Relationship of retinal morphology and retinal sensitivity in the treatment of neovascular age-related macular degeneration using aflibercept.
To relate the functional response to distinct morphological features of the retina during aflibercept treatment for neovascular AMD (nAMD). A total of 726 retinal locations in 22 consecutive eyes presenting with treatment-naive nAMD underwent a standardized examination with spectral-domain optical coherence tomography (SD-OCT) and topographic microperimetry (MP) at baseline, after 3 and 12 months of continuous intravitreal aflibercept therapy. The retinal sensitivity at each stimulus location was registered to the corresponding location on SD-OCT morphology. Subsequently, the microperimetric responses were evaluated with respect to the following underlying SD-OCT features: neovascular complex (NVC), subretinal fluid (SRF), intraretinal fluid (IRF), intraretinal cystoid space (IRC), serous pigment epithelium detachment (sPED), and fibrovascular pigment epithelium detachment (fPED). Baseline sensitivity was reduced to mean values of 1.8 dB in NVC, 2.2 dB in IRC, 2.8 dB in IRF, 2.6 dB in sPED, 3.6 dB in SRF, and 4.6 dB in fPED. Improvements in retinal sensitivity were most pronounced during the initial 3-month interval, when significant recovery was documented for SRF and sPED with +4.0/5.5 dB (P < 0.0001) and to a lesser extent for IRF, IRC, fPED, with +1.1, 1.7, 2.3 dB, respectively. From month 3 to 12, the additional benefit ranged from 0.3 to 1.0 dB (P > 0.05 for each category). Significant functional benefits following intravitreal aflibercept treatment could be detected over all defined morphological pathologies. The level of improvement varied dependent on the associated feature with the best prognosis for visual improvement in SRF and sPED and least with intraretinal fluid and particularly intraretinal cysts.


Identification and characterization of the Luc2-type luciferase in the Japanese firefly, Luciola parvula, involved in a dim luminescence in immobile stages.
Nocturnal Japanese fireflies, Luciola parvula, emit from their lanterns a yellow light, one of the most red-shifted colors found among fireflies. Previously, we isolated and characterized two different types of luciferase gene, Luc1 and Luc2, from the fireflies Luciola cruciata and Luciola lateralis; Luc1 is responsible for the green-yellow luminescence of larval and adult lanterns, whereas Luc2 is responsible for the dim greenish glow of eggs and pupal bodies. The biological role of firefly lanterns in adults is related to sexual communication, but why the eggs and pupae glow remains uncertain. In this study, we isolated the gene Luc2 from L. parvula, and compared its expression profiles and enzymatic characteristics with those of Luc1. A semi-quantitative reverse transcription polymerase chain reaction showed that Luc1 was predominantly expressed in larvae, prepupae, pupae and adults, whereas Luc2 was expressed in eggs, prepupae, pupae and adult females. Enzymatic analyses showed that the luminescent color of Luc1 matches the visual sensitivity of L. parvula eyes, whereas that of Luc2 is very different from it. These results suggest that the biological role of Luc2 expressed in immobile stages is not intraspecific communication.


Towards monitoring of antimicrobial resistance in the environment: For what reasons, how to implement it, and what are the data needs?
Antimicrobial resistance (AMR) is a global threat to human and animal health and well-being. To understand AMR dynamics, it is important to monitor resistant bacteria and resistance genes in all relevant settings. However, while monitoring of AMR has been implemented in clinical and veterinary settings, comprehensive monitoring of AMR in the environment is almost completely lacking. Yet, the environmental dimension of AMR is critical for understanding the dissemination routes and selection of resistant microorganisms, as well as the human health risks related to environmental AMR. Here, we outline important knowledge gaps that impede implementation of environmental AMR monitoring. These include lack of knowledge of the 'normal' background levels of environmental AMR, definition of high-risk environments for transmission, and a poor understanding of the concentrations of antibiotics and other chemical agents that promote resistance selection. Furthermore, there is a lack of methods to detect resistance genes that are not already circulating among pathogens. We conclude that these knowledge gaps need to be addressed before routine monitoring for AMR in the environment can be implemented on a large scale. Yet, AMR monitoring data bridging different sectors is needed in order to fill these knowledge gaps, which means that some level of national, regional and global AMR surveillance in the environment must happen even without all scientific questions answered. With the possibilities opened up by rapidly advancing technologies, it is time to fill these knowledge gaps. Doing so will allow for specific actions against environmental AMR development and spread to pathogens and thereby safeguard the health and wellbeing of humans and animals.


Intussusception in gestational choriocarcinoma (not histologically proven), resolving spontaneously with chemotherapy.
We present a rare case of advanced gestational choriocarcinoma with small bowel metastatic involvement and intussusception, which presented acutely as a lower gastrointestinal bleed with symptomatic anaemia and haemoglobin 3.8 g/dL in a young woman. A diagnosis of gestational choriocarcinoma was made without biopsy, using a combination of clinical history, isolated elevated human chorionic gonadotropin markers of 77,000 IU/mL and radiological findings. Surgical intervention was too high risk due to the presence of active bleeding and increased vascularity surrounding the intussusception. Owing to the highly responsive nature of gestational choriocarcinoma to chemotherapy, frontline chemotherapy alone was used to reduce the size of the metastatic small bowel deposits, with subsequent resolution of the bleeding and intussusception. This is the first time chemotherapy alone has been used to successfully resolve small bowel intussusception secondary to metastatic choriocarcinoma that has been documented according to PubMed searches.


Characterization of two anti-dengue human monoclonal antibodies prepared from PBMCs of patients with dengue illness in Thailand.
The global spread of the four dengue virus (DENV) serotypes (dengue-1 to -4) has made this virus a major and growing public health concern. Generally, pre-existing neutralizing antibodies derived from primary infection play a significant role in protecting against subsequent infection with the same serotype. By contrast, these pre-existing antibodies are believed to mediate a non-protective response to subsequent heterotypic DENV infections, leading to the onset of dengue illness. In this study, two monoclonal antibodies prepared by using peripheral blood mononuclear cells (PBMCs) from patients with dengue fever were characterized. Epitope mapping revealed that amino acid residues 254-278 in domain II of the viral envelope protein E were the target region of these antibodies. A database search revealed that certain sequences in this epitope region showed high conservation among the four serotypes of DENV. These two human monoclonal antibodies could neutralize DENV-2,-4 more effectively than DENV-1,-3. The amino acid sequences could not explain this difference in neutralizing activity. However, the 3D structure results showed that amino acid 274 could be the critical residue for the difference in neutralization. These results may provide basic information for the development of a dengue vaccine.


Supramolecular photosystem II organization in grana thylakoid membranes: evidence for a structured arrangement.
The distribution of photosystem (PS) II complexes in stacked grana thylakoids derived from electron microscopic images of freeze-fractured chloroplasts are examined for the first time using mathematical methods. These characterize the particle distribution in terms of a nearest neighbor distribution function and a pair correlation function. The data were compared with purely random distributions calculated by a Monte Carlo simulation. The analysis reveals that the PSII distribution in grana thylakoids does not correspond to a random protein mixture but that ordering forces lead to a structured arrangement on a supramolecular level. Neighboring photosystems are significantly more separated than would be the case in a purely random distribution. These results are explained by structural models, in which boundary lipids and light-harvesting complex (LHC) II trimers are arranged between neighboring PSII. Furthermore, the diffusion of PSII was analyzed by a Monte Carlo simulation with a protein density of 80% area occupation (determined for grana membranes). The mobility of the photosystems is severely reduced by the high protein density. From an estimate of the mean migration time of PSII from grana thylakoids to stroma lamellae, it becomes evident that this diffusion contributes significantly to the velocity of the repair cycle of photoinhibited PSII.


Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells.
Aim: The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance. Methods: Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance. Results: PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors. Conclusion: PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.


Investigating Molecular Signatures Underlying Trapeziometacarpal Osteoarthritis Through the Evaluation of Systemic Cytokine Expression.
Non-operative management of trapeziometacarpal osteoarthritis (TMOA) demonstrates only short-term symptomatic alleviation, and no approved disease modifying drugs exist to treat this condition. A key issue in these patients is that radiographic disease severity can be discordant with patient reported pain, illustrating the need to identify molecular mediators of disease. This study characterizes the biochemical profile of TMOA patients to elucidate molecular mechanisms driving TMOA progression. Plasma from patients with symptomatic TMOA undergoing surgical (n=39) or non-surgical management (n=44) with 1-year post-surgical follow-up were compared using a targeted panel of 27 cytokines. Radiographic (Eaton-Littler), anthropometric, longitudinal pain (VAS, TASD, quick DASH) and functional (key pinch, grip strength) data were used to evaluate relationships between structure, pain, and systemic cytokine expression. Principal Component Analysis was used to identify clusters of patients. Patients undergoing surgery had greater BMI as well as higher baseline quick DASH, TASD scores. Systemically, these patients could only be distinguished by differing levels of Interleukin-7 (IL-7), with an adjusted odds ratio of 0.22 for surgery for those with increased levels of this cytokine. Interestingly, PCA analysis of all patients (regardless of surgical status) identified a subset of patients with an "inflammatory" phenotype, as defined by a unique molecular signature consisting of thirteen cytokines. Overall, this study demonstrated that circulating cytokines are capable of distinguishing TMOA disease severity, and identified IL-7 as a target capable of differentiating disease severity with higher levels associated with a decreased likelihood of TMOA needing surgical intervention. It also identified a cluster of patients who segregate based on a molecular signature of select cytokines.


Wrinkled Hollow Carbon Spheres with Adjustable Diameter for High-Performance Supercapacitors.
Creating more pleated and collapsed structures for carbon-based electrode materials is an important measure to enhance the performance of supercapacitors. Herein, a polymer formed by the aldimine reaction of terephthalaldehyde and aminopropyltriethoxysilane was utilized as the carbon source, and tetraethoxysilane was added as a silica additive to achieve the wrinkled structure on hollow carbon spheres. The silica had a significant modulating effect on the structure of the obtained wrinkled hollow carbon sphere (WHCS), which displayed a visible pleated structure, hollow structure, high specific surface area, and pore volume. As an electrode material for supercapacitors, WHCS exhibits excellent performance with a capacitance of 312 F ⋅ g-1 and remarkable cycle life stability, demonstrating its great potential for use in supercapacitors.


A Case History Introducing the Oregon Ag Seminar Series-Keys to Program and Research-to-Practice Success.
This case history of Oregon state's Ag Seminar Series is consistent with the Socio-Ecological Model, demonstrating how policy at a state level can influence an organizational approach with impacts that ultimately influence safety practices on the farm. From modest beginnings, the Ag Seminar Series, offered through a workers compensation insurance company, now serves over 2,300 Oregon farmers annually in English and Spanish. This case offers unique but also replicable methods for educators, insurers, and researchers in safety education, safety motivators, and research-to-practice (r2p).


OZSPEC-2: an improved broadband high-resolution elliptical crystal x-ray spectrometer for high-energy density physics experiments (invited).
A novel time, space, and energy-resolved x-ray spectrometer has been developed which produces, in a single snapshot, a broadband and relatively calibrated spectrum of the x-ray emission from a high-energy density laboratory plasma. The opacity zipper spectrometer (OZSPEC-1) records a nearly continuous spectrum for x-ray energies from 240 to 5800 eV in a single shot. The second-generation OZSPEC-2, detailed in this work, records fully continuous spectra on a single shot from any two of these three bands: 270-650, 660-1580, and 1960-4720 eV. These instruments thus record thermal and line radiation from a wide range of plasmas. These instruments' single-shot bandwidth is unmatched in a time-gated spectrometer; conversely, other broadband instruments are either time-integrated (using crystals or gratings), lack spectral resolution (diode arrays), or cover a lower energy band (gratings). The OZSPECs are based on the zipper detector, a large-format (100x35 mm) gated microchannel plate detector, with spectra dispersed along the 100 mm dimension. OZSPEC-1 and -2 both use elliptically bent crystals of OHM, RAP, and/or PET. Individual spectra are gated in 100 ps. OZSPEC-2 provides one-dimensional spatial imaging with 30-50 microm resolution over a 1500 microm field of view at the source. The elliptical crystal design yields broad spectral coverage with resolution E/DeltaE>500, strong rejection of hard x-ray backgrounds, and negligible source broadening for extended sources. Near-term applications include plasma opacity measurements, detailed spectra of inertial fusion Hohlraums, and laboratory astrophysics experiments.


Histone autoantigens in murine lupus. Definition of a major epitope within an accessible region of chromatin.
In SLE and in the (NZB x NZW)F1 murine model of this disease, IgG autoantibodies are frequently produced to DNA and histones. In the present study, we define a linear epitope on histone H2B that is recognized by (NZB x NZW)F1 mice. IgG antibodies from anti-H2B positive (but not anti-H2B negative) mice bound strongly to a peptide containing the first 15 N-terminal amino acids, a region that is exposed in chromatin. Competitive inhibition studies showed that the binding of autoantibodies to H2B in ELISA as well as the binding to soluble H2B was substantially blocked by this peptide. Studies with smaller peptides mapped the epitope to residues 3-12. Individual mice recognized different residues within this region, and a sequence search did not reveal proteins other than H2B that could elicit this spectrum of antibodies. Interestingly, these autoantibody specificities were not a component of those induced in preautoimmune mice by immunization with H2B/RNA complexes or with H2B peptide 1-30 containing the autoantigenic sequence. These findings argue that recognition of a specific N-terminal region of self histone contributes to the anti-H2B autoantibody response in lupus. Autoreactive B cells with specificity for this sequence seem to develop only after the autoimmune process has been initiated.


Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage.
The efficacy and safety of fasudil hydrochloride, a novel protein kinase inhibitor, were evaluated for the treatment of cerebral vasospasm and associated cerebral ischemic symptoms in patients with ruptured cerebral aneurysm. This randomized open trial with nimodipine as the control included 72 patients who underwent subarachnoid hemorrhage surgery for ruptured cerebral aneurysm of Hunt and Hess grades I to IV. For 14 days following surgery, patients were administered either 30 mg of fasudil hydrochloride by intravenous injection over a period of 30 minutes three times a day or 1 mg/hr of nimodipine by continuous intravenous infusion. Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine. Adverse reactions occurred in 13 of 37 patients receiving fasudil hydrochloride and 15 of 35 patients receiving nimodipine. There were no serious adverse events in the fasudil group. The results of this clinical trial indicate that fasudil hydrochloride is a safe and efficient agent for suppressing cerebral vasospasm after subarachnoid hemorrhage surgery for ruptured cerebral aneurysm.


Preliminary Report on the Reduction of Adult Mosquitoes in Housing Compounds in Western Kenya Using the ProVector Flower and Entobac Bait Pads Containing Bacillus thuringiensis israelensis With Honey Bait.
Reducing mosquito populations indoors and outdoors can have a significant impact on malaria and other mosquito-borne diseases. A new formulation and delivery system for Bacillus thuringiensis israelensis (Bti) was tested against adult mosquitoes. One Entobac bait with 7% Bti in a honey solution was placed within each ProVector Flower applicator. The applicators were placed in nine housing compounds, one on the outside of each home in Ahero and Nyalenda, Kenya, in June 2009. Seven housing compounds with no applicators were included as controls in the study area. After 1 mo, there was a significant reduction of mosquitoes in all nine compounds with the ProVector Flower compared to two of the seven control compounds. The overall mosquito population was reduced by 69% in housing compounds with the ProVector Flower whereas the mosquito population grew by nearly 15% in the control compounds. There was a significant reduction of the median number of mosquitoes in the test compounds than in the control compounds. The proportion of mosquitoes collected was significantly reduced in the test compounds within 1 mo for several species of Aedes, Anopheles, Coquillettidia, Culex, and Mansonia. This study provides evidence that Bti-laced bait may be used as an alternative adulticide and be delivered in an applicator to reduce mosquito populations of several species. This method may significantly reduce the cost of pesticide application through target specificity and by reducing the amount of pesticide placed into the environment.


Host-guest interactions in a series of self-assembled As2L2Cl2 macrocycles.
The reaction of AsCl3 with H2L (where L = a rigid dithiolate) results in the self-assembly of As2L2Cl2 supramolecular macrocycles. For ligands 4,4'-bis(mercaptomethyl)biphenyl (H2), 4,4'-bis(mercaptomethyl)-trans-stilbene (H2), and 1,4-dimethoxy-2,5-bis(mercaptomethyl)benzene (H2), the macrocyclic cavities of the resulting assemblies are large enough to host aromatic solvent molecules, as revealed by single crystal X-ray structures of the inclusion complexes. As2L2Cl(2) macrocycles form in solution as a mixture of diastereomers, but the diastereomers can be selectively crystallized and separated. Crystallization of syn- or anti-As(2)3(2)Cl2 can be controlled using host-guest interactions by the prudent choice of crystallization solvents. anti-As(2)3(2)Cl2 crystallizes exclusively from chloroform and benzene, while a [(syn-As(2)(2)Cl(2))(2).p-xylene] dimer crystallizes from p-xylene and a mixture of [(syn-As(2)3(2)Cl(2))(anti-As(2)3(2)Cl2) x toluene] and [(syn-As(2)3(2)Cl2)2 x toluene] dimers crystallize from toluene.


Environmental hazards of interest to the forensic pathologist.
The hazards associated with occupational exposure to various workplace contaminants (lead, silica, etc.) have been known for a number of years. Until recently, the potential toxic effects of exposures on the male reproductive system had not been appreciated. This article not only discusses recent studies in that area, but gives clinical examples of how environmental exposures (water, soil, air, and dwellings) can affect various organs in the human body. Awareness that these injuries can occur without obvious relationship to these environmental exposures may help the forensic pathologist discover previously unsuspected hazards.


Effects of Two Diode Lasers With and Without Photosensitization on Contaminated Implant Surfaces: An Ex Vivo Study.
The aim of this ex vivo study is to assess decontamination potential of two different diode laser wavelengths, with or without the aid of photodynamic therapy, on dental implant surfaces and to evaluate the harmful potential of temperature increase during laser irradiation. One hundred thirty-two machined sterile implants were placed into sterile porcine bone blocks with standardized coronal angular bony defects and inoculated with Streptococcus sanguinis. Four different treatment protocols were used: 810 or 980 nm laser, with or without photosensitization. Two nontreated control groups were used, one with samples coated with indocyanine green dye. Samples were rinsed and plated on agar plates for subsequent colony count. Irradiation was repeated without contamination at room temperature and in a 37°C water bath monitoring the temperature variation. There is a statistically significant decontamination effect when the laser is used. Both wavelengths minimize contamination. There was modest improvement given by the photosensitization being more marked in the 810 nm groups, but was not statistically significant compared to laser only. A critical temperature increase was never observed when the sample was in a 37°C water bath. The use of both diode laser wavelengths in implant surface decontamination was efficacious regardless of the use of photosensitization and without dangerous increase of temperature.


Successional theories.
Succession is a fundamental concept in ecology because it indicates how species populations, communities, and ecosystems change over time on new substrate or after a disturbance. A mechanistic understanding of succession is needed to predict how ecosystems will respond to land-use change and to design effective ecosystem restoration strategies. Yet, despite a century of conceptual advances a comprehensive successional theory is lacking. Here we provide an overview of 19 successional theories ('models') and their key points, group them based on conceptual similarity, explain conceptual development in successional ideas and provide suggestions how to move forward. Four groups of models can be recognised. The first group (patch & plants) focuses on plants at the patch level and consists of three subgroups that originated in the early 20th century. One subgroup focuses on the processes (dispersal, establishment, and performance) that operate sequentially during succession. Another subgroup emphasises individualistic species responses during succession, and how this is driven by species traits. A last subgroup focuses on how vegetation structure and underlying demographic processes change during succession. A second group of models (ecosystems) provides a more holistic view of succession by considering the ecosystem, its biota, interactions, diversity, and ecosystem structure and processes. The third group (landscape) considers a larger spatial scale and includes the effect of the surrounding landscape matrix on succession as the distance to neighbouring vegetation patches determines the potential for seed dispersal, and the quality of the neighbouring patches determines the abundance and composition of seed sources and biotic dispersal vectors. A fourth group (socio-ecological systems) includes the human component by focusing on socio-ecological systems where management practices have long-lasting legacies on successional pathways and where regrowing vegetations deliver a range of ecosystem services to local and global stakeholders. The four groups of models differ in spatial scale (patch, landscape) or organisational level (plant species, ecosystem, socio-ecological system), increase in scale and scope, and reflect the increasingly broader perspective on succession over time. They coincide approximately with four periods that reflect the prevailing view of succession of that time, although all views still coexist. The four successional views are: succession of plants (from 1910 onwards) where succession was seen through the lens of species replacement; succession of communities and ecosystems (from 1965 onwards) when there was a more holistic view of succession; succession in landscapes (from 2000 onwards) when it was realised that the structure and composition of landscapes strongly impact successional pathways, and increased remote-sensing technology allowed for a better quantification of the landscape context; and succession with people (from 2015 onwards) when it was realised that people and societal drivers have strong effects on successional pathways, that ecosystem processes and services are important for human well-being, and that restoration is most successful when it is done by and for local people. Our review suggests that the hierarchical successional framework of Pickett is the best starting point to move forward as this framework already includes several factors, and because it is flexible, enabling application to different systems. The framework focuses mainly on species replacement and could be improved by focusing on succession occurring at different hierarchical scales (population, community, ecosystem, socio-ecological system), and by integrating it with more recent developments and other successional models: by considering different spatial scales (landscape, region), temporal scales (ecosystem processes occurring over centuries, and evolution), and by taking the effects of the surrounding landscape (landscape integrity and composition, the disperser community) and societal factors (previous and current land-use intensity) into account. Such a new, comprehensive framework could be tested using a combination of empirical research, experiments, process-based modelling and novel tools. Applying the framework to seres across broadscale environmental and disturbance gradients allows a better insight into what successional processes matter and under what conditions.


Factors Predictive Of Alcohol Consumption Among Elderly People In A Rural Community: A Case Study In Phayao Province Thailand.
Alcohol consumption is recognized as a public health issue. Study objectives were to identify factors predictive of alcohol consumption among elderly people in Phayao province Thailand, where there was high prevalence of alcohol consumption. This was a cross-sectional study. Four hundred elderly people participated in a survey. Data was collected by face-to-face interviews. Chi-square and multivariate logistic regression were used to determine the factors predictive of alcohol consumption among the study subjects. One thirds of elderly (31.7%) had consumed alcohol in their lifetime, and (15.7%) of them were current drinkers. Following univariate analysis, seven factors included gender, working, sickness, smoking, quality of life (QOL), daily activities and economic recession - were identified as being significantly associated with drinking (p<0.05). Multivariate analysis revealed four factors to be predictive of alcohol among elderly people: gender (OR=6.02, 95% CI=3.58-10.13), smoking (OR=4.34, 95% CI=2.57-7.34), economic recession (OR=2.79, 95%, CI=1.66-4.71), and QOL (OR=1.86, 95%, CI=1.09-3.16). Gender (male) and smoking were strongly predictive factors of elderly alcohol consumption. Hence, an effort to reduce alcohol consumption should be placed on male elderly and those who smoke.


Job stress and coping strategies among nurses: results of a self report survey.
1. Many employers do not have the resources for sophisticated investigation, development, and implementation of stress reduction programs for employee health. This does not eliminate the need for such programs. 2. Occupational health nurses can develop stress reduction programs building on individual coping strategies used by workers. A simple survey of workers could provide baseline information for the development of these programs. 3. Exercise, open atmosphere for discussion, relaxation, and taking a break were the top four coping strategies reported by nurses and non-nurse female employees. Employers could easily support stress reduction programs built on these strategies.


Placental overgrowth in mice lacking the imprinted gene Ipl.
The Ipl (Tssc3) gene lies in an extended imprinted region of distal mouse chromosome 7, which also contains the Igf2 gene. Expression of Ipl is highest in placenta and yolk sac, where its mRNA is derived almost entirely from the maternal allele. Ipl encodes a small cytoplasmic protein with a pleckstrin-homology (PH) domain. We constructed two lines of mice with germ-line deletions of this gene (Ipl(neo) and Ipl(loxP)) and another line deleted for the similar but nonimprinted gene Tih1. All three lines were viable. There was consistent overgrowth of the Ipl-null placentas, with expansion of the spongiotrophoblast. These larger placentas did not confer a fetal growth advantage; fetal size was normal in Ipl nulls with the Ipl(neo) allele and was decreased slightly in nulls with the Ipl(loxP) allele. When bred into an Igf2 mutant background, the Ipl deletion partially rescued the placental but not fetal growth deficiency. Neither fetal nor placental growth was affected by deletion of Tih1. These results show a nonredundant function for Ipl in restraining placental growth. The data further indicate that Ipl can act, at least in part, independently of insulin-like growth factor-2 signaling. Thus, genomic imprinting regulates multiple pathways to control placental size.


Suicide Risk by Unit Component among Veterans Who Served in Iraq or Afghanistan.
This study assessed the risk of suicide by time since separation from the military for US veterans who served in Iraq or Afghanistan. Suicide risk was assessed by comparing the number of suicides among veterans, when stratified by active vs. reserve/National Guard status to the expected number based on rates of suicide in the US general population. Hazard rates were used to assess suicide risk since the time each veteran separated/deactivated from active duty service. Compared to the US general population, active duty veterans had a 56% increased risk of suicide and reserve/National Guard veterans had a 29% increased risk. Suicide risk decreased as time since separation/deactivation increased for both groups. The risk of suicide for both groups was greatest during the first year of follow-up.


Functional invertebrate prey groups reflect dietary responses to phenology and farming activity and pest control services in three sympatric species of aerially foraging insectivorous birds.
Farming activity severely impacts the invertebrate food resources of farmland birds, with direct mortality to populations of above-ground arthropods thorough mechanical damage during crop harvests. In this study we assessed the effects of phenological periods, including the timing of harvest, on the composition and biomass of prey consumed by three species of aerial insectivorous birds. Common Swifts Apus apus, Barn Swallows Hirundo rustica and House Martins Delichon urbica breed sympatrically and most of their diet is obtained from agricultural sources of invertebrate prey, especially from oil-seed rape crops. We categorized invertebrate prey into six functional groups, including oil-seed rape pests; pests of other arable crops; other crop-provisioned taxa; coprophilous taxa; and taxa living in non-crop and mixed crop/non-crop habitats. Seasonality impacted functional groups differently, but the general direction of change (increase/decrease) of all groups was consistent as indexed by prey composition of the three aerial insectivores studied here. After the oil-seed rape crop harvest (mid July), all three species exhibited a dietary shift from oil-seed rape insect pests to other aerial invertebrate prey groups. However, Common Switfts also consumed a relative large quantity of oil-seed rape insect pests in the late summer (August), suggesting that they could reduce pest insect emigration beyond the host plant/crop. Since these aerially foraging insectivorous birds operate in specific conditions and feed on specific pest resources unavailable to foliage/ground foraging avian predators, our results suggest that in some crops like oil-seed rape cultivations, the potential integration of the insectivory of aerial foraging birds into pest management schemes might provide economic benefits. We advise further research into the origin of airborne insects and the role of aerial insectivores as agents of the biological control of crop insect pests, especially the determination of depredation rates and the cascading effects of insectivory on crop damage and yield.


Expression of cytokeratin MNF116 and vimentin in pleural serous effusions.
The purpose of this study is to evaluate the value of cytokeratin (CK) MNF116 and vimentin in the differential diagnosis of malignant pleural effusions. There were evaluated smears from 30 patients with pleural effusions stained with May-Grünwald Giemsa and Papanicolaou techniques for the routine cytological diagnosis. Additional smears were immunostained with CK MNF116 and vimentin using LSAB2 technique. Two independent observers evaluated all smears. Smears were classified first by cytological examination in seven cases (23.33%) as benign, and in 23 cases (76.67%) as malignant pleural effusions. Mesothelial cells expressed CK MNF116 in 96.67% (29/30) of cases and vimentin in 33.33% (10/30) of cases. Malignant cells expressed CK MNF116 in 52.17% (12/23) of cases and vimentin in 30.43% (7/23) of cases. The pattern of immunostaining was diffuse cytoplasmic. In conclusion, CK MNF116 and vimentin may be used as a part of the panel of antibodies for differential diagnosis of malignant pleural effusions with primary unknown.


Impact of the Interval between Previous Endoscopic Exam and Diagnosis on the Mortality and Treatment Modality of Undifferentiated-Type Gastric Cancer.
The impact of the interval between previous endoscopy and diagnosis on the treatment modality or mortality of undifferentiated (UD)-type gastric cancer is unclear. This study aimed to investigate the effect of endoscopic screening interval on the stage, cancer-related mortality, and treatment methods of UD-type gastric cancer. We reviewed the medical records of newly diagnosed patients with UD gastric cancer in 2013, in whom the interval between previous endoscopy and diagnosis could be determined. The patients were classified into different groups according to the period from the previous endoscopy to diagnosis (<12 months, 12-23 months, 24-35 months, ≥36 months, and no history of endoscopy), and the outcomes were compared between the groups. In addition, patients who underwent endoscopic and surgical treatment were reclassified based on the final treatment results. The number of enrolled patients was 440, with males representing 64.1% of the study population; 11.8% of the participants reported that they had undergone endoscopy for the first time in their cancer diagnosis. The percentage of stage I cancer at diagnosis significantly decreased as the interval from the previous endoscopy to diagnosis increased (65.4%, 63.2%, 64.2%, 45.9%, and 35.2% for intervals of <12 months, 12-23 months, 24-35 months, ≥36 months, and no previous endoscopy, respectively, P<0.01). Cancer-related mortality was significantly lower for a 3-year interval of endoscopy (P<0.001). A 3-year interval of endoscopic screening reduces gastric-cancer-related mortality, particularly in cases of UD histology.


Foodborne botulism in Turkey, 1983 to 2017.
The aim of this study is to assess the epidemiology of foodborne botulism cases which were seen and published in Turkey. This study covers the cases and outbreaks of botulism that have been identified and published in any region of Turkey, between 1983 and 2017. This systematic review was performed in accordance with the guidelines for performing and reporting systematic reviews and meta-analyses. The search was done on PubMed and Google in English and Turkish languages. Demographic features of the cases, nutritional sources, the development process of the disease, clinical symptoms and signs, the duration of hospitalization, treatment and mortality rates were analyzed. Totally 95 patients (57 female and 38 male) were assessed from the published. The food which caused the majority of intoxication cases was canned green beans, and all the foods were home-canned goods. There cords showed that botulism antitoxin was given to 56 patients. The time from exposure to illness onset was 26.9 h. While 18 patients died at the end of follow-up and treatment (mortality 19%), 77 patients were discharged with full recovery. Among 95 botulism cases, spread in Turkey over the last 35 years, the predominant source of toxin was home-canned food and green beans, in particular. Since community and emergency room physicians may be the first to treat patients with any type of botulinum intoxication, they must know how to diagnose and treat this rare but potentially lethal disease.


Chromatic properties of texture-shape and of texture-surround suppression of contour-shape mechanisms.
Contour-shape coding is color selective (Gheorghiu & Kingdom, 2007a) and surround textures inhibit the processing of contour shapes (Gheorghiu & Kingdom, 2011; Kingdom & Prins, 2009). These two findings raise two questions: (1) is texture-surround suppression of contour shape color selective, and (2) is texture-shape processing color selective? To answer these questions, we measured the shape-frequency aftereffect using contours constructed from strings of Gabors defined along the red-green, blue-yellow, and luminance axes of cardinal color space. The stimuli were either single sinusoidal-shaped contours or textures made of sinusoidal-shaped contours arranged in parallel. We measured aftereffects for (A) single-contour adaptors and single-contour tests defined along the same versus different cardinal directions, (B) texture adaptors and single-contour tests in which the central-adaptor contour/single-contour test and surround adaptor contours were defined along the same versus different cardinal directions, and (C) texture adaptors and texture tests defined along same versus different cardinal directions. We found that color selectivity was most prominent for contour-shape processing, weaker for texture-surround suppression of contour-shape processing, and absent for texture-shape processing.


Kallichrome: a new stain for erythroblasts.
Using the obscure dye kallichrome, erythroblasts at all stages of maturation demonstrated intense yellow to yellow-brown staining of both nucleus and cytoplasm. Staining of this type was not observed in other types of normal or pathological marrow cells. As such, kallichrome may be a valuable stain for identification of erythroblasts and their distinction from other types of blood cells.


Comparison and visualisation of agreement for paired lists of rankings.
Output from analysis of a high-throughput 'omics' experiment very often is a ranked list. One commonly encountered example is a ranked list of differentially expressed genes from a gene expression experiment, with a length of many hundreds of genes. There are numerous situations where interest is in the comparison of outputs following, say, two (or more) different experiments, or of different approaches to the analysis that produce different ranked lists. Rather than considering exact agreement between the rankings, following others, we consider two ranked lists to be in agreement if the rankings differ by some fixed distance. Generally only a relatively small subset of the k top-ranked items will be in agreement. So the aim is to find the point k at which the probability of agreement in rankings changes from being greater than 0.5 to being less than 0.5. We use penalized splines and a Bayesian logit model, to give a nonparametric smooth to the sequence of agreements, as well as pointwise credible intervals for the probability of agreement. Our approach produces a point estimate and a credible interval for k. R code is provided. The method is applied to rankings of genes from breast cancer microarray experiments.


Effect of atorvastatin on dendritic cells of tubulointerstitium in diabetic rats.
Inflammatory reactology has become increasingly important in diabetic kidney disease. In this study, we estabilished STZ-induced diabetic rat model to investigate whether dendritic cells (DCs) mediated tubulointerstitial damages, and whether the effects by DCs were mediated by P-selectin expression and can be inhibited by atorvastatin. The study demonstrated that there was an accumulation of DCs in diabetic rats mediated by P-selectin. It also showed the accumulation of DCs and expression of P-selectin was closely correlated with the degree of renal tubulointerstitial injury. These effects were markedly attenuated by atorvastatin. Thus, DCs play a role in tubulointerstitial damages, atorvasttin can prevent renal tubulointerstitium from damage by inhibiting the P-selectin expression and DCs migration.


Development of a novel biofilm continuous culture method for simultaneous assessment of architecture and gaseous metabolite production.
The way that gaseous metabolite production changes along with biofilm architecture development is poorly understood. To address this question, we developed a novel flow reactor biofilm culture method that allows for simultaneous assessment of gaseous metabolite production and architecture visualization. In this report, we establish the utility of this method using denitrification by Pseudomonas aeruginosa biofilms as a model system. Using this method, we were able to collect and analyze gaseous metabolites produced by denitrification and also visualize biofilm architecture in a nondestructive manner. Thus, we propose that this novel method is a powerful tool to investigate potential relationships between biofilm architecture and the gas-producing metabolic activity of biofilms, providing new insights into biofilm ecology.


Dose response of dexamethasone for the enhanced ocular hypotensive response to epinephrine in rabbits with prior dexamethasone treatment.
We have previously shown that administration of epinephrine to the rabbit eye with dexamethasone pretreatment resulted in a significant decrease in intraocular pressure (IOP), compared to the use of epinephrine alone. Furthermore, this decrease in IOP is dose-dependent on epinephrine with the largest response of decrease of IOP occurring at the lower doses of epinephrine. We now extend this study to determine whether the decrease in IOP is dose-dependent on dexamethasone. Rabbit eyes were pretreated with five applications of topical dexamethasone or saline, administered at fifteen-minute intervals. Eyes were then treated with 0.005% epinephrine (0.01% epinephrine bitartrate). IOP was monitored for the next four hours. Different groups of rabbits received varying concentrations of dexamethasone base, from 0.0004% to 0.07% (dexamethasone phosphate), and a dose response curve was obtained. When compared to eyes treated with epinephrine alone, eyes pretreated with dexamethasone showed a significantly greater decrease in pressure at free base dexamethasone concentrations of 0.07%, 0.007% and 0.0007%, with the greatest difference at the 0.007% concentration (mean = 6.8 mm Hg). Similarly, the duration taken for the IOP to return to baseline levels was prolonged in the groups receiving dexamethasone pretreatment. The synergism between dexamethasone and epinephrine in lowering IOP may be a useful alternative in the treatment of ocular hypertension and glaucoma especially using a combination of a low dose of epinephrine with a low dose of dexamethasone.


The process of ageing.
An increasing elderly population involves nurses with older people in a wide sphere of activities. It is essential that an understanding of ageing and its effects is included as part of the knowledge which to common to all nurses. The study of gerontology has intensified in recent years but an interest in the phenomenon of ageing can be traced back through the centuries. A number of theories about the causes of ageing have been put forward but the evidence in support of these is still inconclusive. Control of hte ageing process remains beyond mankind, but it is known that environmental and hereditary factors contribute to the rate of ageing. Knowledge about the effects of ageing is accumulating. The influence of ageing on the functions of the body can be measured. Most functions are reduced in efficiency and the lowered levels of performance have to be considered in their relation to the medical and nursing care of older people. Ageing also has psychological and social implications. Changes in behaviour patterns can occur as a result of the influence of ageing on personality, intellect and memory. There are also changes in the social circumstances of older people resulting from such factors as retirement and bereavement. The growing problem of an elderly population is stimulating increasing research into the causes and effects of ageing.


Expression and clinical relevance of MET and ALK in Ewing sarcomas.
Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 μmol/L), NVP-TAE684 (IC50 0.15-0.79 μmol/L) and cabozantinib (IC50 2.69-8.27 μmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.


Sharing in practice: new partnerships for health.
A vital part of health care, sharing in practice is not a vision for the future but the reality of today. Below, the meaning and implications of sharing in practice not just for nursing but for health care.


Psychometric limitations of the mini-mental state examination among nondemented older adults: an evaluation of neurocognitive and magnetic resonance imaging correlates.
BACKGROUND/STUDY CONTEXT: Although many of the Mini-Mental State Examination's (MMSE) limitations are well accepted among geriatricians, neuropsychologists, and other interested clinicians and researchers, its continued use in psychometrically unsound ways suggests that additional investigation and dissemination of information are sorely needed. The authors aimed to describe the reliability and validity of the MMSE as a measure of cognitive function among healthy older adults. The authors examined MMSE performance in 124 stroke- and dementia-free, community-dwelling older adults (65% male; mean age = 66.5 years). All participants were administered an extensive neuropsychological battery composed of measures of attention, executive function, memory, and visuospatial function. A subset of 99 participants also underwent magnetic resonance imaging (MRI). MMSE test-retest reliability was examined among 65 participants who underwent repeat MMSE testing over an average interval of 83.2 days. Spearman test-retest correlation for total MMSE scores was r S = .35 (p = .004), for Serial Sevens was r S = .40 (p = .001), and for Word Recall was r S = -.01 (p = .96). Total MMSE performance correlated significantly with a minority of neuropsychological tests and MRI-derived indices of white matter disease and brain atrophy. A subset of 17% of participants demonstrated inappropriate intrusion of MMSE Pentagon Copy during another test of visuospatial recall. Overall, MMSE scores exhibited ceiling effects, poor test-retest reliability, limited sensitivity to subtle brain abnormalities, and a high rate of intrusion elsewhere in the neuropsychological battery. Individual MMSE items demonstrated poor construct validity. These qualities illustrate the serious limitations of the MMSE in detecting individual differences in cognitive function among healthy older adults.


Automated production of [68 Ga]Ga-DOTANOC and [68 Ga]Ga-PSMA-11 using a TRACERlab FXFN synthesis module.
The interest in gallium-68 labelled positron-emission tomography probes continues to increase around the world. However, one of the barriers for routine clinical use is the cost of the automated synthesis units for relatively simple labelling procedures. Herein, we describe the adaptation of a TRACERlab FXFN synthesis module for the automated production of gallium-68 radiopharmaceuticals using a cation-exchange cartridge for postprocessing of the 68 Ge/68 Ga generator eluate. The recovery of activity from the cartridge was 95.6% to 98.9% using solutions of acidified sodium chloride (5 M with pH = 1-3). The radiosyntheses of [68 Ga]Ga-DOTANOC and [68 Ga]Ga-PSMA-11 were performed using acetate sodium buffer or 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, with a total duration of 21 and 23 minutes, respectively, including generator elution and radiopharmaceutical dispensing. Activity yields were 77% ± 2% for [68 Ga]Ga-PSMA-11 and 68% ± 3% for [68 Ga]Ga-DOTANOC (n > 100). The labelled peptides had a radiochemical purity exceeding 97%, and all quality control parameters were in conformity with the limits prescribed by the European Pharmacopoeia.


Use of Rapid Antigen Testing for SARS-CoV-2 in Remote Communities - Yukon-Kuskokwim Delta Region, Alaska, September 15, 2020-March 1, 2021.
Controlling the spread of SARS-CoV-2, the virus that causes COVID-19, in Alaska is challenging. Alaska includes many remote and isolated villages with small populations (ranging from 15 to >1,000 persons) that are accessible only by air from larger communities. Until rapid point-of-care testing became widely available, a primary challenge in the diagnosis of COVID-19 in rural Alaska was slow turnaround times for SARS-CoV-2 test results, attributable to the need to transport specimens to testing facilities. To provide more timely test results and isolation of cases, the Yukon Kuskokwim Health Corporation (YKHC) introduced Abbott BinaxNOW COVID-19 Ag rapid antigen test (BinaxNOW) on November 9, 2020, in the rural Yukon-Kuskokwim Delta region in southwestern Alaska. To evaluate the impact of implementing antigen testing, YKHC reviewed the results of 54,981 antigen and molecular tests for SARS-CoV-2 performed in the Yukon-Kuskokwim Delta during September 15, 2020-March 1, 2021. Introduction of rapid, point-of-care testing was followed by a more than threefold reduction in daily SARS-CoV-2 case rates during approximately 1 month before the introduction of COVID-19 vaccination. The median turnaround time for SARS-CoV-2 test results decreased by >30%, from 6.4 days during September 15-November 8, 2020, to 4.4 days during November 9, 2020-March 1, 2021 (p<0.001). Daily incidence decreased 65% after the introduction of BinaxNOW, from 342 cases per 100,000 population during the week of November 9 to 119 during the week of December 13 (p<0.001). These findings indicate that point-of-care rapid antigen testing can be a valuable tool in reducing turnaround times in rural communities where local access to laboratory-based nucleic acid amplification testing (NAAT) is not readily available and could thereby reduce transmission by facilitating rapid isolation of infected persons, contact tracing, and implementation of local mitigation strategies.


Intra-oral scan segmentation using deep learning.
Intra-oral scans and gypsum cast scans (OS) are widely used in orthodontics, prosthetics, implantology, and orthognathic surgery to plan patient-specific treatments, which require teeth segmentations with high accuracy and resolution. Manual teeth segmentation, the gold standard up until now, is time-consuming, tedious, and observer-dependent. This study aims to develop an automated teeth segmentation and labeling system using deep learning. As a reference, 1750 OS were manually segmented and labeled. A deep-learning approach based on PointCNN and 3D U-net in combination with a rule-based heuristic algorithm and a combinatorial search algorithm was trained and validated on 1400 OS. Subsequently, the trained algorithm was applied to a test set consisting of 350 OS. The intersection over union (IoU), as a measure of accuracy, was calculated to quantify the degree of similarity between the annotated ground truth and the model predictions. The model achieved accurate teeth segmentations with a mean IoU score of 0.915. The FDI labels of the teeth were predicted with a mean accuracy of 0.894. The optical inspection showed excellent position agreements between the automatically and manually segmented teeth components. Minor flaws were mostly seen at the edges. The proposed method forms a promising foundation for time-effective and observer-independent teeth segmentation and labeling on intra-oral scans. Deep learning may assist clinicians in virtual treatment planning in orthodontics, prosthetics, implantology, and orthognathic surgery. The impact of using such models in clinical practice should be explored.


Simple method to purify chicken immunoglobulin G.
A new method for purifying IgG was adapted for use with chicken serum. Chicken serum was mixed with caprylic acid, precipitated with ammonium sulfate, and dialyzed against PBS. Analysis by SDS-PAGE and Western blot confirmed successful purification of chicken IgG. Large quantities of highly purified IgG were easily obtainable for use in immunological investigations or for labeling. This technique is rapid, inexpensive, and simpler to perform than traditional ion exchange or gel filtration chromatography.


Seborrheic dermatitis and daylight.
Patients with mood depression have been found to have a higher prevalence of seborrheic dermatitis (SD), possibly related to their tendency to live indoors. The prevalence of outpatients with SD has now been found to be directly related to the number of gloomy days in the area. Since UV light might not be the only reason for the well-known improvement in SD in summer, an explanation possibly related to melatonin is envisaged.


Investigation of reported aflatoxin production by fungi outside the Aspergillus flavus group.
A screening study of 121 fungus isolates, representing 29 species, for aflatoxin synthesis demonstrated this property only in Aspergillus flavus and A. parasiticus. Eight of the organisms found negative were isolates reported by other investigators to produce aflatoxin. Since similar negative reports have come from several other workers, it is concluded that only the A. flavus group of Aspergillus can presently be certified as sources of these toxins. Reasons for possible false-positive findings are discussed along with precautionary measures and differential analytical procedures useful in aflatoxin screening studies.


Economic simulation of batch and continuous aqueous two-phase purification for viral products.
Vaccine manufacturing strategies that lower capital and production costs could improve vaccine access by reducing the cost per dose and encouraging localized manufacturing. Continuous processing is increasingly utilized to drive lower costs in biological manufacturing by requiring fewer capital and operating resources. Aqueous two-phase systems (ATPS) are a liquid-liquid extraction technique that enables continuous processing for viral vectors. To date, no economic comparison between viral vector purifications using traditional methods and ATPS has been published. In this work, economic simulations of traditional chromatography-based virus purification were compared to ATPS-based virus purification for the same product output in both batch and continuous modes. First, the modeling strategy was validated by re-creating a viral subunit manufacturing economic simulation. Then, ATPS capital and operating costs were compared to that of a traditional chromatography purification at multiple scales. At all scales, ATPS purification required less than 10% of the capital expenditure compared to chromatography-based purification. At an 11 kg per year production scale, the ATPS production costs were 50% less than purification with chromatography. Other chromatography configurations were explored, and may provide a production cost benefit to ATPS, but the purity and recovery were not experimentally verified. Batch and continuous ATPS were similar in capital and production costs. However, manual price adjustments suggest that continuous ATPS plant-building costs could be less than half that of batch ATPS at the 11 kg per year production scale. These simulations show the significant reduction in manufacturing costs that ATPS-based purification could deliver to the vaccine industry.


Strain-induced proliferation requires the phosphatidylinositol 3-kinase/AKT/glycogen synthase kinase pathway.
The intestinal epithelium is repetitively deformed by shear, peristalsis, and villous motility. Such repetitive deformation stimulates the proliferation of intestinal epithelial cells on collagen or laminin substrates via ERK, but the upstream mediators of this effect are poorly understood. We hypothesized that the phosphatidylinositol 3-kinase (PI3K)/AKT cascade mediates this mitogenic effect. PI3K, AKT, and glycogen synthase kinase-3beta (GSK-3beta) were phosphorylated by 10 cycles/min strain at an average 10% deformation, and pharmacologic blockade of these molecules or reduction by small interfering RNA (siRNA) prevented the mitogenic effect of strain in Caco-2 or IEC-6 intestinal epithelial cells. Strain MAPK activation required PI3K but not AKT. AKT isoform-specific siRNA transfection demonstrated that AKT2 but not AKT1 is required for GSK-3beta phosphorylation and the strain mitogenic effect. Furthermore, overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3beta, but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not. These data delineate a role for PI3K, AKT2, and GSK-3beta in the mitogenic effect of strain. PI3K is required for both ERK and AKT2 activation, whereas AKT2 is sequentially required for GSK-3beta. Furthermore, AKT2 specificity requires its catalytic domain and tail region. Manipulating this pathway may prevent mucosal atrophy and maintain the mucosal barrier in conditions such as ileus, sepsis, and prolonged fasting when peristalsis and villous motility are decreased and the mucosal barrier fails.


Magnetic resonance imaging in ophthalmoplegic migraine of children.
To present 2 children with ophthalmoplegic migraine and characteristic magnetic resonance imaging (MRI) findings post enhancement with gadopentetate dimeglumine diethylenetriamine pentaacetic acid (Gd-DTPA). Two patients, ages 3 years and 7 years, underwent MRI during the acute phases of a recurring oculomotor palsy. MRI was repeated several weeks later as symptoms resolved. In both cases, enhancement and thickening of the cisternal segment of the oculomotor nerve were present at initial presentation. Ophthalmoplegia resolved spontaneously in 1 child and after steroid treatment in the other. Both postresolution MRIs demonstrated decrease in enhancement and thickening of the third nerve. The enhancing, thickened lesion identified on MRI in our patients may represent an inflammatory process similar to Tolosa-Hunt syndrome occurring in the interpeduncular segment of the oculomotor nerve. Patients with ophthalmoplegic migraine may, therefore, benefit from the use of steroids. MRI of the brain post enhancement is a useful adjunct in the diagnosis and treatment of ophthalmoplegic migraine and should be considered as part of a workup of ophthalmoplegic migraine in children.


Acute simultaneous bilateral avulsion fractures of the tibial tubercles in a 15-year-old male hurler: case report and literature review.
Avulsion fractures of the tibial tubercle are an unusual injury pattern generally occurring in the adolescent male during sporting activities. Bilateral simultaneous fractures are extremely rare. They are often associated with other underlying orthopaedic pathology. We present a case of bilateral tibial tubercle avulsions occurring in a 15 year-old male hurler. We describe the management and necessary investigations required for this type of trauma and present a literature review on this rarely encountered injury. Although this type of atypical fracture pattern is associated with high energy trauma and other underlying pathology, we have shown that once treated, the patient can expect to make a prompt return to sporting activities with no significant long-term functional deficit.


Transcription regulation mechanism of the syntaxin 1A gene via protein kinase A.
Syntaxin 1A (Stx1a) is primarily involved in the docking of synaptic vesicles at active zones in neurons. Its gene is a TATA-less gene, with several transcription initiation sites, which is activated by the binding of Sp1 and acetylated histone H3 (H3) in the core promoter region (CPR) through the derepression of class I histone deacetylase (HDAC). In the present study, to clarify the factor characterizing Stx1a gene expression via the protein kinase A (PKA) pathway inducing the Stx1a mRNA, we investigated whether the epigenetic process is involved in the Stx1a gene transcription induced by PKA signaling. We found that the PKA activator forskolin induced Stx1a expression in non-neuronal cells, FRSK and 3Y1, which do not endogenously express Stx1a, unlike PC12. HDAC8 inhibition by shRNA knockdown and specific inhibitors induced Stx1a expression in FRSK. The PKA inhibitor H89 suppressed HDAC8-Ser39 phosphorylation, H3 acetylation and Stx1a induction by forskolin in FRSK cells. Finally, we also found that forskolin led to the dissociation of HDAC8-CPR interaction and the association of Sp1 and Ac-H3 to CPR in FRSK. The results of the current study suggest that forskolin phosphorylates HDAC8-Ser39 via the PKA pathway and increases histone H3 acetylation in cells expressing HDAC8, resulting in the induction of the Stx1a gene.


Physical activity in patients with COPD: the impact of comorbidities.
Comorbidities are common in patients with chronic obstructive pulmonary disease (COPD) and it plays an important role on physical activity (PA) in this population. Since low PA levels have been described as a key factor to predict morbi-mortality in COPD, it seems crucial to review the current literature available on this topic. Areas covered: This review covers the most common comorbidities found in COPD, their prevalence and prognostic implications. We explore the differences in PA between COPD patients with and without comorbidities, as well as the impact of the number or type of comorbidities on activity levels of this population. The effect of different comorbidities on activities of daily living in patients with COPD is also reviewed. Finally, we discuss options for the treatment of inactivity in COPD patients considering their comorbidities and limitations. Expert commentary: Comorbidities are highly prevalent in patients with COPD and further deteriorate PA levels in this population. Despite the wide range of interventions available in COPD, the evidence in the field seems to point at PA coaching with feedback on individual goals and longer lasting PR programmes with more than 12 weeks of duration when attempting to raise the activity levels of this population.


Roles for osteocalcin in proliferation and differentiation of spermatogonial cells cocultured with somatic cells.
Spermatogonial cells (SCs) are key cells for spermatogenesis. These cells are affected by paracrine signals originated from nearby somatic cells, among them Leydig cells have receptors for osteocalcin, a hormone known for exerting positive roles in the promotion of spermatogenesis. The aim of this study was to evaluate roles for osteocalcin on SCs proliferative and differentiation features after coculture with Leydig cells. SCs and Leydig cells were isolated from neonate NMRI offspring mice and adult NMRI mice, respectively. SCs population were then enriched in a differential attachment technique and assessed for morphological features and identity. Then, SCs were cocultured with Leydig cells and incubated with osteocalcin for 4 weeks. Evaluation of proliferation and differentiation-related factors were surveyed using immunocytochemistry (ICC), Western blot, and quantitative real-time polymerase chain reaction (PCR). Finally, the rate of testosterone release to the culture media was measured at the end of 4th week. Morphological and flow cytometry results showed that the SCs were the population of cells able to form colonies and to express ID4, α6-, and β1-integrin markers, respectively. Leydig cells were also able to express Gprc6α as a specific marker for the cells. Incubation of SCs/Leydig coculture with osteocalcin has resulted in an increase in the rate of expressions for differentiation-related markers. Levels of testosterone in the culture media of SCs/Leydig was positively influenced by osteocalcin. It could be concluded that osteocalcin acts as a positive inducer of SCs in coculture with Leydig cells probably through stimulation of testosterone release from Leydig cells and associated signaling.


Polynucleotide analogs: acrylic acid and maleic acid copolymers of 1-vinyluracil and 9-vinyladenine.
Radical-induced copolymerization of 1-vinyluracil and maleic anhydride gave, after hydrolysis, a polymer containing a 1:1 monomer ratio of 1-vinyluracil-maleic acid. Gamma-Ray-induced copolymerization of 1-vinyluracil with acrylic acid gave a polymer with a ratio of 1:1.7. Similar treatment of 9-vinlyadenine and acrylic acid resulted in a polymer with a 1:3.2 ratio. These three compounds are potent stimulants of poly (uridylic acid) coded polyphenylalanine synthesis in an in vitro cell free system purified from Escherichia coli MRE 600. The double-stranded polymer, poly(inosinic acid)-poly(cytidylic acid), also stimulates polyphenylalanine synthesis in this assay.


Intravenous administration of metoclopramide by 2 min bolus vs 15 min infusion: does it affect the improvement of headache while reducing the side effects?
To determine the therapeutic effect (alleviation of vascular type headache) and side effects of a slow intravenous metoclopramide infusion over 15 min compared with those effects of a bolus intravenous metoclopramide infusion over 2 min in the treatment of patients with recent onset vascular type headache. All adults treated with metoclopramide for vascular type headache were eligible for entry into this clinical randomised double blinded trial. This study compared the effects of two different rates of intravenous infusion of metoclopramide over a period of 13 months at a university hospital emergency department. During the trial, side effects and headache scores were recorded at baseline (0 min), and then at 5, 15, 30 and 60 min. Repeated measures analysis of variance was used to compare the medication's efficacy and side effects. A total of 120 patients presenting to the emergency department met the inclusion criteria. Of these, 62 patients (51.7%) were given 10 mg metoclopramide as a slow intravenous infusion over 15 min (SIG group) and 58 patients (48.3%) were given 10 mg metoclopramide intravenous bolus infusion over 2 min (BIG group). 17 of the 58 patients in the BIG group (29.3%) and 4 of the 62 patients (6.5%) in the SIG group had akathisia (p = 0.001). There were no significant differences between the BIG and SIG groups in terms of mean headache scores (p = 0.34) and no adverse reactions in the study period. Metoclopramide successfully relieved the headache symptom(s) of patients in both the BIG and SIG groups. Slowing the infusion rate of metoclopramide is an effective strategy for the improvement of headache and reducing the incidence of akathisia in patients with vascular type headache.


Pharmacokinetics of sulfobutylether-beta-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemodiafiltration.
Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 +/- 0.6 h (Genius dialysis) to 2.4 +/- 0.9 h (hemodialysis) and 2.0 +/- 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.


Strategy for Identification of Phosphorylation Levels of Low Abundance Proteins in Vivo for Which Antibodies Are not Available.
Protein function is mainly modulated by dynamic reversible or irreversible post-translational modifications. Among them, the identification of protein phosphorylation sites and changes in phosphorylation levels in vivo are of considerable interest for a better understanding of the protein function. Thus, effective strategies for the quantitative determination of phosphorylation degrees for low abundant proteins, for which antibodies are not available, are required in order to evaluate the functional regulation of proteins attributed to phosphorylation. In this study, we used the heart β1-adrenergic receptor (Adrb1) as a model protein and developed FLAG-Adrb1 knock-in mice, in which the FLAG tag was inserted at the N-terminus of Adrb1. The phosphorylation sites and levels of Adrb1 in the heart were elucidated by immuno-affinity purification followed by quantitative mass spectrometry analysis using ion intensity ratio of the phosphorylated peptide versus corresponding unphosphorylated peptide. The phosphorylation levels at Ser274 and Ser462 of Adrb1 were approximately 0.25 and 0.0023. This effective strategy should be useful for not only analyzing site-specific phosphorylation levels of target proteins, but also quantifying the expression levels of proteins of interest when appropriate antibodies are not available.


Solitary morphoea profunda.
This study describes a series of patients with an unusual form of scleroderma. All five patients presented clinically with solitary, indurated plaques involving the upper trunk. Histologically the lesions were characterized by a dense, mononuclear cell infiltrate mainly in the subcutis, which was rich in plasma cells, and was associated with marked sclerosis and hyalinization of the connective tissue at this level. Lymphoid aggregates with germinal centre formation were present in three patients and tissue eosinophilia in one. No lesion has shown spontaneous resolution but neither has systemic involvement occurred, despite a maximum follow-up of 17 years. Immunohistochemical studies revealed a mixed population of T and B lymphocytes with no evidence of immunoglobulin light-chain restriction. We believe that the clinical and histological features in these five cases are sufficiently distinct to merit description under the title of 'solitary morphoea profunda'.


Effect of catheter diameter on left innominate vein in breast cancer patients after totally implantable venous access port placement.
To evaluate the effect of catheter diameter on left innominate vein stenosis in breast cancer patients after placement of totally implantable venous access ports. Totally implantable venous access ports were placed via the left internal jugular vein in 241 women with right breast cancer from January 2010 to December 2014 (mean age, 51.5 years; range, 19-83 years). There were 67 totally implantable venous access ports with a 6.5F catheter and 142 totally implantable venous access ports with an 8F catheter. Medical records were retrospectively reviewed. The presence of significant left innominate vein stenosis and tip location of the catheter was evaluated on chest computed tomography images. Statistical analysis was performed. Left innominate vein stenosis developed in 1 (1.5%) and 13 (9.2%) patients after implantation with 6.5 and 8F catheters, respectively. Difference in the cumulative incidence of left innominate vein stenosis was statistically significant between the two groups (log rank test p-value: 0.002). In Cox regression analysis, the hazard ratio for left innominate vein stenosis was 20.766 ( p = 0.005) for an 8F catheter. The incidence of left innominate vein stenosis was higher after implantation of totally implantable venous access ports with 8F catheter rather than with 6.5F catheter. Considering that using 8F catheter versus 6.5F catheter has no advantage in terms of performance of the device, the results of our study suggest that ports with catheters >7F should be avoided.


Prevalence of cerebrovascular accident in 4349 diabetic cases.
1. Prevalence of cerebrovascular accident in 4349 cases of diabetes admitted in the Bombay Hospital, Bombay between 1967 and 1975 was in 411 (9.45 percent) cases. 2. Number of males predominated, but was of no significance as compared to the occurrence of cerebrovascular in females. 3. Highest number of cases were in the age group of 61-70 years (statistically significant), which was a decade higher than the age of (51-60 years) maximum number of admitted cases in 4349 cases. The mortality increases with age, highest in age above 70 years-statistically significant. 4. The type and site of cerebrovascular accident had no relation to the age group or sex, duration and severity of diabetes. 5. Cerebrovascular accident was much less in the last 3 months of the year and was highest in the month of June, and is of no statistical significance. 6. Cerebrovascular accident was more prevalent in mild type diabetes, but mortality was higher in severe type of diabetes. 7. Cerebrovascular accident was prevalent in all types of blood pressure, but had highest mortality in severe hypertension. 8. Occurrence of CVA had no relation with the duration of diabetes.


Neuroectodermal Diseases: A Comparative Case Report Study.
Neuroectodermal disease involves abnormalities that arise from the ectodermal origin, such as the nervous system, eyeball, retina, and skin. Due to the rarity of the disease, it is often underdiagnosed or misdiagnosed. In this study, the researcher presents two cases of pediatric patients with no fetomaternal complications who presented with focal seizures as their initial complaint. During the examination, varying skin color pigmentation and an abnormal neurophysical examination were observed. Cranial imaging showed hemimegalencephaly and voltage asymmetry on EEG. Skin biopsy was performed on both cases, which revealed basketweave orthokeratosis. The combination of a triad of intractable epilepsy, developmental delay, and cutaneous lesion prompted the consideration of a neuroectodermal disease. The study shows two cases of hypomelanosis of Ito and nevus syndrome, both of which may be due to mTOR and RAS pathways, respectively.


The impact of pump fluence on carrier relaxation dynamics in optically excited graphene.
The carrier dynamics in optically excited graphene is determined by an interplay between the Coulomb- and phonon-induced scattering processes. The pump fluence of the excitation pulse plays a crucial role: for high fluences the ultrafast relaxation dynamics is determined by carrier–carrier scattering, whereas for low fluences the carrier–phonon relaxation channels are predominant. On the basis of a microscopic approach, we shed light on the influence of the pump fluence on the temporal evolution of carrier and phonon occupations as well as on the many-particle dephasing of the microscopic polarization. The new insights obtained contribute to a better understanding of the ultrafast carrier dynamics in graphene and can guide future pump–probe experiments.


A method for distinguishing ionized, complexed and protein-bound Mg in normal and diseased subjects.
Since 1932, it has been known that Mg exists in blood in several forms: protein-bound, complexed to certain anions, and ionized. However, there is discrepancy and debate on what these fractions are, how to accurately assess them, and whether they are important in diagnosis and prognosis of disease syndromes. Using the NOVA ISE for IMg2+, a controlled method for ultrafiltration of Mg and atomic absorption spectrophotometry, we have found four distinct fractions of Mg in healthy normal plasma and serum: 1. ultrafilterable Mg (81%) (made up of ionized and complexed); 2. ionized Mg (67%); 3. protein-bound Mg (19%); and 4. complexed Mg (14%). The amount of each fraction appears to depend upon the pathophysiologic state of the patients. Previous observations on the amount of complexed and ionized Mg are at best, only approximations, due to the absence of a device (i.e., ISE) to measure accurately IMg2+.


Structural manifestations of diabetic cardiomyopathy in the rat and its reversal by insulin treatment.
The structural effects of diabetes and subsequent insulin treatment upon the contractile and supporting elements of the rat myocardium were examined at progressive stages of both untreated and treated disease. Diabetes was induced by intravenous injection of alloxan, and tissue was examined after 6, 12, and 26 weeks. Insulin treatment began after 12 weeks of diabetes and tissue from these animals was examined after the same intervals. Within the cardiocytes, diabetes produced a focal yet progressive loss of myofibrils, transverse tubules, and sarcoplasmic reticulum, and separation of the fasciae adherens was evident at the intercalated disk. Mitochondrial damage was not evident. These cytoplasmic alterations were accompanied by intercellular and perivascular deposition of connective tissue, thickening of the endothelial cytoplasm with pinocytotic hyperactivity, and characteristic basal laminar changes. When insulin treatment began after 12 weeks of diabetes, most, but not all, of these changes were reversed, and this reversal was essentially complete within 6-12 weeks. Even with longer periods of insulin treatment, cardiocytes still exhibited scattered areas of myofibril loss and extracellular matrix was retained. In contrast, diabetic changes in the intercalated disk and capillaries, including their basal laminae, were completely and rapidly reversed. It is hypothesized that the structural manifestations of diabetic cardiomyopathy consist of two major components; the first is a short-term, physiologic adaptation to metabolic alterations, while the other represents degenerative changes for which the myocardium has only a limited capacity for repair.


Criteria for using imaging ultrasound during brain and spinal cord surgery.
Imaging ultrasonography was performed during 23 brain and five spinal cord operations with real-time B-mode instruments. Criteria for the utilization of ultrasound at neurosurgical procedures were identified in terms of assistance in the diagnosis or better definition of lesions. The diagnosis criteria were detection and exclusion. Because of the accuracy of preoperative imaging, usually little further help was provided by operative ultrasonography in detecting previously totally unknown abnormalities or excluding lesions found on positive studies. The definition criteria were localization, distinction of tissue features, and assessment of spatial relations. Operative ultrasonography was most useful when applied on the basis of these definition criteria. Operative ultrasonography was considered to be useful in 22 of 28 operations (79 per cent) in which it assisted in exposing, accessing, and extirpating disease.


Neurochemical measurements in the zebrafish brain.
The zebrafish is an ideal model organism for behavioral genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behavior can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterization of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain.


Mutations in the lac P2 promoter.
We used site-directed mutagenesis to generate mutations in the -10 region of the lac P2 promoter. The mutations were crossed onto lambda bacteriophage carrying the lac regulatory elements and an intact lacZ gene, and the effects of the various mutations were determined in vivo and in vitro. Two of four mutations had effects on the start point of the P2-directed transcript and had very little effect on lac expression. Another mutation, which abolishes P2 promoter activity in vitro, also had very little effect on lac expression in vivo. We suggest that the P2 promoter plays little or no role in the activation of the P1 promoter by catabolite activator protein in complex with cyclic AMP.


Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn.
Mucosal integrity can be assessed in patients with gastroesophageal reflux disease (GERD) by measuring intraluminal baseline impedance (BI). However, it is not clear whether BI is abnormal in patients with functional heartburn (FH), or can be used to distinguish them from patients with GERD. We compared differences in BI between patients with FH vs GERD. We performed a prospective study of 52 patients (16 men; mean age, 55 y; range, 23-78 y) seen at a tertiary university hospital from February 2009 through December 2012. Thirty-five patients had GERD (19 had nonerosive reflux disease [NERD], 16 had erosive reflux disease [ERD]) and 17 had FH. All patients discontinued proton pump inhibitor therapy and then underwent esophagogastroduodenoscopy and multichannel intraluminal impedance and pH monitoring. BI was assessed at 3, 5, 7, 9, 15, and 17 cm proximal to the lower esophageal sphincter in recumbent patients. Biopsy specimens were taken from 3 cm above the gastroesophageal junction; histology analysis was performed to identify and semiquantitatively score (scale, 0-3) dilated intercellular spaces. Baseline impedance in the distal esophagus was significantly lower in patients with NERD or erosive reflux disease (ERD) than FH (P = .0006). At a cut-off value of less than 2100 Ω, BI measurements identified patients with GERD with 78% sensitivity and 71% specificity, with positive and negative predictive values of 75%. Also in the proximal esophagus, reduced levels of BI levels were found only in patients with ERD. There were negative correlations between level of BI and acid exposure time (r = -0.45; P = .0008), number of acidic reflux episodes (r = -0.45; P = .001), and proximal extent (r = -0.40; P = .004). Biopsy specimens from patients with NERD or ERD had significant increases in dilation of intercellular spaces, compared with those from patients with FH; there was an inverse association between dilated intercellular spaces and BI in the distal esophagus (r = -0.28; P = .06). Measurement of BI in the lower esophagus can differentiate patients with ERD or NERD from patients with FH (78% sensitivity and 71% specificity), and therefore should be considered as a diagnostic tool for patients with proton pump inhibitor-refractory reflux. Low levels of BI are associated with increased exposure to acid and dilation of intercellular spaces, indicating that BI is a marker of mucosal integrity.


Low metabolic rates in salamanders are correlated with weak selective constraints on mitochondrial genes.
Mitochondria are the site for the citric acid cycle and oxidative phosphorylation (OXPHOS), the final steps of ATP synthesis via cellular respiration. Each mitochondrion contains its own genome; in vertebrates, this is a small, circular DNA molecule that encodes 13 subunits of the multiprotein OXPHOS electron transport complexes. Vertebrate lineages vary dramatically in metabolic rates; thus, functional constraints on mitochondrial-encoded proteins likely differ, potentially impacting mitochondrial genome evolution. Here, we examine mitochondrial genome evolution in salamanders, which have the lowest metabolic requirements among tetrapods. We show that salamanders experience weaker purifying selection on protein-coding sequences than do frogs, a comparable amphibian clade with higher metabolic rates. In contrast, we find no evidence for weaker selection against mitochondrial genome expansion in salamanders. Together, these results suggest that different aspects of mitochondrial genome evolution (i.e., nucleotide substitution, accumulation of noncoding sequences) are differently affected by metabolic variation across tetrapod lineages.


Syntheses, Crystal Structures, and Nonlinear Optical Activity of Cs2Ba[AnO2(C2H5COO)3]4 (An = U, Np, Pu) and Unprecedented Octanuclear Complex Units in KR2(H2O)8[UO2(C2H5COO)3]5 (R = Sr, Ba).
X-ray diffraction was applied to the elucidation of crystal structures of single crystals of Cs2Ba[AnO2(C2H5COO)3]4, where An = U(I), Np(II), Pu(III), and KR2(H2O)8[UO2(C2H5COO)3]5, where R = Sr(IV), Ba (polymorphs V-a and V-b). FTIR spectra were analyzed for the uranium-containing crystals I, IV, and V-b. Isostructural cubic crystals I-III are constructed of typical mononuclear anionic complex units [AnO2(C2H5COO)3]- and charge-balancing Cs and Ba cations. Features of actinide contraction in the six U-Np-Pu isostructural series known to date are analyzed. In crystal structures of IV and V two typical complexes [UO2(C2H5COO)3]- bind with a hydrated Sr or Ba cation to form the rare trinuclear neutral complex unit {R(H2O)4[UO2(C2H5COO)3]2}, where R = Sr, Ba. Two such trinuclear units and one typical mononuclear unit further bind with a K cation to form the unprecedented octanuclear neutral complex unit K[UO2(C2H5COO)3]{R(H2O)4[UO2(C2H5COO)3]2}2. As the derived polynuclear complexes of uranyl ion with carboxylate ligands in the crystal structures of IV and V are not the first but are rare examples, the equilibrium between mono and polynuclear complex units in aqueous solutions is discussed. The two polymorphic modifications V-a and V-b were studied at 100 K and at room temperature, respectively. Peculiarities of noncovalent interactions in crystal structures of the two polymorphs are revealed using Voronoi-Dirichlet tessellation. The nonlinear optical activity of noncentrosymmetric crystals I was estimated by its ability for second harmonic generation.


Effects of high-intensity interval training frequency on perceptual responses and future physical activity participation.
The effectiveness of high-intensity interval training (HIIT) in inducing positive physiological adaptations is well documented. However, its impact on perceptual responses and on future physical activity (PA) engagement is less evaluated. The present study aimed to examine the effects of HIIT frequency on perceptual responses, health-related quality of life (HRQOL), and its influence in future PA participation. Thirty-five inactive adults were randomly assigned to a control (CON) and to 2 training groups that performed HIIT (10 × 60 s cycling, ∼83% peak power output) for 2 (HIIT-2) or 3 (HIIT-3) times per week for 8 weeks. Following the HIIT intervention, exercise enjoyment, HRQOL, and the intention to implement HIIT in the future were evaluated. Eight weeks after cessation of training, follow-up evaluations of HRQOL and PA were performed. Following the intervention, both training frequencies induced high levels of enjoyment (HIIT-2: 6.0 ± 1.1, HIIT-3: 6.0 ± 1.1, scale 1-7), improved HRQOL (HIIT-2: p = 0.040; HIIT-3: p = 0.024), and reported intention to implement HIIT in the future (HIIT-3: 100%, HIIT-2: 93% of participants). At follow-up, HIIT-3 participants reported higher completion of HIIT compared with HIIT-2 and CON (p < 0.05). Both training groups sustained improved HRQOL and increased vigorous and total PA (p < 0.05). This study showed that performing HIIT either 2 or 3 times per week is an enjoyable exercise modality that promotes a sustainable increase in habitual PA levels and improves HRQOL. Moreover, the higher training frequency resulted in greater HIIT completion in the 8-week period following the cessation of training.


Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells.
Down-regulation of soluble or membrane-bound co-stimulatory molecules by RNAi in dendritic cells can prevent the activation of immune responses. Therefore, this study was designed to evaluate the therapeutic efficacy of bone marrow-derived DCs (BMDCs) transduced with lentiviral vectors to permanently expressed shRNA specific for CD40 (CD40LV-DCs) and/or p19 subunit of interleukin (IL)-23 (p19LV-DCs) mRNAs in experimental autoimmune encephalomyelitis (EAE). In-vitro studies showed that double-transduced BMDCs (CD40(+) p19LV-DCs) resemble tolerogenic DCs due to profound down-regulation of CD40, lower expression of proinflammatory cytokines (IL-6 and IL-12), increased IL-10 production and stronger stimulation of myelin oligodendrocyte glycoprotein (MOG)35-55 -specific T cells for production of IL-10 compared with CD40LV-DCs, p19LV-DCs and BMDCs transduced with control lentiviral vector (CoLV-DCs). Moreover, injection of transduced CD40(+) p19LV- BMDCs in EAE mice resulted in more reduction in clinical score, significant reduction in IL-17 or increased production of IL-10 by mononuclear cells derived from the lymph nodes or spinal cord compared with CoLV-DCs-treated EAE mice. In conclusion, simultaneous knock-down of CD40 and IL-23 production by BMDCs may represent a promising therapeutic tool for the treatment of IL-17-dependent autoimmune diseases, including multiple sclerosis.


High-Density Surface EMG Decomposition by Combining Iterative Convolution Kernel Compensation With an Energy-Specific Peel-off Strategy.
Objective- This study aims to develop a novel framework for high-density surface electromyography (HD-sEMG) signal decomposition with superior decomposition yield and accuracy, especially for low-energy MUs. Methods- An iterative convolution kernel compensation-peel off (ICKC-P) framework is proposed, which consists of three steps: decomposition of the motor units (MUs) with relatively large energy by using the iterative convolution kernel compensation (ICKC) method and extraction of low-energy MUs with a Post-Processor and novel 'peel-off' strategy. Results- The performance of the proposed framework was evaluated by both simulated and experimental HD-sEMG signals. Our simulation results demonstrated that, with 120 simulated MUs, the proposed framework extracts more MUs compared to K-means convolutional kernel compensation (KmCKC) approach across six noise levels. And the proposed 'peel-off' strategy estimates more accurate MUAP waveforms at six noise levels than the 'peel-off' strategy proposed in the progressive FastICA peel-off (PFP) framework. For the experimental sEMG signals recorded from biceps brachii, an average of 16.1 ±3.4 MUs were identified from each contraction, while only 10.0 ± 2.8 MUs were acquired by the KmCKC method. Conclusion- The high yield and accuracy of MUs decomposed from simulated and experimental HD-sEMG signals demonstrate the superiority of the proposed framework in decomposing low-energy MUs compared to existing methods for HD-sEMG signal decomposition. Significance- The proposed framework enables us to construct a more representative motor unit pool, consequently enhancing our understanding pertaining to various neuropathological conditions and providing invaluable information for the diagnosis and treatment of neuromuscular disorders and motor neuron diseases.