosylation sites on the hemagglutinin (HA). Even though these NA deletion mutations occur in several AIV subtypes, they have not been analyzed comprehensively. In this study, 4,920 NA nucleotide sequences, 5,596 HA nucleotide and 4,702 HA amino acid sequences were analyzed to elucidate the widespread emergence of NA stalk deletions in gallinaceous hosts, the genetic polymorphism of the deletion patterns and association between the stalk deletions in NA and amino acid variants in HA. Forty-seven different NA stalk deletion patterns were identified in six NA subtypes, N1-N3 and N5-N7. An analysis that controlled for phylogenetic dependence due to shared ancestry showed that NA stalk deletions are statistically correlated with gallinaceous hosts and certain amino acid features on the HA protein. Those HA features included five glycosylation sites, one insertion and one deletion. The correlations between NA stalk deletions and HA features are HA-NA-subtype-specific. Our results demonstrate that stalk deletions in the NA proteins of AIV are relatively common. Understanding the NA stalk deletion and related HA features may be important for vaccine and drug development and could be useful in establishing effective early detection and warning systems for the poultry industry.


HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy.
Human immunodeficiency virus type 1 (HIV-1) eradication is prevented by the establishment on infection of cellular HIV-1 reservoirs that are not fully characterized, especially in genital mucosal tissues (the main HIV-1 entry portal on sexual transmission). Here, we show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cell activator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication.


Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients.
The incidence, pathogenesis, consequences and treatment of mammalian target of rapamycin (mTOR) inhibitor dyslipidemia are not well described. We conducted a systematic review of randomized controlled trials reporting cholesterol and triglycerides in mTOR versus non-mTOR inhibitor immunosuppressive treatment regimens in kidney transplant recipients. All but one of 17 trials reported higher levels of cholesterol and triglycerides, or an increased prevalence of treatment with lipid-lowering agents. Approximately 60% of mTOR inhibitor-treated patients received lipid-lowering agents (2-fold higher than controls). There appeared to be little difference between dyslipidemias caused by sirolimus (14 trials) versus everolimus (3 trials). It was difficult to determine the extent to which declines in lipids over time posttransplant were due to lipid-lowering therapy, changes in doses and/or discontinuations of mTOR inhibitors. From the four trials that measured lipoproteins, it appeared that at least some of the increase in total cholesterol with mTOR inhibitors was due to increased low-density lipoprotein cholesterol. What direct or indirect effects mTOR inhibitors have on atherosclerotic cardiovascular disease in kidney transplant patients are unknown. However, in the absence of the necessary clinical trials, dyslipidemia should be managed, as it would be in nontransplant patients at high risk for cardiovascular disease.


Cell-type specific increases in female hamster nucleus accumbens spine density following female sexual experience.
Female sexual behavior is an established model of a naturally motivated behavior which is regulated by activity within the mesolimbic dopamine system. Repeated activation of the mesolimbic circuit by female sexual behavior elevates dopamine release and produces persistent postsynaptic alterations to dopamine D1 receptor signaling within the nucleus accumbens. Here we demonstrate that sexual experience in female Syrian hamsters significantly increases spine density and alters morphology selectively in D1 receptor-expressing medium spiny neurons within the nucleus accumbens core, with no corresponding change in dopamine receptor binding or protein expression. Our findings demonstrate that previous life experience with a naturally motivated behavior has the capacity to induce persistent structural alterations to the mesolimbic circuit that can increase reproductive success and are analogous to the persistent structural changes following repeated exposure to many drugs of abuse.


Killing of Serratia marcescens biofilms with chloramphenicol.
Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate-80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate-80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms.


Modifying the microstructure of algae-based active carbon and modelling supercapacitors using artificial neural networks.
An improved activated carbon material is synthesized from nostoc flagelliforme algae (NF) using an acid immersing method. The material has more pores and lower internal resistance compared with raw NF. Hydrofluoric acid can effectively decompose cellulose fibers and remove inorganic impurities, giving the carbon materials high mesopore volumes, which makes electrolyte ions rapidly transfer to the active site on the electrode surface. The specific capacitance of the sample was increased from 200 to 283 F g-1 after immersing in hydrofluoric acid. In addition, the symmetric supercapacitor shows an excellent energy density of 22 W h kg-1 at a power density of 80 W kg-1. The capacitance remains at 101.7% after 10 000 cycles. Furthermore, in order to find the relationship between the biochar structure and electrochemical performance in supercapacitors, an artificial neural network (ANN) method is used for studying the complex synergy mechanism. The specific capacitance is modelled using various input factors like aspect ratio (r L/D), cellulose ratio (CL(%)), specific surface area (S BET), pore volume (V tot), internal resistance (R s) and so on. The Levenberg-Marquart back propagation algorithm with sigmoid and ReLu active function is adopted to train the model. Random forest is used to analyse the relative importance of every input factor on specific capacitance. Results show that the model can estimate the energy storage with a mean squared error of 4.39 for materials with specific structure. Importance analyses indicate the first three significant variables are S BET, R s and V por. The ANN model can accurately predict the electrical properties of biomass-based carbon materials, and also provide guidance for the selection of energy storage materials in the future.


Complete genome sequencing of the luminescent bacterium, Vibrio qinghaiensis sp. Q67 using PacBio technology.
Vibrio qinghaiensis sp.-Q67 (Vqin-Q67) is a freshwater luminescent bacterium that continuously emits blue-green light (485 nm). The bacterium has been widely used for detecting toxic contaminants. Here, we report the complete genome sequence of Vqin-Q67, obtained using third-generation PacBio sequencing technology. Continuous long reads were attained from three PacBio sequencing runs and reads >500 bp with a quality value of >0.75 were merged together into a single dataset. This resultant highly-contiguous de novo assembly has no genome gaps, and comprises two chromosomes with substantial genetic information, including protein-coding genes, non-coding RNA, transposon and gene islands. Our dataset can be useful as a comparative genome for evolution and speciation studies, as well as for the analysis of protein-coding gene families, the pathogenicity of different Vibrio species in fish, the evolution of non-coding RNA and transposon, and the regulation of gene expression in relation to the bioluminescence of Vqin-Q67.


Nonexcisional tissue tightening: creating skin surface area reduction during abdominal liposuction by adding radiofrequency heating.
Recent publications show that heat-mediated tissue tightening is a promising treatment for the lax abdomen and may provide better long-term outcomes than traditional suction-assisted liposuction (SAL). The author evaluates the degree and duration of skin surface area contraction, as well as the influence of anatomic location of the treatment region on the degree of tissue tightening, in a study comparing SAL alone vs SAL plus radiofrequency-assisted liposuction (RFAL). In this prospective, randomized, split abdominal study, 12 consecutive patients were treated with SAL alone on 1 side and with SAL plus RFAL on the other side. Each patient had 4 (3 × 3-cm) squares-2 per treatment type-tattooed in the lower abdominal region (2 on the right and 2 on the left). The surface area of these squares was measured with the Vectra computerized measurement system (Canfield, Inc, Fairfield, New Jersey) at pretreatment, at 6 weeks posttreatment, and at 1 year posttreatment. All measurements were subjected to statistical analysis using predictive analytic software and were evaluated for statistical significance. In regions treated with SAL alone, there was a 10.4% mean skin surface area contraction at 6 weeks and 8.3% at 1 year posttreatment. The mean skin surface area reduction was 25.8% in regions treated with radiofrequency plus SAL at 6 weeks and at 1 year. The anatomic location of each square (medial vs lateral) did not statistically correlate with more or less tissue tightening. Radiofrequency-assisted tissue tightening, when applied in conjunction with SAL, is effective in achieving greater skin surface area reduction.


Older persons' existential loneliness, as interpreted by their significant others - an interview study.
In order to better understand people in demanding medical situations, an awareness of existential concerns is important. Studies performed over the last twenty years conclude that when dying and death come closer, as in the case with older people who are stricken by infirmity and diseases, existential concerns will come to the fore. However, studies concerning experiences of existential loneliness (EL) are sparse and, in addition, there is no clear definition of EL. EL is described as a complex phenomenon and referred to as a condition of life, an experience, and a process of inner growth. Listening to someone who knows the older person well, as significant others often do, may be one way of learning more about EL. This study is part of a larger research project on EL, the LONE study, where EL is explored through interviews with frail older people, their significant others and health care professionals. The aim of this study was to explore frail older (>75) persons' EL, as interpreted by their significant others. The study is qualitative and based on eighteen narrative interviews with nineteen significant others of older persons. The data was analysed using Hsieh and Shannon's conventional content analysis. According to the interpretation of significant others, the older persons experience EL (1) when they are increasingly limited in body and space, (2) when they are in a process of disconnecting, and (3) when they are disconnected from the outside world. The result can be understood as if the frail older person is in a process of letting go of life. This process involves the body, in that the older person is increasingly limited in his/her physical abilities. The older person's long-term relationships are gradually lost, and finally the process entails the older person's increasingly withdrawing into him- or herself and turning off the outside world. The result of this study is consistent with previous research that has shown that EL is a complex phenomenon, but the implications of this research include a deepened understanding of EL. In addition, the study highlights the interpretations of significant others.


Size and scaling in human evolution.
Our general conclusion is simply stated: many lineages display phyletic size increase; allometric changes almost always accompany increase in body size. We cannot judge adaptation until we separate such changes into those required by increasing size and those serving as special adaptations to changing environments. In our view, the three australopithecines are, in a number of features, scaled variants of the "same" animal. In these characters, A. africanus is no more "advanced" than the larger, more robust forms. The one early hominid to show a significant departure from this adaptive pattern toward later hominids-cranially, dentally, and postcranially-is H. habilis from East Africa. The australopithecines, one of which was probably a precursor of the Homolineage, were apparently a successful group of basically vegetarian hominids, more advanced behaviorally than apes (87), but not hunter-gatherers. The fossil hominids of Africa fall into two major groupings. One probable lineage, the australopithecines, apparently became extinct without issue; the other evolved to modern man. Both groups displayed steady increase in body size. We consider quantitatively two key characters of the hominid skull: cranial capacity and cheek tooth size. The variables are allometrically related to body size in both lineages. In australopithecines, the manner of relative growth neatly meets the predictions for functional equivalence over a wide range of sizes (negative allometry of cranial capacity with a slope against body weight of 0.2 to 0.4 and positive allometry of postcanine area with a slope near 0.75). In the A. africanus to H. sapiens lineage, cranial capacity increases with positive allometry (slope 1.73) while cheek teeth decrease absolutely (slope - 0.725). Clearly, these are special adaptations unrelated to the physical requirements of increasing body size. We examined qualitatively other features, which also seem to vary allometrically. Of course, many characters should be studied quantitatively, but we think that the scheme outlined here should be treated as the null hypothesis to be disproved.


Selective capture and identification of pathogenic bacteria using an immobilized siderophore.
Rapid identification of infectious pathogens constitutes an important step toward limiting the spread of contagious diseases. Whereas antibody-based detection strategies are often selected because of their speed, mutation of the pathogen can render such tests obsolete. In an effort to develop a rapid yet mutation-proof method for pathogen identification, we have explored the use of "immutable ligands" to capture the desired microbe on a detection device. In this "proof-of-principle" study, we immobilize pyoverdine, a siderophore that Pseudomonas aeruginosa must bind to obtain iron, onto gold-plated glass chips and then examine the siderophore's ability to capture P. aeruginosa for its subsequent identification. We demonstrate that exposure of pyoverdine-coated chips to increasing dilutions of P. aeruginosa allows detection of the bacterium down to concentrations as low as 10(2)/mL. We further demonstrate that printing of the siderophore in a periodic pattern on the detection chip enables a sensitive method of detecting the bound pathogen by a Fourier transform analysis of light scattered by the patterned chip. Because unrelated bacteria are not captured on the pyoverdine chip, we conclude that pyoverdine can be exploited for the specific binding and identification of P. aeruginosa. It follows that the utilization of other microbe-specific "immutable ligands" may allow the specific identification of their cognate pathogens.


Infection-Mediated Priming of Phagocytes Protects against Lethal Secondary Aspergillus fumigatus Challenge.
Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection.


The effects of detergents on t-butyl hydroperoxide-induced chemiluminescence.
We examined the effects of Triton X-100, digitonin, sodium dodecyl sulfate, taurocholic acid, and cetylpyridinium chloride on hemoglobin-catalyzed and t-butyl hydroperoxide-induced chemiluminescence. The experimental system contained hemoglobin, luminol, t-butyl hydroperoxide, and different concentrations of detergents (5-100 mg/dl) in TRIS-HCl buffer. Control assays were performed by excluding detergents. Chemiluminescence was detected using a liquid scintillation counter in single photon mode. All concentrations chosen for each detergent reduced the maximum chemiluminescence value and retarded the time that maximum chemiluminescence occurred. The most prominent reduction in maximum chemiluminescence was observed with 50 and 100 mg/dl digitonin. The smallest reduction was observed with 5 mg/dl sodium dodecyl sulfate, without retardation of the time that maximum chemiluminescence occurred. Our aim was to use detergents in membrane-containing experimental systems and hence to identify the detergent with the least effect on chemiluminescence. Our results suggest that sodium dodecyl sulfate is the most suitable detergent for chemiluminescence studies in membrane systems.


Integrating water resources management in eco-hydrological modelling.
In this paper the integration of water resources management with regard to reservoir management in an eco-hydrological model is described. The model was designed to simulate different reservoir management options, such as optimized hydropower production, irrigation intake from the reservoir or optimized provisioning downstream. The integrated model can be used to investigate the impacts of climate variability/change on discharge or to study possible adaptation strategies in terms of reservoir management. The study area, the Upper Niger Basin located in the West African Sahel, is characterized by a monsoon-type climate. Rainfall and discharge regime are subject to strong seasonality. Measured data from a reservoir are used to show that the reservoir model and the integrated management options can be used to simulate the regulation of this reservoir. The inflow into the reservoir and the discharge downstream of the reservoir are quite distinctive, which points out the importance of the inclusion of water resources management.


Sexting and sexual behavior in at-risk adolescents.
This study aimed to examine the prevalence of sexting behaviors (sexually explicit messages and/or pictures) among an at-risk sample of early adolescents as well as the associations between sexting behaviors and sexual behaviors, risk-related cognitions, and emotional regulation skills. It also aimed to determine whether differences in risk were associated with text-based versus photo-based sexts. Seventh-grade adolescents participating in a sexual risk prevention trial for at-risk early adolescents completed a computer-based survey at baseline regarding sexting behavior (having sent sexually explicit messages and/or pictures), sexual activities, intentions to have sex, perceived approval of sexual activity, and emotional regulation skills. Twenty-two percent of the sample reported having sexted in the past 6 months; sexual messages were endorsed by 17% (n = 71), sexual messages and photos by 5% (n = 21). Pictures were endorsed significantly more often by females (χ(2)[2] = 7.33, P = .03) and Latinos (χ(2)[2] = 7.27, P = .03). Sexting of any kind was associated with higher rates of engaging in a variety of sexual behaviors, and sending photos was associated with higher rates of sexual activity than sending text messages only. This was true for a range of behaviors from touching genitals over clothes (odds ratio [OR] = 1.98, P = .03) to oral sex (OR = 2.66, P < .01) to vaginal sex (OR = 2.23, P < .01). Sexting behavior (both photo and text messages) was not uncommon among middle school youth and co-occurred with sexual behavior. These data suggest that phone behaviors, even flirtatious messages, may be an indicator of risk. Clinicians, parents, and health programs should discuss sexting with early adolescents.


Sex steroid metabolism polymorphisms and mammographic density in pre- and early perimenopausal women.
We examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17beta-HSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women. The Study of Women's Health Across the Nation is a longitudinal community-based cohort study. We analyzed data from 451 pre- and early perimenopausal participants of the ancillary SWAN Mammographic Density study for whom we had complete information regarding mammographic density, genotypes, and covariates. With multivariate linear regression, we examined the relation between percentage mammographic breast density (outcome) and each SNP (primary predictor), adjusting for age, race/ethnicity, parity, cigarette smoking, and body mass index (BMI). After multivariate adjustment, the CYP1B1 rs162555 CC genotype was associated with a 9.4% higher mammographic density than the TC/TT genotype (P = 0.04). The CYP19A1 rs936306 TT genotype was associated with 6.2% lower mammographic density than the TC/CC genotype (P = 0.02). The positive association between CYP1A1 rs2606345 and mammographic density was significantly stronger among participants with BMI greater than 30 kg/m2 than among those with BMI less than 25 kg/m2 (Pinteraction = 0.05). Among white participants, the ESR1 rs2234693 CC genotype was associated with a 7.0% higher mammographic density than the CT/TT genotype (P = 0.01). SNPs in certain genes encoding sex steroid metabolism enzymes and ESRs were associated with mammographic density. Because the encoded enzymes and ESR1 are expressed in breast tissue, these SNPs may influence breast cancer risk by altering mammographic density.


Principles of tinnitology: tinnitus diagnosis and treatment a tinnitus-targeted therapy.
To provide to the tinnitus professional a rationale for establishing accuracy in tinnitus diagnosis and the selection of modalities of therapy (i.e., medication, instrumentation, and surgery) for attempting tinnitus relief for patients with tinnitus diagnosed by completion of a medical-audiological tinnitus protocol (MATPP) and clinical course and found to be subjective idiopathic tinnitus of the severe disabling type (SIT). The completion of a MATPP has been recommended since 1977 for each tinnitus patient in an attempt to establish an accurate diagnosis. A tinnitus-targeted therapy (TTT), a combined treatment of medication and instrumentation focusing on pharmacotherapy, has evolved from our ongoing clinical experience since 1977 (now in excess of 10,000 SIT patients) [1-4]. Principles for SIT treatment have evolved from the TTT experience that provides a rationale for attempting tinnitus relief. In this report, the term tinnitus refers to SIT. The strategies of TTT are based on the clinical translation for SIT diagnosis and treatment of (1) fundamentals of neuro-otological diagnosis; (2) fundamentals of sensory physiology; (3) extrapolation for treatment of known underlying neurochemistries from nuclear medicine imaging results e.g. single-photon emission computed tomography and positron emission tomography; (4) hypothesis of mechanism of tinnitus production , Tinnitus Dysynchrony Synchrony Theory (TDST) [5] , and hypothesis of the transformation-transition of the sensation of an aberrant auditory sensation-tinnitus (i.e., sensory component)-to one of affect (i.e., the emotional-behavioral component), Final Common Pathway of Tinnitus (FCP)[8]; and (5) innovative application of drug therapies designed for indications other than tinnitus [2,3]. The ongoing clinical application of a rationale based on principles of diagnosis and treatment for SIT, which has evolved from our TTT clinical experience in SIT patients, continues to result in long-term tinnitus relief: in excess of 1 year in approximately 75% to 85% with medication and in 10% to 15% with instrumentation. SIT patients resistant to therapy persist at 10% to 15%.


Early intervention to promote oral feeding in patients with intracerebral hemorrhage: a retrospective cohort study.
Stroke is a major cause of dysphagia, but little is known about when and how dysphagic patients should be fed and treated after an acute stroke. The purpose of this study is to establish the feasibility, risks and clinical outcomes of early intensive oral care and a new speech and language therapist/nurse led structured policy for oral feeding in patients with an acute intracerebral hemorrhage (ICH). A total of 219 patients with spontaneous ICH who were admitted to our institution from 2004 to 2007 were retrospectively analyzed. An early intervention program for oral feeding, which consisted of intensive oral care and early behavioral interventions, was introduced from April 2005 and fully operational by January 2006. Outcomes were compared between an early intervention group of 129 patients recruited after January 2006 and a historical control group of 90 patients recruited between January 2004 and March 2005. A logistic regression technique was used to adjust for baseline differences between the groups. To analyze time to attain oral feeding, the Kaplan-Meier method and Cox proportional hazard model were used. The proportion of patients who could tolerate oral feeding was significantly higher in the early intervention group compared with the control group (112/129 (86.8%) vs. 61/90 (67.8%); odds ratio 3.13, 95% CI, 1.59-6.15; P < 0.001). After adjusting for baseline imbalances, the odds ratio was 4.42 (95% CI, 1.81-10.8; P = 0.001). The incidence of chest infection was lower in the early intervention group compared with the control group (27/129 (20.9%) vs. 32/90 (35.6%); odds ratio 0.48, 95% CI, 0.26-0.88; P = 0.016). A log-rank test found a significant difference in nutritional supplementation-free survival between the two groups (hazard ratio 1.94, 95% CI, 1.46-2.71; P < 0.001). Our data suggest that the techniques can be used safely and possibly with enough benefit to justify a randomized controlled trial. Further investigation is needed to solve the eating problems that are associated with patients recovering from a severe stroke.


Antibiotic management and early discharge from hospital: an economic analysis.
To evaluate potential costs and savings from implementing an evaluation tool that uses bedside review of antibiotic use and infection management to assess whether patients with infections in acute medical and surgical wards could have their antibiotic regimen changed and be safely managed out of hospital. The tool was implemented in 30 acute wards in five UK hospital trusts. Data were collected on demographic variables, diagnosis, social situation, hospital stay and all current antibiotic prescribing for 291 patients. A physician and pharmacist assessed antibiotic therapy and feasibility of discharge. Resource use was measured for each patient, unit costs attached, and mean and total costs of implementing recommendations were calculated. Implementation of these recommendations could reduce total inpatient days by 494 at a saving of £186 731, and save £20 215 from adjustment of antibiotic therapy. Additional costs were associated with implementation of the assessment (£2468), community support (£6227) and outpatient parenteral antimicrobial therapy (£5616). As a result, the net potential savings would be £192 635 in total or £662 (95% CI: £393, £930) for every patient assessed. Excluding eight patients with the highest potentially avoidable inpatient stays (>15 days), mean savings would fall to £363 per patient assessed but remain highly significant (95% CI: £261, £465). Careful assessment of antibiotic use in acute wards has the potential to reduce the use and cost of antibiotics, and length of stay. Added costs of assessment and out-of-hospital support services would offset a small proportion of these potential savings. Randomized studies are now needed to test these results.


Optimal algorithm for fluorescence suppression of modulated Raman spectroscopy.
Raman spectroscopy permits probing of the molecular and chemical properties of the analyzed sample. However, its applicability has been seriously limited to specific applications by the presence of a strong fluorescence background. In our recent paper [Anal. Chem. 82, 738 (2010)], we reported a new modulation method for separating Raman scattering from fluorescence. By continuously changing the excitation wavelength, we demonstrated that it is possible to continuously shift the Raman peaks while the fluorescence background remains essentially constant. In this way, our method allows separation of the modulated Raman peaks from the static fluorescence background with important advantages when compared to previous work using only two [Appl. Spectrosc. 46, 707 (1992)] or a few shifted excitation wavelengths [Opt. Express 16, 10975 (2008)]. The purpose of the present work is to demonstrate a significant improvement of the efficacy of the modulated method by using different processing algorithms. The merits of each algorithm (Standard Deviation analysis, Fourier Filtering, Least-Squares fitting and Principal Component Analysis) are discussed and the dependence of the modulated Raman signal on several parameters, such as the amplitude and the modulation rate of the Raman excitation wavelength, is analyzed. The results of both simulation and experimental data demonstrate that Principal Component Analysis is the best processing algorithm. It improves the signal-to-noise ratio in the treated Raman spectra, reducing required acquisition times. Additionally, this approach does not require any synchronization procedure, reduces user intervention and renders it suitable for real-time applications.


Oscillation of the refractive index at the focal region of a femtosecond laser pulse inside a glass.
The temporal evolution of refractive-index change produced by a tightly focused femtosecond (fs) laser pulse inside a soda-lime glass plate was investigated by use of a transient lens method with subpicosecond time resolution. An oscillating behavior of the light intensity in the central region of the probe beam was observed 0-1500 ps after irradiation of the plate. The oscillation was interpreted in terms of a rapid temperature increase and the ensuing propagation of the pressure wave. This study is to our knowledge the first real-time observation of refractive-index change inside a glass induced by a fs laser pulse.


Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model.
Mutations in canine superoxide dismutase 1 (SOD1) have recently been shown to cause canine degenerative myelopathy, a disabling neurodegenerative disorder affecting specific breeds of dogs characterized by progressive motor neuron loss and paralysis until death, or more common, euthanasia. This discovery makes canine degenerative myelopathy the first and only naturally occurring non-human model of amyotrophic lateral sclerosis (ALS), closely paralleling the clinical, pathological, and genetic presentation of its human counterpart, SOD1-mediated familial ALS. To further understand the biochemical role that canine SOD1 plays in this disease and how it may be similar to human SOD1, we characterized the only two SOD1 mutations described in affected dogs to date, E40K and T18S. We show that a detergent-insoluble species of mutant SOD1 is present in spinal cords of affected dogs that increases with disease progression. Our in vitro results indicate that both canine SOD1 mutants form enzymatically active dimers, arguing against a loss of function in affected homozygous animals. Further studies show that these mutants, like most human SOD1 mutants, have an increased propensity to form aggregates in cell culture, with 10-20% of cells possessing visible aggregates. Creation of the E40K mutation in human SOD1 recapitulates the normal enzymatic activity but not the aggregation propensity seen with the canine mutant. Our findings lend strong biochemical support to the toxic role of SOD1 in canine degenerative myelopathy and establish close parallels for the role mutant SOD1 plays in both canine and human disorders.