Insecticide-treated net wall hangings for malaria vector control: an experimental hut study in north-eastern Tanzania.
Alternative long-lasting, practical and effective tools for applying insecticides on home walls against malaria vectors need to be developed. The use of wall hangings made from netting on interior walls for aesthetic purposes is a common practice in rural communities. Insecticide-treated net wall hangings can be produced in a long-lasting format and used in an approach that simulates indoor residual spraying (IRS). The efficacy of net wall hangings (NWH) treated with the residual organophosphate insecticide, pirimiphos methyl (1 g/sq m), was evaluated in experimental huts against malaria vectors in Muheza, Tanzania. To determine the optimum level of wall coverage required, NWH were tested on ceiling only, two walls, four walls, or four walls plus ceiling. Comparison was made with deltamethrin-treated NWH on two walls. Pirimiphos methyl (p-methyl)-treated NWH (on two walls) killed significantly higher proportions of anophelines (92% of Anopheles gambiae and 79% of Anopheles funestus) than the deltamethrin-treated NWH (15% of An. gambiae and 17% of An. funestus) (P<0.001). WHO susceptibility tests showed that the local vector population was susceptible to the organophosphates but resistant to pyrethroids. Mortality rates were significantly higher in huts with p-methyl NWH on two walls (92% for An. gambiae and 79% for An. funestus) than on ceiling only (61% for An. gambiae and 62% for An. funestus, P<0.05). There was no improvement in mortality when wall coverage with p-methyl NWH increased beyond two walls. Blood-feeding rates with p-methyl NWH were generally high across all the treatments (52-77%) and did not differ significantly from the control (64-67%). There was no evidence of reduced blood-feeding or increased exiting with increase in wall coverage with p-methyl NWH. Net wall hangings are an effective means of delivering insecticides in the domestic environment against malaria vectors. They could be more practical and acceptable than IRS thus showing enormous potential for malaria vector control. Appropriate binding or incorporation technology needs to be developed to enable the production of p-methyl NWH with residual activity lasting over a number of years.


Differential expression of extracellular matrix and growth factors by embryoid bodies in hydrodynamic and static cultures.
During development, cell fate specification and tissue development are orchestrated by the sequential presentation of soluble growth factors (GF) and extracellular matrix (ECM) molecules. Similarly, differentiation of stem cells in vitro relies upon the temporal presence of extracellular cues within the microenvironment. Hydrodynamic culture systems are not limited by volume restrictions and therefore offer several practical advantages for scalability over static cultures; however, hydrodynamic cultures expose cells to physical parameters not present in static culture, such as fluid shear stress and mass transfer through convective forces. In this study, the differences between static and hydrodynamic culture conditions on the expression of ECM and GF molecules during the differentiation of mouse embryonic stem cells were examined at both the gene and protein level. The expression of ECM and GF genes exhibited an early decrease in static cultures based on heat map and hierarchical clustering analysis and a relative delayed increase in hydrodynamic cultures. Although the temporal patterns of specific ECM and GF protein expression were comparable between static and hydrodynamic cultures, several notable differences in the magnitudes of expression were observed at similar time points. These results describe the establishment of an analytical framework that can be used to examine the expression patterns of ECM and GF molecules expressed by pluripotent stem cells undergoing differentiation as 3D multicellular aggregates under different culture conditions, and suggest that physical parameters of stem cell microenvironments can alter endogenous ECM and GF expression profiles that may, in turn, influence cell fate decisions.


Cooperative self-assembly of porphyrins with polymers possessing bioactive functions.
Natural porphyrin derivatives possess many interesting functions in biological systems. They are integrated into proteins that are essential for biological activities. Many efforts have been dedicated to mimic the microenvironment and augment the function of porphyrin/protein scaffolds. To achieve such goals, self-assembly has become one of the popular methods to construct porphyrin/protein-mimicking materials owing to its various choices of building blocks and a simple preparation process over chemical modification. Desirable characteristics of building blocks for protein mimicking include high molecular weight, predictable conformations in solution, and appropriate functional residuals. With these aims in mind, polymers are ideal candidates due to their multiple-level hierarchies derived from their chemical and spatial structures. In this review, design strategies for the cooperative self-assembly of porphyrins with polymers and the main efforts towards the implementation of porphyrin/polymer assembly for biomimetic composites with bioactive functions will be addressed.


Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook.
Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes. The aim of this article is to review the binding characteristics of GM to the 5-HT receptor subtypes in the brains using our own data and previous findings. Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of GM were searched in PubMed. GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5- HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was metabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5- HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cortex. These results suggest that GM is a pharmacologically important alkaloid that regulates various serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological effects of YKS.


Morphological characterization and molecular profiling of malignant pericardial effusion in patients with pulmonary adenocarcinoma.
Malignant pericardial effusions (MPCEs) is a common complication observed in advanced pulmonary adenocarcinoma. In such cases, investigating molecular alterations can have significant therapeutic implication in determining anticancer drugs. The objective was to evaluate the significance of cell block technique in the diagnosis of MPCE and further investigate the morphological and molecular profiles of MPCE in patients with pulmonary adenocarcinoma. Cytopathological and molecular profiles of 19 MPCE cases in patients with pulmonary adenocarcinoma were retrospectively analyzed. The control group consisted of 14 malignant pleural effusion (MPE) cases in patients with pulmonary adenocarcinoma. Anaplastic lymphoma kinase (ALK) and tyrosine-protein kinase Met (C-MET) expression was evaluated by fluorescence in situ hybridization (FISH). Epithelial growth factor receptor (EGFR) and K-Ras (KRAS) mutations were detected by ARMS real-time polymerase chain reaction (RT-PCR). Associations between MPCE and MPE were analyzed using Fisher's exact test. MPCE was found to have micropapillary and solid pattern predominant with mucin secretion compared to acinar patterns, as seen in MPE. Seventeen MPCE cases (89.5%) and all MPE cases (100%) underwent molecular analysis. Mutations in EGFR and KRAS, ALK rearrangement, and C-MET amplification were observed in MPCE and MPE with statistical differences. Additionally, two MPCE cases demonstrated EGFR T790M mutation and multiple insertions at L858. MPCE shows micropapillary and solid cytological patterns predominant with mucin secretion. MPCE are suitable to analyze oncogenic mutations and to develop targeted therapy for patients with pulmonary adenocarcinoma. Further molecular investigations may reveal novel molecular alterations.


The Greek (Hellenic) rheumatology over the years: from ancient to modern times.
Rheumatology has its roots in ancient Greece. Hippocrates and other prominent Greek (Hellenes) physicians in ancient times, Hellenistic, Roman, and Byzantine period were acute observers of disease course and of patients and were able to define many disorders. They wrote books on various aspects of medicine and these writings were the basis of medical practice and education in Europe and the Arabic world well into the seventeenth century. In 1821, Greece emerged from a long occupation by the Turks. In 1930, Adamantiades, a Greek Ophthalmologist, before Behcet of Turkey, described what is known as (Adamantiades)-Behcet disease. The first scientific Hellenic Society for Rheumatology (ERE) was established in 1960 and today ERE having been merged with the Professional Union of Greek rheumatologists (EPERE) is known as ERE-EPERE. Rheumatology is a strong specialty with 348 rheumatologists for a population of around 11 million. Greek rheumatologists have contributed to rheumatology science and practice, and are active physicians participating in the American College of Rheumatology and the EULAR annual congresses and in many educational postgraduate courses. ERE-EPERE formed therapeutic protocols for inflammatory and autoimmune rheumatic diseases which were incorporated in the electronic National prescription system. Rheumatologists are authorized to use this platform to prescribe biologicals free of charge for patients. ERE-EPERE publishes a peer-reviewed English language journal, the Mediterranean Journal of Rheumatology (MJR), an open access journal with no publication fees. MJR is a quarterly journal with international Editorial Board.


Plasmonic materials in transparency and cloaking problems: mechanism, robustness, and physical insights.
The possibility of making a given object transparent to the impinging radiation, or cloaking it, by employing a suitable metamaterial or plasmonic cover has been recently studied theoretically, showing how this technique may overcome the limitations of other currently available techniques. Here we discuss the underlying mechanisms, physical insights and some computer simulations on the role of such homogeneous isotropic metamaterial covers near their plasma frequency in order to dramatically reduce the fields scattered by a given object. Not requiring any absorptive process, any anisotropy or inhomogeneity, and any interference cancellation, in this contribution we demonstrate, using full-wave numerical simulations, how a homogeneous isotropic plasmonic material shell may basically "re-route" the impinging field in such a way to make dielectric and even conducting or metallic objects of a certain size nearly transparent to an outside observer placed in its near as well as in its far field. In addition, it is discussed in detail how this technique, relying on a non-resonant phenomenon, is fairly robust to relatively high variations of the shape and of the geometrical and electromagnetic properties of the cloaked object.


Global spinal deformity from the upper cervical perspective. What is "Abnormal" in the upper cervical spine?
Reciprocal changes in the upper cervical spine correlate with adult TL deformity modifiers. This was a retrospective review. The upper cervical spine has remarkable adaptability to wide ranges of thoracolumbar (TL) deformity. Patients >18 years with adult spinal deformity (ASD) and complete radiographic data at baseline (BL) and 1 year were identified. Patients were grouped into component types of the Roussouly classification system (Type 1: Pelvic incidence [PI] <45° and lumbar lordosis [LL] apex below L4; Type 2: PI <45° and LL apex above L4; Type 3:45°<PI <65°; and Type 4: PI >65°). Patients were categorized by increasing severity of Schwab modifiers at BL (0, +, and ++) and further grouped by regional malalignment moving cranially (P: pelvic only; LP: lumbopelvic; TL: thoracic and LP; C: subaxial and TL). Analysis of variance and Pearson's r assessed changes in BL upper cervical parameters (C0-2, C0 slope, McGregor's Slope [MGS], and CBVA) across groups. A total of 343 ASD patients were analyzed. When grouped by BL Schwab and Roussouly, Group P had the lowest BL disability compared to other Groups, while Roussouley Type 1 correlated with higher BL disability compared to Type 2. Moving cranially up the spine, Group P, Group LP, and Group TL did not differ in C0-2 angle, C0 slope, MGS, or CBVA. Group C had a significantly smaller C0-C2, and more negative MGS, C0 slope, and CBVA than noncervical groups. Type 1 trended slightly higher CBVA and MGS than types 2-4, but no differences in cervical lordosis, C0-C2, or C0S were found. MGS (r = -0.131, P = 0.015), CBVA (r = -0.473, P < 0.001), and C0S (r = -0.099, P = 0.042) correlated most strongly with sagittal vertical axis (SVA) compared to other Schwab modifiers. We found SVA > 34 mm predicted a 1 unit (°°) decrease in MGS (odds ratio [OR]: 0.970 [0.948-0.993], P = 0.010), while cervical SVA >51 mm predicted a 1 unit increase in MGS (OR: 1.25 [1.12-1.38], P < 0.001). Our study suggests that upper cervical alignment remains relatively stable through most broad variations of adult TL deformity. Changes in SVA correlated most with upper cervical changes.


Proposed characterization of the syndrome of epidural pneumatosis (pneumorrhachis) in patients with forceful vomiting from diabetic ketoacidosis as a clinico-radiologic pentad based on systematic literature review & an illustrative case report.
Previous literature on epidural pneumatosis (pneumorrhachis, or air in epidural cavity) associated with forceful vomiting in a patient with diabetic ketoacidosis (DKA) has consisted of individual case reports without comprehensive syndrome characterization due to syndromic rarity, with the largest previous literature review comprising 6 cases. Presumed pathophysiology is air escaping from alveolar rupture from forceful vomiting via tissue planes to cause epidural pneumatosis. Systematically review literature to facilitate syndromic diagnosis, evaluation, and treatment. A new illustrative case is reported. Systematic review of literature using 2 independent readers, 2 computerized databases, and the following medical terms/keywords: ["epidural pneumatosis" OR "pneumorrhachis"] AND ["diabetes" OR "diabetic ketoacidosis" or "DKA"]. Discrepancies between 2 readers were resolved by consensus using prospectively developed study inclusion criteria. Two readers independently abstracted case report. Prospective review protocol and patients, problems, intervene, comparison group, outcomes discussed in Methods section of paper. Revealed 10 previously reported cases plus 1 new case (see below) that shows this syndrome presents rather stereotypically with the tentatively proposed following pentad (% of patients fulfilling individual criterion): 1-forceful vomiting (100%), 2-during DKA (100%), 3-pneumomediastinum from forceful alveolar rupture (100%), 4-epidural pneumatosis from air escape from pneumomediastinum (100%), and 5-no complications of Boerhaave syndrome or of focal neurological deficits (100%). Pentad is pathophysiologically reasonable because forceful vomiting can cause alveolar rupture, pneumomediastinum, and air entry into epidural space. Epidural pneumatosis occurred in a 33-year-old-male with poorly controlled diabetes mellitus type 1 who presented with forceful vomiting while in DKA. Radiologic findings also included subcutaneous emphysema, pneumomediastinum, and small pneumothorax. The patient rapidly improved while receiving acute therapy for DKA, and was discharged after 2 hospital days. Limited number of analyzed, retrospectively reported cases. Case reports subject to reporting bias. Specificity, positive predictive value, and negative predictive value not meaningfully analyzed in this homogeneous population. Based on systematic review, syndrome is tentatively proposed as a pentad with: 1-forceful vomiting, 2-during DKA, 3- pneumomediastinum, 4-epidural pneumatosis, and 5-no complications of Boerhaave syndrome or focal neurological deficits. Proposed pentad should be prospectively tested in a larger population including patients with this versus closely related syndromes.


Avian influenza viruses at the wild-domestic bird interface in Egypt.
Wild birds of the orders Anseriformes (mainly ducks, geese and swans) and Charadriiformes (mainly gulls, terns and waders) constitute the natural reservoir for low pathogenic avian influenza (LPAI) viruses. In Egypt, highly pathogenic avian influenza (HPAI) H5N1 and LPAI H9N2 viruses are endemic in domestic poultry, forming a threat to animal and human health and raising questions about the routes of introduction and mechanisms of persistence. Recently, HPAI H5N8 virus was also introduced into Egyptian domestic birds. Here we review the literature on the role of wild birds in the introduction and endemicity of avian influenza viruses in Egypt. Dabbling ducks in Egypt harbor an extensive LPAI virus diversity and may constitute the route of introduction for HPAI H5N1 and HPAI H5N8 viruses into Egypt through migration, however their role in the endemicity of HPAI H5N1, LPAI H9N2 and potentially other avian influenza virus (AIV) strains - by means of reassortment of viral genes - is less clear. Strengthened surveillance programs, in both domestic and wild birds, that include all LPAI virus subtypes and full genome sequencing are needed to better assess the wild-domestic bird interface and form a basis for evidence-based measures to limit and prevent AIV transmission between wild and domestic birds.


Problematic use of energy drinks by adolescents.
Energy drinks (EDs) are caffeine-based beverages that commonly contain large doses of sugar, carbohydrates, and a variety of legal stimulants and supplements, such as guarana, taurine, ginseng, and vitamin B complex. These drinks are marketed for young people as natural alternatives that increase fun and improve physical and cognitive performance such as concentration, attention, and alertness. There are commonly held false perceptions that the consumption of EDs can reverse alcohol-related impairment, including motor coordination and visual reaction time, which are crucial for driving safety. This article reviews the literature on EDs and examines problematic use and potential negative consequences in young people. Special emphasis is devoted to safety concerns following combination of EDs with alcohol, which gives the user a false sense of control.


Selected pro- and anti-inflammatory cytokines in cerebrospinal fluid in normal pressure hydrocephalus.
Normal pressure hydrocephalus (NPH) is a treatable neurological syndrome developing in the elderly. It is characterized by balance impairment, urinary incontinence and dementia development caused by disorders in the cerebrospinal fluid (CSF) circulation. The diagnosis can be easily mistaken for other neurodegenerative diseases, which are often accompanied by inflammation and the production of cytokines. The aim of our study was to determine and compare selected CSF and plasma cytokines with respect to their informative value for laboratory diagnostics of NPH. The levels of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in the CSF and plasma in age-matched subjects with NPH (n=20) and controls (n=20) by multiplex assay. CSF IL-1β, IL-6 and IL-10 were significantly increased on the 1st day of lumbar drainage in NPH (p<0.01). No significant changes were observed in the plasma. The CSF cytokines were one to three orders of magnitude higher compared to the plasma. CSF can better show the neurodegenerative changes in the brain. The cytokines IL-1β, IL-6 and IL-10 may be helpful in NPH diagnostics.


Parasite rearing and infection temperatures jointly influence disease transmission and shape seasonality of epidemics.
Seasonal epidemics erupt commonly in nature and are driven by numerous mechanisms. Here, we suggest a new mechanism that could determine the size and timing of seasonal epidemics: rearing environment changes the performance of parasites. This mechanism arises when the environmental conditions in which a parasite is produced impact its performance-independently from the current environment. To illustrate the potential for "rearing effects", we show how temperature influences infection risk (transmission rate) in a Daphnia-fungus disease system through both parasite rearing temperature and infection temperature. During autumnal epidemics, zooplankton hosts contact (eat) fungal parasites (spores) reared in a gradually cooling environment. To delineate the effect of rearing temperature from temperature at exposure and infection, we used lab experiments to parameterize a mechanistic model of transmission rate. We also evaluated the rearing effect using spores collected from epidemics in cooling lakes. We found that fungal spores were more infectious when reared at warmer temperatures (in the lab and in two of three lakes). Additionally, the exposure (foraging) rate of hosts increased with warmer infection temperatures. Thus, both mechanisms cause transmission rate to drop as temperature decreases over the autumnal epidemic season (from summer to winter). Simulations show how these temperature-driven changes in transmission rate can induce waning of epidemics as lakes cool. Furthermore, via thermally dependent transmission, variation in environmental cooling patterns can alter the size and shape of epidemics. Thus, the thermal environment drives seasonal epidemics through effects on hosts (exposure rate) and the infectivity of parasites (a rearing effect). Presently, the generality of parasite rearing effects remains unknown. Our results suggest that they may provide an important but underappreciated mechanism linking temperature to the seasonality of epidemics.


Feel the Time. Time Perception as a Function of Interoceptive Processing.
The nature of time is rooted in our body. Constellations of impulses arising from the flesh constantly create our interoceptive perception and, in turn, the unfolding of these perceptions defines human awareness of time. This study explored the connection between time perception and interoception and proposes the Interoceptive Buffer saturation (IBs) index. IBs evaluates subjects' ability to process salient stimuli from the body by measuring subjective distortions of interoceptive time perception, i.e., the estimated duration of tactile interoceptive stimulations. Thirty female healthy subjects were recruited through consecutive sampling and assessed for common variables related to interoceptive alterations: depressive symptoms (Beck Depression Inventory, BDI-II), eating disorders (EDI-3) risk, and anxiety levels (State Trait Anxiety Inventory, STAI). Interoceptive cardiac accuracy (IAc) was assessed as well. Subjects performed verbal time estimation of interoceptive stimuli (IBs) delivered using a specifically designed interoceptive tactile stimulator, as well as verbal time estimation of visual and auditory stimuli. Results showed that IBs index positively correlated with IAc, and negatively with EDI-3 Drive for Thinness (DT) risk subscale. Moreover, IBs index was positively predicted by IAc, and negatively predicted by DT and somatic factors of depression. Our results suggest that underestimations in interoceptive time perception are connected to different psychological conditions characterized by a diminished processing of high salience stimuli from the body. Conversely, overestimations of the duration of interoceptive stimuli appear to be function of subjects' ability to correctly perceive their own bodily information. Evidence supported IBs index, fostering the concept of interoceptive treatments for clinical purposes.


Study of anemia in long-term care (SALT): prevalence of anemia and its relationship with the risk of falls in nursing home residents.
The objectives of the current study were twofold. First, this study examined the prevalence of anemia in nursing home residents in the USA and its relationship with key resident characteristics and medical conditions. Second, the study explored whether an association between anemia and falls is evident in this same population. Chart review was conducted in 40 nursing homes across the USA. Residents were randomly sampled and considered eligible if they: were > or =18 years of age; had > or =1 hemoglobin (Hb) level reported during the data uptake period of 1/1/04-2/1/05 (first occurrence defined as index Hb); had a recorded serum creatinine level; maintained residency in the facility; and did not receive dialysis during the 6-month post-index follow-up period. Resident demographics, laboratory values, comorbid conditions, medication regimens, falling events, physical functioning measures, and hospitalizations were obtained from chart data. The relationship between selected resident characteristics and comorbidities was explored with index Hb level, using multiple linear regression. Logistic regression was used to analyze the relationship between falling and recurrent falls with anemia (index Hb < 13 g/dL and < 12 g/dL in men and women > or =15 years, respectively) adjusting for selected variables presumed to be related to falls. Study limitations include the retrospective design and limited follow-up, potential for biased selection of relevant covariates, gaps in time between index Hb levels and falling events, non-random selection of nursing homes, limits to quality and detail in data extracted from residents' medical charts, and confounding of anemia therapy with index hemoglobin level. A total of 564 sampled residents met the criteria for data completeness and were retained for analysis; of these, 70% were female. Mean age was 81 +/- 12.3 years (+/-SD). Mean index Hb level was 11.9 +/- 1.8 g/dL (12.2 +/- 2.0 for males, 11.7 +/- 1.6 for females). Of all residents studied, 56% were identified as anemic (64% males, 53% females) from index Hb level. In all, 53% of anemic residents were receiving an identified therapy, with 72% of these treated residents receiving iron. None received an erythropoietic-stimulating agent (ESA). For index Hb level, the regression coefficient was significant for female (p = 0.002), African-American race (p = 0.012), glomerular filtration rate (GFR) < 60 mL/min/1.73 m(2) (p < 0.001), diabetes (p = 0.004), cancer (p < 0.001), asthma (p = 0.002), GI bleeding (p = 0.012), and inflammatory disease (p = 0.039). Except for asthma, these factors were associated with a decrease in Hb. In the regression model for the dependent variable of falling, anemia (OR = 2.26, p = 0.001), psychoactive medication use (OR = 2.18, p = 0.001), and age 85+ years (OR = 2.08, p = 0.016) were associated with more than twice the risk of falling. Anemia in nursing home residents appears to be under-recognized. For residents over 70 years, the prevalence of anemia in both male and female residents was approximately four times the rate reported in a study of older community dwellers (Salive et al., 1992). Both anemia and the use of psychoactive medications are potentially modifiable factors strongly associated with falling. Since falls and related fractures are events associated with high morbidity and mortality, each of these factors deserves special consideration for potentially reducing the risk of such events in the nursing home.


Nonadherence in patients with breast cancer receiving oral therapies.
Adherence is a potentially significant issue in oral therapy for breast cancer. Suboptimal adherence to medication regimens impacts clinical benefit and can result in treatment resistance, disease progression, and even death. Nonadherence is a greater issue with oral medications because the majority of responsibility shifts from healthcare professionals to the patient. Improving adherence to medication regimens can impact patients' likelihood of successful clinical outcomes. Many factors contribute to adherence behavior, such as complex dosing or administration requirements, cost, and a lack of understanding of the importance of adherence. Most of the factors are controlled by the patient, but nurses can play a significant role by monitoring patients, identifying potential barriers to adherence, and implementing intervention strategies. If barriers to adherence with oral therapies cannot be overcome, the use of IV therapies with equivalent efficacy and acceptable safety should be considered. Using IV medication, when available, can improve outcomes by ensuring that the patient receives the correct and optimal dose of medication at every cycle.


Experimental analysis of co-evolution within protein complexes: the yeast exosome as a model.
Extensive bioinformatics analysis suggests that the stability and function of protein complexes are maintained throughout evolution by coordinated changes (co-evolution) of complex subunits. Yet, relatively little is known regarding the actual dynamics of such processes and the functional implications of co-evolution within protein complexes, since most of the bioinformatics predictions were not analyzed experimentally. Here, we describe a systematic experimental approach that allows a step-by-step observation of the co-evolution process in protein complexes. The exosome complex, an essential complex exhibiting a 3'→5' RNA degradation activity, served as a model system. In this study, we show that exosome subunits diverged very early during fungal evolution. Interestingly, we found that despite significant differences in conservation between Rrp41 and Mtr3 both subunits exhibit similar divergence pattern and co-evolutionary behavior through fungi evolution. Activity analysis of mutated exosomes exposes another layer of co-evolution between the core subunits and RNA substrates. Overall, our approach allows the experimental analysis of co-evolution within protein complexes and together with bioinformatics analysis can significantly deepen our understanding of the evolution of these complexes.


Characterizing the information content of a newly hatched chick's first visual object representation.
How does object recognition emerge in the newborn brain? To address this question, I examined the information content of the first visual object representation built by newly hatched chicks (Gallus gallus). In their first week of life, chicks were raised in controlled-rearing chambers that contained a single virtual object rotating around a single axis. In their second week of life, I tested whether subjects had encoded information about the identity and viewpoint of the virtual object. The results showed that chicks built object representations that contained both object identity information and view-specific information. However, there was a trade-off between these two types of information: subjects who were more sensitive to identity information were less sensitive to view-specific information, and vice versa. This pattern of results is predicted by iterative, hierarchically organized visual processing machinery, the machinery that supports object recognition in adult primates. More generally, this study shows that invariant object recognition is a core cognitive ability that can be operational at the onset of visual object experience.


Evolutionary tipping points in the capacity to adapt to environmental change.
In an era of rapid climate change, there is a pressing need to understand how organisms will cope with faster and less predictable variation in environmental conditions. Here we develop a unifying model that predicts evolutionary responses to environmentally driven fluctuating selection and use this theoretical framework to explore the potential consequences of altered environmental cycles. We first show that the parameter space determined by different combinations of predictability and timescale of environmental variation is partitioned into distinct regions where a single mode of response (reversible phenotypic plasticity, irreversible phenotypic plasticity, bet-hedging, or adaptive tracking) has a clear selective advantage over all others. We then demonstrate that, although significant environmental changes within these regions can be accommodated by evolution, most changes that involve transitions between regions result in rapid population collapse and often extinction. Thus, the boundaries between response mode regions in our model correspond to evolutionary tipping points, where even minor changes in environmental parameters can have dramatic and disproportionate consequences on population viability. Finally, we discuss how different life histories and genetic architectures may influence the location of tipping points in parameter space and the likelihood of extinction during such transitions. These insights can help identify and address some of the cryptic threats to natural populations that are likely to result from any natural or human-induced change in environmental conditions. They also demonstrate the potential value of evolutionary thinking in the study of global climate change.


Active Involvement of End Users When Developing Web-Based Mental Health Interventions.
Although many web-based mental health interventions are being released, the actual uptake by end users is limited. The marginal level of engagement of end users when developing these interventions is recognized as an important cause for uptake problems. In this paper, we offer our perceptive on how to improve user engagement. By doing so, we aim to stimulate a discourse on user involvement within the field of online mental health interventions. We shortly describe three different methods (the expert-driven method, intervention mapping, and scrum) that were currently used to develop web-based health interventions. We will focus to what extent the end user was involved in the developmental phase, and what the additional challenges were. In the final paragraph, lessons learned are summarized, and recommendations provided. Every method seems to have its trade-off: if end users are highly involved, availability of end users and means become problematic. If end users are less actively involved, the product may be less appropriate for the end user. Other challenges to consider are the funding of the more active role of technological companies, and the time it takes to process the results of shorter development cycles. Thinking about user-centered design and carefully planning, the involvement of end users should become standard in the field of web-based (mental) health. When deciding on the level of user involvement, one should balance the need for input from users with the availability of resources such as time and funding.


Light-stimulated degradation of an unassembled Rieske FeS protein by a thylakoid-bound protease: the possible role of the FtsH protease.
Unassembled subunits of the cytochrome b6f complex as well as components of other unassembled chloroplastic complexes are rapidly degraded within the organelle. However, the mechanisms involved in these proteolytic processes are obscure. When the Rieske FeS protein (RISP) is imported into isolated chloroplasts in vitro, some of the protein does not property assemble with the cytochrome complex, as determined by its sensitivity to exogenous protease. When assayed in intact, lysed, or fractionated chloroplasts, the imported RISP was found to be sensitive to endogenous proteases as well. The activity responsible for degradation of the unassembled protein was localized to the thylakoid membrane and characterized as a metalloprotease requiring zinc ions for its activity. The degradation rate was stimulated by light, but no involvement of ATP or redox control was observed. Instead, when the RISP that was attached to thylakoid membranes was first illuminated on ice, degradation proceeded in either light or darkness at equal rates suggesting a light-induced conformational change making the protein prone to degradation. Antibodies raised against native FtsH, a bacterial, membrane-bound, ATP-dependent, zinc-stimulated protease, effectively inhibited degradation of the unassembled RISP, suggesting a role for the chloroplastic FtsH in this process.


Quantification of individual sensitivities to ethanol in selective breeding experiments: difference scores versus regression residuals.
Nagoshi et al. (Alcohol Clin Exp Res 10:343-349, 1986) have argued recently that the use of postdrug minus predrug difference scores to assess individual variability in sensitivity or tolerance to ethanol is not to be recommended. Unreliability of variables can result in biased estimates of response to treatment. Instead of difference scores, they recommend using residual scores from the regression of posttreatment on pretreatment measures. We were interested in the consequences of employing difference scores versus regression residuals for a related, but different purpose: the choice of individual animals to be mated for a selective breeding study. The availability of data from such a selective breeding experiment ongoing in the laboratory of one of us (JCC) allowed us to compare directly the effects of use of change and residual scores as criteria for selection. The selection is for maximal hypothermic sensitivity of mice to an acute dose of ethanol. In our sample, difference scores were highly correlated with regression residuals. In practical terms, almost 75% of the individuals chosen for mating by the change score method would also have been chosen by the residual score method. We conclude that for selective breeding experiments, the use of difference scores does not necessarily introduce sampling bias, is unlikely to affect the ultimate outcome of selection, and may be a more meaningful variable for the physiological process studied.


Light insensitive silver(I) cyanoximates as antimicrobial agents for indwelling medical devices.
Ten silver(I) cyanoximates of AgL composition (L = NC-C(NO)-R, where R is electron withdrawing groups: -CN, -C(O)NR(2), -C(O)R' (alkyl), -C(O)OEt, 2-heteroaryl fragments such as 2-pyridyl, 2-benzimidazolyl, 2-benzoxazolyl, 2-benzthiazolyl) were synthesized and characterized using spectroscopic methods and X-ray analysis. Crystal structures of four complexes were determined and revealed the formation of two-dimensional (2D) coordination polymers of different complexity in which anions exhibit bridging or combined chelate and bridging binding modes. In these compounds, anions are in the nitroso form. All studied AgL complexes are sparingly soluble in water and are thermally stable to 150 °C. Synthesized compounds demonstrated remarkable insensitivity toward visible light and UV-radiation, which was explained based on their polymeric structures with multiple covalent bonds between bridging cyanoxime ligands and Ag(I) centers. All 10 silver(I) cyanoximates were tested in vitro on the subject of their antimicrobial activity against both Gram-positive and Gram-negative microorganisms such as Escherichia coli, Klebsiella pneumoniae, Proteus sp., Pseudomonas aeruginosa, Enterococcus hirae, Streptococcus mutans, Staphylococcus aureus, and Mycobacterium fortuitum as well as against Candida albicans in solutions, and in the solid state as pressed pellets and dried filter paper disks presoaked with solutions of AgL in DMF. Results showed pronounced antimicrobial activity for all investigated complexes. A combination of five factors: (1) light insensitivity, (2) poor water solubility, (3) high thermal stability, (4) lack of toxicity of organic ligands, and (5) in vitro antimicrobial activity allows development of silver(I) cyanoximates for medical applications. These include antimicrobial additives to acrylate glue, cured by UV-radiation, used in introduction of prosthetic joints and dental implants, and prevention of biofilm formation on several types of indwelling medical devices.


Preexisting semantic representation improves working memory performance in the visuospatial domain.
Working memory (WM) for spoken language improves when the to-be-remembered items correspond to preexisting representations in long-term memory. We investigated whether this effect generalizes to the visuospatial domain by administering a visual n-back WM task to deaf signers and hearing signers, as well as to hearing nonsigners. Four different kinds of stimuli were presented: British Sign Language (BSL; familiar to the signers), Swedish Sign Language (SSL; unfamiliar), nonsigns, and nonlinguistic manual actions. The hearing signers performed better with BSL than with SSL, demonstrating a facilitatory effect of preexisting semantic representation. The deaf signers also performed better with BSL than with SSL, but only when WM load was high. No effect of preexisting phonological representation was detected. The deaf signers performed better than the hearing nonsigners with all sign-based materials, but this effect did not generalize to nonlinguistic manual actions. We argue that deaf signers, who are highly reliant on visual information for communication, develop expertise in processing sign-based items, even when those items do not have preexisting semantic or phonological representations. Preexisting semantic representation, however, enhances the quality of the gesture-based representations temporarily maintained in WM by this group, thereby releasing WM resources to deal with increased load. Hearing signers, on the other hand, may make strategic use of their speech-based representations for mnemonic purposes. The overall pattern of results is in line with flexible-resource models of WM.


Spatial-temporal analysis of breast cancer in upper Cape Cod, Massachusetts.
The reasons for elevated breast cancer rates in the upper Cape Cod area of Massachusetts remain unknown despite several epidemiological studies that investigated possible environmental risk factors. Data from two of these population-based case-control studies provide geocoded residential histories and information on confounders, creating an invaluable dataset for spatial-temporal analysis of participants' residency over five decades. The combination of statistical modeling and mapping is a powerful tool for visualizing disease risk in a spatial-temporal analysis. Advances in geographic information systems (GIS) enable spatial analytic techniques in public health studies previously not feasible. Generalized additive models (GAMs) are an effective approach for modeling spatial and temporal distributions of data, combining a number of desirable features including smoothing of geographical location, residency duration, or calendar years; the ability to estimate odds ratios (ORs) while adjusting for confounders; selection of optimum degree of smoothing (span size); hypothesis testing; and use of standard software. We conducted a spatial-temporal analysis of breast cancer case-control data using GAMs and GIS to determine the association between participants' residential history during 1947-1993 and the risk of breast cancer diagnosis during 1983-1993. We considered geographic location alone in a two-dimensional space-only analysis. Calendar year, represented by the earliest year a participant lived in the study area, and residency duration in the study area were modeled individually in one-dimensional time-only analyses, and together in a two-dimensional time-only analysis. We also analyzed space and time together by applying a two-dimensional GAM for location to datasets of overlapping calendar years. The resulting series of maps created a movie which allowed us to visualize changes in magnitude, geographic size, and location of elevated breast cancer risk for the 40 years of residential history that was smoothed over space and time. The space-only analysis showed statistically significant increased areas of breast cancer risk in the northern part of upper Cape Cod and decreased areas of breast cancer risk in the southern part (p-value = 0.04; ORs: 0.90-1.40). There was also a significant association between breast cancer risk and calendar year (p-value = 0.05; ORs: 0.53-1.38), with earlier calendar years resulting in higher risk. The results of the one-dimensional analysis of residency duration and the two-dimensional analysis of calendar year and duration showed that the risk of breast cancer increased with increasing residency duration, but results were not statistically significant. When we considered space and time together, the maps showed a large area of statistically significant elevated risk for breast cancer near the Massachusetts Military Reservation (p-value range:0.02-0.05; ORs range: 0.25-2.5). This increased risk began with residences in the late 1940s and remained consistent in size and location through the late 1950s. Spatial-temporal analysis of the breast cancer data may help identify new exposure hypotheses that warrant future epidemiologic investigations with detailed exposure models. Our methods allow us to visualize breast cancer risk, adjust for known confounders including age at diagnosis or index year, family history of breast cancer, parity and age at first live- or stillbirth, and test for the statistical significance of location and time. Despite the advantages of GAMs, analyses are for exploratory purposes and there are still methodological issues that warrant further research. This paper illustrates that GAM methods are a suitable alternative to widely-used cluster detection methods and may be preferable when residential histories from existing epidemiological studies are available.


Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome.
We determined prospectively the incidence of chromosomal abnormalities in patients with high-risk breast cancer (HRBC) after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), and correlated the cytogenetic abnormalities with the development of post-transplant myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). From 1990 to 1999, 229 women with HRBC underwent ASCT. Cytogenetic analysis of bone marrow (BM) cells was performed 12-59 months after ASCT in 60 consecutive women uniformly treated with six courses of FAC/FEC followed by HDCT and ASCT. With a median follow-up of 36 months after ASCT, there were no cases of MDS/AML among the 229 patients. In the selected cohort of 60 patients, three (5%) showed clonal chromosomal abnormalities (two single trisomy X and one t(1;6)), whereas two additional patients showed non-clonal reciprocal translocations. Two of the patients with clonal aberrations had blood cytopenias as well as subtle dysplastic pictures in BM which were not classifiable as MDS according to the FAB criteria. Similar dysplastic features were also observed in four patients with normal karyotypes. All cytogenetic aberrations were transient and disappeared, except a +X detected by FISH in a residual cell population in one of the patients. Retrospective cytogenetic and FISH studies of samples obtained after six cycles of FAC/FEC and before transplant demonstrated no chromosomal abnormalities in any of the five patients with post-ASCT karyotypic changes. Early changes in karyotype detected in breast cancer patients following ASCT are transient and do not correlate with or predict development of MDS/AML. As these aberrations were not present before ASCT, they may be related to the HDCT regimen or transplant procedure rather than to the prior adjuvant therapy. Our results suggest that ASCT may be less likely to cause MDS or AML in breast cancer patients as compared to other malignancies. Bone Marrow Transplantation (2000) 25, 1203-1208.


Constellation of phase singularities in a speckle-like pattern for optical vortex metrology applied to biological kinematic analysis.
A novel technique for biological kinematic analysis is proposed that makes use of the pseudophase singularities in a complex signal generated from a speckle-like pattern. In addition to the information about the locations and the anisotropic core structures of the pseudophase singularities, we also detect the spatial structures of a cluster of phase singularities, which serves as a unique constellation characterizing the mutual position relation between the individual pseudophase singularities. Experimental results of in vivo measurements for a swimming fish along with its kinematic analysis are presented, which demonstrate the validity of the proposed technique.


The role of food quality and competition in shaping the seasonal cycle in the reproductive activity of the sycamore aphid.
The hypothesis that seasonal changes in sycamore aphid,Drepanosiphum platanoidis (Schr.), recruitment are determined by changes in food quality and aphid population density was tested. There was no clear association between the reproductive activity of the sycamore aphid and the seasonal changes in specific amino acids or groups of amino acids in extracts of sycamore,Acer pseudoplatanus L., leaves. Seasonal changes in reproductive activity tracked the changes in total amino acids of the leaf tissue of the host, but with a short time delay. High numbers of adult aphids appeared to depress reproductive activity. A regression analysis of the results revealed that total amino acids the previous week and current numbers of adult aphids significantly affected sycamore aphid reproductive activity. The results of this analysis support the above hypothesis, that the marked seasonal changes in the total quantity of amino acids in sycamore leaves and intraspecific competition for this resource, through its effect on adult weight, shape the seasonal cycle in the reproductive activity of the sycamore aphid.


A Novel Educational Control Group Mobile App for Meditation Interventions: Single-Group Feasibility Trial.
Smartphone ownership is becoming ubiquitous among US adults, making the delivery of health interventions via a mobile app (ie, mobile health [mHealth]) attractive to many researchers and clinicians. Meditation interventions have become popular and have been delivered to study participants via mobile apps to improve a range of health outcomes in both healthy adults and those with chronic diseases. However, these meditation mHealth interventions have been limited by a lack of high-quality control groups. More specifically, these studies have lacked consistency in their use of active, time-matched, and attention-matched control groups. The purpose of this study is to beta test a novel health education podcast control condition delivered via a smartphone app that would be a strong comparator to be used in future studies of app-based meditation interventions. Patients with myeloproliferative neoplasm (MPN) cancer were recruited nationally. Upon enrollment, participants were informed to download the investigator-developed health education podcast app onto their mobile phone and listen to ~60 min/week of cancer-related educational podcasts for 12 weeks. The benchmarks for feasibility included ≥70% of participants completing ≥70% of the prescribed 60 min/week of podcasts, ≥70% of participants reporting that they were satisfied with the intervention, and ≥70% of participants reporting that they enjoyed the health education podcasts. A total of 96 patients with MPN were enrolled in the study; however, 19 never began the intervention. Of the 77 patients who participated in the intervention, 39 completed the entire study (ie, sustained participation through the follow-up period). Participation averaged 103.2 (SD 29.5) min/week. For 83.3% (10/12) of the weeks, at least 70% of participants completed at least 70% of their total prescribed use. Almost half of participants reported that they enjoyed the health education podcasts (19/39, 48.7%) and were satisfied with the intervention (17/39, 43.6%). There were no significant changes in cancer-related outcomes from baseline to postintervention. A 12-week, health education podcast mobile app was demanded but not accepted in a sample of patients with cancer. Using the mobile app was not associated with significant changes in cancer-related symptoms. Based on findings from this study, a health education podcast mobile app may be a feasible option as a time- and attention-matched control group for efficacy trials with more extensive formative research for the content of the podcasts and its acceptability by the specific population. ClinicalTrials.gov NCT03907774; https://clinicaltrials.gov/ct2/show/NCT03907774.


Characterization of an iron-sulfur cluster assembly protein (ISU1) from Schizosaccharomyces pombe.
Genetic studies of bacteria and eukaryotes have led to identification of several gene products that are involved in the biosynthesis of protein-bound iron-sulfur clusters. One of these proteins, ISU, is homologous to the N-terminus of bacterial NifU. The mature forms of His-tagged wild-type and D37A Schizosaccharomyces pombe ISU1 were cloned and overexpressed as inclusion bodies in Escherichia coli. The recombinant D37A protein was purified under denaturing conditions and subsequently reconstituted in vitro. By use of a 5-fold excess of iron and sulfide the reconstituted product was found to be red-brown in color, forming a homodimer of 17 kDa per subunit with approximately two iron atoms per monomer determined by protein and iron quantitation. UV-vis absorption and Mössbauer spectroscopies (delta = 0.29 +/- 0.05 mm/s; DeltaE(Q) = 0.59 +/- 0.05 mm/s) were used to characterize D37A ISU1 and show the presence of [2Fe-2S](2+) clusters in each subunit. Formation of the holo form of wild-type ISU1 was significantly less efficient using the same reconstitution conditions and is consistent with prior observations that the D37A substitution can stabilize protein-bound clusters. Relative to the human homologue, the yeast ISU is significantly less soluble at ambient temperatures. In both cases the native ISU1 is more sensitive to proton-mediated degradation relative to the D37A derivative. The lability of this family of proteins relative to [2Fe-2S] bearing ferredoxins most likely is of functional relevance for cluster transfer chemistry. Mössbauer parameters obtained for wild-type ISU1 (delta = 0.31 +/- 0.05 mm/s; DeltaE(Q) = 0.64 +/- 0.05 mm/s) were similar to those obtained for the D37A derivative. Cluster transfer from ISU1 to apo Fd is demonstrated: the first example of transfer from an ISU-type protein. A lower limit for k(2) of 80 M(-1) min(-1) was established for WT cluster transfer and a value of 18 M(-1) min(-1) for the D37A derivative. Finally, we have demonstrated through cross-linking studies that ferredoxin, an electron-transport protein, forms a complex with ISU1 in both apo and holo states. Cross-linking of holo ISU1 with holo Fd is consistent with a role for redox chemistry in cluster assembly and may mimic the intramolecular complex already defined in NifU.


History of wildlife toxicology.
The field of wildlife toxicology can be traced to the late nineteenth and early twentieth centuries. Initial reports included unintentional poisoning of birds from ingestion of spent lead shot and predator control agents, alkali poisoning of waterbirds, and die-offs from maritime oil spills. With the advent of synthetic pesticides in the 1930s and 1940s, effects of DDT and other pesticides were investigated in free-ranging and captive wildlife. In response to research findings in the US and UK, and the publication of Silent Spring in 1962, public debate on the hazards of pollutants arose and national contaminant monitoring programs were initiated. Shortly thereafter, population-level effects of DDT on raptorial and fish-eating birds were documented, and effects on other species (e.g., bats) were suspected. Realization of the global nature of organochlorine pesticide contamination, and the discovery of PCBs in environmental samples, launched long-range studies in birds and mammals. With the birth of ecotoxicology in 1969 and the establishment of the Society of Environmental Toxicology and Chemistry in 1979, an international infrastructure began to emerge. In the 1980s, heavy metal pollution related to mining and smelting, agrichemical practices and non-target effects, selenium toxicosis, and disasters such as Chernobyl and the Exxon Valdez dominated the field. Biomarker development, endocrine disruption, population modeling, and studies with amphibians and reptiles were major issues of the 1990s. With the turn of the century, there was interest in new and emerging compounds (pharmaceuticals, flame retardants, surfactants), and potential population-level effects of some compounds. Based upon its history, wildlife toxicology is driven by chemical use and misuse, ecological disasters, and pollution-related events affecting humans. Current challenges include the need to more thoroughly estimate and predict exposure and effects of chemical-related anthropogenic activities on wildlife and their supporting habitat.


Vascular access in hemodialysis patients older than 80 years.
There is a worldwide surge in numbers of elderly people requiring hemodialysis accompanying the prevailing increase in longevity. There is a trend for central venous catheters to be preferentially placed in elderly patients, whereas others recommend routine use of grafts for surgical access. In our center, age has not been a consideration in deciding to construct arteriovenous access for hemodialysis. We reviewed our experience with arteriovenous access surgery in all hemodialysis patients aged 80 years and older to determine if this approach is justified in terms of patency and life expectancy. A retrospective study was made of all patients aged 80 years and older who had surgery from January 2005 to December 2009 at our national vascular access referral center. All patients had preoperative mapping and had fistula construction if the vein size was at least 3 mm. Otherwise they had brachiobasilic or brachioaxillary grafts. All patients had routine access surveillance by Doppler ultrasound (duplex) and physical examination at regular intervals, and interventions were carried out according to the findings. Type of access, success rate, maturation, primary and secondary patency, and patient survival in the age group older than 80 years were noted. During the study period, 134 patients had 146 new accesses. There were 128 autogenous accesses (30 forearm, 91 upper arm, and seven transposed basilic veins) and 18 prosthetic accesses. Overall primary patency was 39%, 33%, and 23% at 12, 24, and 36 months. Secondary patency was 92%, 83%, and 77% at 12, 24, and 36 months. There was no significant difference in patency between the different types of accesses and between diabetic and nondiabetic patients. Eleven upper arm and four forearm fistulas had delayed maturation or nonmaturation. The relative risk for delayed maturation or nonmaturation of forearm fistulas (13.3%) compared with brachial-cephalic fistula (12.1%) was 1.1030 (95% confidence interval, 0.3973-3.204; P = .8571). Median patient survival was 38 months, with 49 dying during follow-up. Contrary to recent recommendations favoring grafts for hemodialysis in patients older than 80 years, most elderly patients in this study were found to have vasculature that was suitable for autogenous access construction, with patency rates similar to those of their younger counterparts when adequate preoperative planning and postoperative maintenance were carried out. Age alone should not disqualify patients older than 80 years from access surgery for hemodialysis, nor should age disqualify these patients from the Fistula First Initiative.


Surface-orientation- and ligand-dependent quenching of the spin magnetic moment of Co porphyrins adsorbed on Cu substrates.
Porphyrin molecules are particularly interesting candidates for spintronic applications due to their bonding flexibility, which allows to modify their properties substantially by the addition or transformation of ligands. Here, we investigate the electronic and magnetic properties of cobalt octaethylporphyrin (CoOEP), deposited on copper substrates with two distinct crystallographic surface orientations, Cu(100) and Cu(111), with X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD). A significant magnetic moment is present in the Co ions of the molecules deposited on Cu(100), but it is completely quenched on Cu(111). Heating the molecules on both substrates to 500 K induces a ring-closure reaction with cobalt tetrabenzoporphyrin (CoTBP) as reaction product. In these molecules, the magnetic moment is quenched on both surfaces. Our XMCD and XAS measurements suggest that the filling of the dz2 orbital leads to a non-integer valence state and causes the quench of the spin moments on all samples except CoOEP/Cu(100), where the molecular conformation induces variations to the ligand field that lift the quench. We further employ density functional theory calculations, supplemented with on-site Coulomb correlations (DFT+U), to study the adsorption of these spin-bearing molecules on the Cu substrates. Our calculations show that charge transfer from the Cu substrates as well as charge redistribution within the Co 3d orbitals lead to the filling of the Co minority spin dz2 orbital, causing a 'turning off' of the exchange splitting and quenching of the spin moment at the Co magnetic centers. Our investigations suggest that, by this mechanism, molecule-substrate interactions can be used to control the quenching of the magnetic moments of the adsorbed molecules.


Integrating technology into standard weight loss treatment: a randomized controlled trial.
A challenge in intensive obesity treatment is making care scalable. Little is known about whether the outcome of physician-directed weight loss treatment can be improved by adding mobile technology. We conducted a 2-arm, 12-month study (October 1, 2007, through September 31, 2010). Seventy adults (body mass index >25 and ≤40 [calculated as weight in kilograms divided by height in meters squared]) were randomly assigned either to standard-of-care group treatment alone (standard group) or to the standard and connective mobile technology system (+mobile group). Participants attended biweekly weight loss groups held by the Veterans Affairs outpatient clinic. The +mobile group was provided personal digital assistants to self-monitor diet and physical activity; they also received biweekly coaching calls for 6 months. Weight was measured at baseline and at 3-, 6-, 9-, and 12-month follow-up. Sixty-nine adults received intervention (mean age, 57.7 years; 85.5% were men). A longitudinal intent-to-treat analysis indicated that the +mobile group lost a mean of 3.9 kg more (representing 3.1% more weight loss relative to the control group; 95% CI, 2.2-5.5 kg) than the standard group at each postbaseline time point. Compared with the standard group, the +mobile group had significantly greater odds of having lost 5% or more of their baseline weight at each postbaseline time point (odds ratio, 6.5; 95% CI, 2.5-18.6). The addition of a personal digital assistant and telephone coaching can enhance short-term weight loss in combination with an existing system of care. Mobile connective technology holds promise as a scalable mechanism for augmenting the effect of physician-directed weight loss treatment. clinicaltrials.gov Identifier: NCT00371462.


Human Papillomavirus (HPV) Genotyping Assay Suitable for Monitoring the Impact of the 9-Valent HPV Vaccine.
In Japan, a bivalent human papillomavirus (HPV) vaccine against carcinogenic HPV16/18 was licensed in 2009, and a quadrivalent vaccines against HPV16/18 and non-carcinogenic HPV6/11 was licensed in 2011. Recently, the next-generation 9-valent vaccine targeting HPV6/11/16/18/31/33/45/52/58 has been approved. Accurate HPV genotyping is essential for HPV vaccine research and surveillance. The Roche Linear Array (LA) has long been a standard assay for HPV genotyping, but its recent product discontinuation notice has urged us to introduce an alternative assay with comparable performance. In the present study, an in-house HPV genotyping assay that employs PCR with PGMY09/11 primers and reverse blotting hybridization (PGMY-CHUV) was compared with LA to assess genotype-specific agreement. A total of 100 cervical precancer specimens were subjected to both PGMY-CHUV and LA. For detection of genotypes included in the 9-valent vaccine, PGMY-CHUV completely agreed with LA for detection of HPV6, HPV11, HPV16, HPV18, HPV33 and HPV45, and showed near-complete agreement for HPV31 and HPV58 (98% and 99%, respectively). Moreover, PGMY-CHUV detected a significantly higher prevalence of HPV52 than LA (22% vs. 14%, P = 0.008 by McNemar's exact test), with 92.0% overall agreement, 63.6% positive agreement and a kappa value of 0.73. Most (87.5%) of HPV52 discordant cases involved mixed infections with HPV35 or HPV58. In conclusion, while the two assays present equivalent data for assessing the effectiveness of the bivalent and quadrivalent vaccines, PGMY-CHUV is more suitable for evaluating the impact of the current 9-valent vaccine because of its superior detection of HPV52 in co-infection cases.


Serial measurement of the C-reactive protein is a poor predictor of treatment outcome in prosthetic joint infection.
Prosthetic joint infection is usually treated using surgery and antibiotics. The response to the treatment regimen is often evaluated using serial monitoring of plasma C-reactive protein (CRP) concentrations. In order to examine how useful this monitoring is, we calculated the sensitivity and specificity of CRP concentrations for predicting treatment failure. We examined 3732 CRP measurements from 260 patients who were treated by either two-stage revision or debridement and retention. We tested the association between CRP concentration and outcome using logistic regression models, and assessed sensitivity and specificity by using receiver operator curves. The areas under receiver operator curves for CRP concentrations predicting outcome ranged from 0.55 to 0.65. CRP concentrations did not accurately predict treatment failure. Serial monitoring may not be of benefit.


Correlation between volumetric oxygenation responses and electrophysiology identifies deep thalamocortical activity during epileptic seizures.
Visualization of whole brain activity during epileptic seizures is essential for both fundamental research into the disease mechanisms and the development of efficient treatment strategies. It has been previously discussed that pathological synchronization originating from cortical areas may reinforce backpropagating signaling from the thalamic neurons, leading to massive seizures through enhancement of high frequency neural activity in the thalamocortical loop. However, the study of deep brain neural activity is challenging with the existing functional neuroimaging methods due to lack of adequate spatiotemporal resolution or otherwise insufficient penetration into subcortical areas. To investigate the role of thalamocortical activity during epileptic seizures, we developed a new functional neuroimaging framework based on spatiotemporal correlation of volumetric optoacoustic hemodynamic responses with the concurrent electroencephalogram recordings and anatomical brain landmarks. The method is shown to be capable of accurate three-dimensional mapping of the onset, spread, and termination of the epileptiform events in a 4-aminopyridine acute model of focal epilepsy. Our study is the first to demonstrate entirely noninvasive real-time visualization of synchronized epileptic foci in the whole mouse brain, including the neocortex and subcortical structures, thus opening new vistas in systematic studies toward the understanding of brain signaling and the origins of neurological disorders.


Unusual diffusing regimes caused by different adsorbing surfaces.
A confined liquid with dispersed neutral particles is theoretically studied when the limiting surfaces present different dynamics for the adsorption-desorption phenomena. The investigation considers different non-singular kernels in the kinetic equations at the walls, where the suitable choice of the kernel can account for the relative importance of physisorption or chemisorption. We find that even a small difference in the adsorption-desorption rate of one surface (relative to the other) can drastically affect the behavior of the whole system. The surface and bulk densities and the dispersion are calculated when several scenarios are considered and anomalous-like behaviors are found. The approach described here is closely related to experimental situations, and can be applied in several contexts such as dielectric relaxation, diffusion-controlled relaxation in liquids, liquid crystals, and amorphous polymers.


The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis.
To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion. In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria. The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; P = 0.001; I2, 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups. Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion.


Health and healthcare provision to asylum seekers and refugees in Germany.
The wars and devastation of recent years have driven many people to flee their homes. Great numbers of asylum seekers and refugees have sought protection in Europe. In 2015 and 2016 alone, over one million people applied for asylum in Germany. This has posed a great challenge for Germany's healthcare provision facilities. The health of asylum seekers and refugees and the provision of their healthcare is therefore an important issue in terms of public health. The first part of this article describes the extent and legal framework of immigration to Germany during the past two years. The second part then discusses the issue of health and medical care for asylum seekers and refugees. Until now, no representative data on the health of this population exists. Studies so far have all relied on a small number of cases and been limited to particular regions and are therefore hard to compare. Moreover, there are no sufficiently standardised medical examinations during initial reception across all German federal states. Relevant findings suggest an urgent need to take action in the fields of mental health, chronic diseases and the provision of care to children of asylum seekers. A review of the data available proves the need for a national and systematic collection of valid data as a basis for adequate preventive and medical care. Different initiatives currently aim to improve the data collection basis in Germany. Over time, these new initiatives will significantly improve the data available on the health situation of asylum seekers and refugees in Germany. Once politics and broader society take these findings into account, this should contribute to an objective debate and evidence-based decisions.


Gynecologic Concerns in the Adolescent Girl.
The ever-evolving role of the health care provider can present a variety of challenges, not the least of which is becoming familiar with basic knowledge of other specialties, including gynecologic care. The primary care office provides a comfortable, familiar environment in which the patient can seek medical attention. It is essential that most pediatric offices be equipped to deal with basic adolescent gynecologic care, and that their patients have access to sensitive and confidential care.


A systematic review investigating healthy lifestyle interventions incorporating goal setting strategies for preventing excess gestational weight gain.
Excess gestational weight gain (GWG) is an important risk factor for long term obesity in women. However, current interventions aimed at preventing excess GWG appear to have a limited effect. Several studies have highlighted the importance of linking theory with empirical evidence for producing effective interventions for behaviour change. Theorists have demonstrated that goals can be an important source of human motivation and goal setting has shown promise in promoting diet and physical activity behaviour change within non-pregnant individuals. The use of goal setting as a behaviour change strategy has been systematically evaluated within overweight and obese individuals, yet its use within pregnancy has not yet been systematically explored. To explore the use of goal setting within healthy lifestyle interventions for the prevention of excess GWG. Searches were conducted in seven databases alongside hand searching of relevant journals and citation tracking. Studies were included if interventions used goal setting alongside modification of diet and/or physical activity with an aim to prevent excess GWG. The PRISMA guidelines were followed and a two-stage methodological approach was used. Stage one focused on systematically evaluating the methodological quality of included interventions. The second stage assessed intervention integrity and the implementation of key goal setting components. From a total of 839 citations, 54 full-text articles were assessed for eligibility and 5 studies met the inclusion criteria. Among interventions reporting positive results a combination of individualised diet and physical activity goals, self-monitoring and performance feedback indicators were described as active components. Interventions based on goal setting appear to be useful for helping women achieve optimal weight gain during pregnancy. However, overweight and obese women may require more theoretically-designed interventions. Further high quality, theoretically-designed interventions are required to determine the most effective and replicable components for optimal GWG.


Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis.
To evaluate the effectiveness of surgery, medical treatment and expectant management of tubal ectopic pregnancy (EP) in terms of treatment success (i.e. complete elimination of trophoblast tissue), financial costs and future fertility. We searched for randomized controlled trials which described treatment interventions that have been widely adopted in clinical practice. A systemic literature search identified 15 trials. Laparoscopic salpingostomy was significantly less successful than the open surgical approach (relative risk, RR 0.9, 95% CI 0.82-0.99) due to a higher persistent trophoblast rate, but was significantly less costly. A prophylactic single shot methotrexate (MTX), given intramuscularly (i.m.) immediately post-operatively, significantly reduced persistent trophoblast after laparoscopic salpingostomy (RR 0.89, 95% CI 0.82-0.98, number needed to treat of 10). With systemic MTX in a fixed multiple dose i.m. regimen the likelihood of treatment success was higher than with laparoscopic salpingostomy (RR 1.15, 95% CI 0.93-1.43), but the difference was not significant. Systemic MTX in a fixed multiple dose i.m. regimen was only cost-effective if serum human chorionic gonadotrophin (hCG) concentrations were <3000 IU/l. If serum hCG concentrations were <1500 IU/l, then the single-dose MTX i.m. regimen-if necessary with additional MTX injections-was also cost-effective. Expectant management could not be evaluated yet. Subsequent fertility did not differ between the interventions studied. This meta-analysis shows that laparoscopic surgery is the most cost-effective treatment for tubal EP. Systemic MTX is a good alternative in selected patients with low serum hCG concentrations.


A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.
Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.


The epidemiology of Plasmodium vivax and Plasmodium falciparum malaria in China, 2004-2012: from intensified control to elimination.
In China, the national malaria elimination programme has been operating since 2010. This study aimed to explore the epidemiological changes in patterns of malaria in China from intensified control to elimination stages. Data on nationwide malaria cases from 2004 to 2012 were extracted from the Chinese national malaria surveillance system. The secular trend, gender and age features, seasonality, and spatial distribution by Plasmodium species were analysed. In total, 238,443 malaria cases were reported, and the proportion of Plasmodium falciparum increased drastically from <10% before 2010 to 55.2% in 2012. From 2004 to 2006, malaria showed a significantly increasing trend and with the highest incidence peak in 2006 (4.6/100,000), while from 2007 onwards, malaria decreased sharply to only 0.18/100,000 in 2012. Males and young age groups became the predominantly affected population. The areas affected by Plasmodium vivax malaria shrunk, while areas affected by P. falciparum malaria expanded from 294 counties in 2004 to 600 counties in 2012. This study demonstrated that malaria has decreased dramatically in the last five years, especially since the Chinese government launched a malaria elimination programme in 2010, and areas with reported falciparum malaria cases have expanded over recent years. These findings suggest that elimination efforts should be improved to meet these changes, so as to achieve the nationwide malaria elimination goal in China in 2020.


Bovine Milk Lactoferrin Selectively Kills Highly Metastatic Prostate Cancer PC-3 and Osteosarcoma MG-63 Cells In Vitro.
Prostate cancer and osteosarcoma are the second most common type of cancer affecting men and the fifth most common malignancy among adolescents, respectively. The use of non-toxic natural or natural-derived products has been one of the current strategies for cancer therapy, owing to the reduced risks of induced-chemoresistance development and the absence of secondary effects. In this perspective, lactoferrin (Lf), a natural protein derived from milk, emerges as a promising anticancer agent due to its well-recognized cytotoxicity and anti-metastatic activity. Here, we aimed to ascertain the potential activity of bovine Lf (bLf) against highly metastatic cancer cells. The bLf effect on prostate PC-3 and osteosarcoma MG-63 cell lines, both displaying plasmalemmal V-ATPase, was studied and compared with the breast cancer MDA-MB-231 and the non-tumorigenic BJ-5ta cell lines. Cell proliferation, cell death, intracellular pH, lysosomal acidification, and extracellular acidification rate were evaluated. Results show that bLf inhibits proliferation, induces apoptosis, intracellular acidification, and perturbs lysosomal acidification only in highly metastatic cancer cell lines. By contrast, BJ-5ta cells are insensitive to bLf. Overall, our results establish a common mechanism of action of bLf against highly metastatic cancer cells exhibiting plasmalemmal V-ATPase. This study opens promising perspectives for further research on the anticancer role of Lf, which ultimately will contribute to its safer and more rational application in the human therapy of these life-threatening cancers.


Occupational exposure to magnetic fields and the risk of brain tumors.
We investigated the association between occupational exposure to extremely low-frequency magnetic fields (MFs) and the risk of glioma and meningioma. Occupational exposure to MF was assessed for 489 glioma cases, 197 meningioma cases, and 799 controls enrolled in a hospital-based case-control study. Lifetime occupational history questionnaires were administered to all subjects; for 24% of jobs, these were supplemented with job-specific questionnaires, or "job modules," to obtain information on the use of electrically powered tools or equipment at work. Job-specific quantitative estimates for exposure to MF in milligauss were assigned using a previously published job exposure matrix (JEM) with modification based on the job modules. Jobs were categorized as < or =1.5 mG, >1.5 to <3.0 mG, and > or =3.0 mG. Four exposure metrics were evaluated: (1) maximum exposed job; (2) total years of exposure >1.5 mG; (3) cumulative lifetime exposure; and (4) average lifetime exposure. Odds ratios (ORs) were calculated using unconditional logistic regression with adjustment for the age, gender, and hospital site. The job modules increased the number of jobs with exposure > or =3.0 mG from 4% to 7% relative to the JEM. No statistically significant elevation in ORs or trends in ORs across exposure categories was observed using four different exposure metrics for the three tumor types analyzed. Occupational exposure to MFs assessed using job modules was not associated with an increase in the risk for glioma, glioblastoma, or meningioma among the subjects evaluated in this study.


An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model.
Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll-AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes.


Genetic diversity and species diversity of stream fishes covary across a land-use gradient.
Genetic diversity and species diversity are expected to covary according to area and isolation, but may not always covary with environmental heterogeneity. In this study, we examined how patterns of genetic and species diversity in stream fishes correspond to local and regional environmental conditions. To do so, we compared population size, genetic diversity and divergence in central stonerollers (Campostoma anomalum) to measures of species diversity and turnover in stream fish assemblages among similarly sized watersheds across an agriculture-forest land-use gradient in the Little Miami River basin (Ohio, USA). Significant correlations were found in many, but not all, pair-wise comparisons. Allelic richness and species richness were strongly correlated, for example, but diversity measures based on allele frequencies and assemblage structure were not. In-stream conditions related to agricultural land use were identified as significant predictors of genetic diversity and species diversity. Comparisons to population size indicate, however, that genetic diversity and species diversity are not necessarily independent and that variation also corresponds to watershed location and glaciation history in the drainage basin. Our findings demonstrate that genetic diversity and species diversity can covary in stream fish assemblages, and illustrate the potential importance of scaling observations to capture responses to hierarchical environmental variation. More comparisons according to life history variation could further improve understanding of conditions that give rise to parallel variation in genetic diversity and species diversity, which in turn could improve diagnosis of anthropogenic influences on aquatic ecosystems.


Pitch and longitudinal fluting effects on the primary stability of miniscrew implants.
To test the hypotheses that pitch and fluting have no effect on the primary stability of miniscrew implants (MSIs). Maximum placement torque and pullout strength of experimental MSIs were compared with those of control MSIs with the use of synthetic and cadaver bone. MSIs with 1.00 mm pitch were compared with those with 1.25 mm and 0.75 mm pitch; MSIs with three longitudinal flutes were compared with the same MSIs without flutes. A total of 60 MSIs (15 of each design) were evaluated with synthetic bone; a split-mouth cadaver model was used to compare the three experimental designs against the 1 mm control MSIs (total of 90 MSIs). The synthetic bone model showed higher placement torque and pullout strength for the 0.75 pitch than for the 1.0 mm and 1.25 mm pitch MSIs, but differences were significant (P < .05) only for pullout strength. The cadaver model showed no significant differences in placement torque or pullout strength associated with pitch. Both synthetic and cadaver bone models showed that MSIs with flutes had significantly (P < .05) higher placement torque and pullout strength. Spearman correlations between placement torque and pullout strength were statistically significant for both synthetic (r = .504) and cadaver (r = .502) bone. Within limits, decreasing MSI pitch increases pullout strength, and fluting increases both placement torque and pullout strength.


Twin study of illness history variables in psychosis.
Genetic factors are important in the aetiology of psychotic disorders, but it is unclear how far they influence aspects of illness history within psychoses. To investigate the extent, and type of familial aggregation for a range of illness history variables in psychosis. Two-hundred-and-twenty-four proband-wise twin pairs (106 monozygotic, 118 same-sex dizygotic), where probands had psychosis, were ascertained from the Maudsley Twin Register in London. We investigated the following illness history variables, rated using the OPCRIT checklist: age at onset; chronicity of course; mode of onset; psychotic/affective predominance; pre-morbid social adjustment; and the presence of a psychosocial precipitant. We used Mx statistical modelling software to analyse correlations of variables within pairs of monozygotic twins concordant for psychosis; and relationships between variables in probands and risk of psychosis in monozygotic and dizygotic co-twins. There was a high monozygotic within-pair correlation for age at onset (intra-class correlation=0.9); moderate correlations for chronicity of course (polychoric correlation=0.4) and psychotic/affective predominance (polychoric correlation=0.5); and lower non-significant correlations for other variables. No variables consistently predicted risk of psychosis in co-twins. Illness history variables in psychosis show a broad range of familial aggregation. It is likely that familial influences are predominantly modifying effects, independent of susceptibility factors for psychosis.


Protective effects of Lactobacillus rhamnosus [corrected] and Bifidobacterium infantis in murine models for colitis do not involve the vagus nerve.
The vagus nerve is an important pathway signaling immune activation of the gastrointestinal tract to the brain. Probiotics are live organisms that may engage signaling pathways of the brain-gut axis to modulate inflammation. The protective effects of Lactobacillus rhamnosus [corrected] (LR) and Bifidobacterium infantis (BI) during intestinal inflammation were studied after subdiaphragmatic vagotomy in acute dextran sulfate sodium (DSS) colitis in BALB/c mice and chronic colitis induced by transfer of CD4(+) CD62L(+) T lymphocytes from BALB/c into SCID mice. LR and BI (1 x 10(9)) were given daily. Clinical score, myeloperoxidase (MPO) levels, and in vivo and in vitro secreted inflammatory cytokine levels were found to be more severe in mice that were vagotomized compared with sham-operated animals. LR in the acute DSS model was effective in decreasing the MPO and cytokine levels in the tissue in sham and vagotomized mice. BI had a strong downregulatory effect on secreted in vitro cytokine levels and had a greater anti-inflammatory effect in vagotomized- compared with sham-operated mice. Both LR and BI retained anti-inflammatory effects in vagotomized mice. In SCID mice, vagotomy did not enhance inflammation, but BI was more effective in vagotomized mice than shams. Taken together, the intact vagus has a protective role in acute DSS-induced colitis in mice but not in the chronic T cell transfer model of colitis. Furthermore, LR and BI do not seem to engage their protective effects via this cholinergic anti-inflammatory pathway, but the results interestingly show that, in the T cell, transfer model vagotomy had a biological effect, since it increased the effectiveness of the BI in downregulation of colonic inflammation.


Exploring the trend of stream sulfate concentrations as U.S. power plants shift from coal to shale gas.
Since the early 2000s, an increasing number of power plants in the U.S. have switched from burning coal to burning gas and thus have released less SO2 emissions into the atmosphere. We investigated whether stream chemistry (i.e., SO42-) also benefits from this transition. Using publicly available data from Pennsylvania (PA), a U.S. state with heavy usage of coal as fuel, we found that the impact of SO2 emissions on stream SO42- can be observed as far as 63 km from power plants. We developed a novel model that incorporates an emission-control technology trend for coal-fired power plants to quantify potentially avoided SO2 emissions and stream SO42- as power plants switched from coal to gas. The results show that, if 30% of the electricity generated by coal in PA in 2017 had been replaced by that from natural gas, a total of 20.3 thousand tons of SO2 emissions could have been avoided and stream SO42- concentrations could have decreased as much as 10.4%. Extrapolating the model to other states in the U.S., we found that as much as 46.1 thousand tons of SO2 emissions per state could have been avoided for a similar 30% coal-to-gas switch, with potential amelioration of water quality near power plants. The emission-control technology trend model provides a valuable tool for policy makers to assess the benefits of coal-to-gas shifts on water quality improvements as well as the effectiveness of emission control technologies.


Evaluation of Nonpathogenic Fusarium oxysporum and Pseudomonas fluorescens for Panama Disease Control.
Nonpathogenic Fusarium oxysporum endophytes from healthy banana roots were evaluated for their ability to reduce Fusarium wilt of banana (Panama disease). Isolates were identified morphologically and by using species-specific primers. Pathogenicity was confirmed by inoculating banana plantlets in the greenhouse. Nonpathogenic F. oxysporum isolates were grouped into 14 haplotype groups by polymerase chain reaction restriction fragment length polymorphism analysis of the intergenic spacer region, and representative isolates evaluated for biocontrol of F. oxysporum f. sp. cubense. In the greenhouse, 10 nonpathogenic F. oxysporum isolates were able to significantly reduce Fusarium wilt of banana. The isolate that protected banana plantlets best in the greenhouse, a nonpathogenic F. oxysporum from the root rhizosphere, and Pseudomonas fluorescens WCS 417 were then field tested. When the putative biological control organisms were tested in the field, neither the nonpathogenic F. oxysporum, P. fluorescens, nor combinations thereof reduced Fusarium wilt development significantly. A number of factors could contribute to the lack of field protection, including soil microbial and chemical composition and reduced survival of biocontrol organisms in banana roots. A lack of knowledge regarding the etiology of Fusarium wilt of 'Cavendish' banana in the subtropics and the effect of F. oxysporum f. sp. cubense race and banana cultivar in protection of banana by biocontrol organisms should be further investigated.


Dynamics of the microbiota in response to host infection.
Longitudinal studies of the microbiota are important for discovering changes in microbial communities that affect the host. The complexity of these ecosystems requires rigorous integrated experimental and computational methods to identify temporal signatures that promote physiologic or pathophysiologic responses in vivo. Employing a murine model of infectious colitis with the pathogen Citrobacter rodentium, we generated a 2-month time-series of 16S rDNA gene profiles, and quantitatively cultured commensals, from multiple intestinal sites in infected and uninfected mice. We developed a computational framework to discover time-varying signatures for individual taxa, and to automatically group signatures to identify microbial sub-communities within the larger gut ecosystem that demonstrate common behaviors. Application of this model to the 16S rDNA dataset revealed dynamic alterations in the microbiota at multiple levels of resolution, from effects on systems-level metrics to changes across anatomic sites for individual taxa and species. These analyses revealed unique, time-dependent microbial signatures associated with host responses at different stages of colitis. Signatures included a Mucispirillum OTU associated with early disruption of the colonic surface mucus layer, prior to the onset of symptomatic colitis, and members of the Clostridiales and Lactobacillales that increased with successful resolution of inflammation, after clearance of the pathogen. Quantitative culture data validated findings for predominant species, further refining and strengthening model predictions. These findings provide new insights into the complex behaviors found within host ecosystems, and define several time-dependent microbial signatures that may be leveraged in studies of other infectious or inflammatory conditions.


Central Mechanisms for Thermoregulation.
Maintenance of a homeostatic body core temperature is a critical brain function accomplished by a central neural network. This orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges or declining energy homeostasis and in support of immune responses and many behavioral states. This review summarizes the anatomical, neurotransmitter, and functional relationships within the central neural network that controls the principal thermoeffectors: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for heat production. The core thermoregulatory network regulating these thermoeffectors consists of parallel but distinct central efferent pathways that share a common peripheral thermal sensory input. Delineating the neural circuit mechanism underlying central thermoregulation provides a useful platform for exploring its functional organization, elucidating the molecular underpinnings of its neuronal interactions, and discovering novel therapeutic approaches to modulating body temperature and energy homeostasis.