An Acute Injury Model for the Phenotypic Characteristics of Geographic Atrophy.
Geographic atrophy (GA) is the late stage of non-neovascular age-related macular degeneration. A lack of animal models for GA has hampered treatment efforts. Presented herein is a rat model for GA using subretinal injection of sodium iodate (NaIO3). Rats were given subretinal injections of NaIO3 (5 μg/μL) using a pico-injector. Fundus photographs and spectral domain optical coherent tomography scans were collected at 1, 3, 7, 14, and 28 days after injection, at which time rats were euthanized and eyes were enucleated. Eyes were either cryopreserved or dissected into retinal and choroidal flatmounts. Fluorescence immunohistochemistry was performed for retinal glial fibrillary acidic protein (activated Müller cells and astrocytes) and vimentin (Müller cells), as well as peanut agglutin lectin (photoreceptors) labeling. RPE/choroids were labeled for RPE65 and CD34. Images were collected on Zeiss confocal microscopes. Fundus photos, spectral domain optical coherent tomography, and RPE65 staining revealed well-demarcated areas with focal loss of RPE and photoreceptors in NaIO3-treated rats. At 1 day after injection, RPE cells appeared normal. By 3 days, there was patchy RPE and photoreceptor loss in the injected area. RPE and photoreceptors were completely degenerated in the injected area by 7 days. A large subretinal glial membrane occupied the degenerated area. Choriocapillaris was highly attenuated in the injected area at 14 and 28 days. The rat model reported herein mimics the photoreceptor cell loss, RPE atrophy, glial membrane formation, and choriocapillaris degeneration seen in GA. This model will be valuable for developing and testing drugs and progenitor cell regenerative therapies for GA.


Anesthesia for functional neurosurgery: review of complications.
The use of functional stereotactic neurosurgery is increasing for treatment of patients with movement disorders and other chronic illnesses. The anesthetic considerations include the influence of the anesthetic agents on the microelectrode recordings and stimulation testing of an awake patient. The purpose of this study was to review the anesthetic management and incidences of intraoperative complications during functional neurosurgery in our institution. One hundred seventy-eight patients underwent an ablative procedure (n = 6) or the insertion of deep brain stimulator (n = 172) under monitored anesthesia care for movement disorders (n = 124), chronic pain (n = 20), and other procedures (n = 34). Local anesthetic was used for head frame pin sites and burr holes. No sedation/analgesia was administered to 57 (32%) patients. One patient required conscious sedation and another general anesthesia for the entire procedure. The remainder received small increments (mean +/- SD) of propofol (113 +/- 73 mg), midazolam (1.6 +/- 0.8 mg), and/or fentanyl (93 +/- 55 mug). Intraoperative complications that occurred in 16% of the patients included seizures (n = 8), change in neurologic status (n = 5), airway obstruction (n = 2), and hypertension (n = 7). Functional neurosurgery can be performed with minimal anesthesia in many patients. Awareness and vigilance can improve the identification and early treatment of intraoperative complications such as seizures, loss of airway, and changes in the neurologic status.


Immune up regulatory response of a non-caloric natural sweetener, stevioside.
Immunomodulation is a process, which alters the immune system of an organism by interfering with its functions. This interference results in either immunostimulation or immunosuppression. An immunomodulator is any substance that helps to regulate the immune system. This "regulation" is a normalization process, so that an immunomodulator helps to optimise immune response. Immunomodulators are becoming very popular in the worldwide natural health industry as these do not tend to boost immunity, but to normalize it. Keeping this in view, major efforts have to be directed to modulate the immune responses, to permit effective treatment of various ailments associated with immune system and thus the development of a safe and effective immunomodulator for clinical us. Leaves of Stevia rebaudiana are a source of several sweet glycosides of steviol. The major glycoside, stevioside, diterpenoid glycoside--is used in oriental countries as a food sweetener. Its medical use is also reported as a heart tonic. Besides, it is used against obesity, hypertension, and stomach burn and to lower uric acid levels. Here in this study, stevioside was tested for its immunomodulatory activity on different parameters of the immune system at three different doses (6.25, 12.5 and 25 mg/kg p.o.) on normal as well as cyclophosphamide treated mice. Stevioside was found effective in increasing phagocytic activity, haemagglutination antibody titre and delayed type hypersensitivity. In parallel, stevioside substantially increase proliferation in the LPS and Con A stimulated B and T cells, respectively. Present study, therefore, reveals that the drug holds promise as immunomodulating agent, which acts by stimulating both humoral as well as cellular immunity and phagocytic function.


Mice Lacking beta2-Integrin Function Remain Glucose Tolerant in Spite of Insulin Resistance, Neutrophil Infiltration and Inflammation.
Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.


TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway.
In acute experimental autoimmune encephalomyelitis (EAE), demyelination is induced by myelin-specific CD4(+) T lymphocytes and myelin-specific antibodies. Recovery from the disease is initiated by cytokines which suppress T cell expansion and the production of myelin-toxic molecules by macrophages. Th2/3 cell-derived signals may also be involved in central nervous system (CNS) repair. Remyelination is thought to be initiated by the recruitment and differentiation of oligodendrocyte precursor cells (OPC) in demyelinated CNS lesions. Here, we report that unlike Th1 cytokines (TNF-alpha, IFN-gamma), the Th2/3 cytokine TGF-beta induces primary microglia from C57BL/6 mice to secrete a chemotactic factor for primary OPC. We identified this factor to be the hepatocyte growth factor (HGF). Our studies show that TGF-beta-1-2-3 as well as IFN-beta induce HGF secretion by microglia and that antibodies to the HGF receptor c-Met abrogate OPC chemotaxis induced by TGF-beta2-treated microglia. In addition we show spinal cord lesions in EAE induced in SJL/J mice to contain both OPC and HGF producing macrophages in the recovery phase, but not in the acute stage of disease. Taken these findings, TGF-beta may play a pivotal role in remyelination by inducing microglia to release HGF which is both a chemotactic and differentiation factor for OPC.


Regulation of the vapBC-1 toxin-antitoxin locus in nontypeable Haemophilus influenzae.
Nontypeable Haemophilus influenzae (NTHi) are human-adapted commensal bacteria that can cause a number of chronic mucosal infections, including otitis media and bronchitis. One way for these organisms to survive antibiotic therapy and cause recurrent disease is to stop replicating, as most antimicrobials target essential biosynthetic pathways. Toxin-antitoxin (TA) gene pairs have been shown to facilitate entry into a reversible bacteriostatic state. Characteristically, these operons encode a protein toxin and an antitoxin that associate following translation to form a nontoxic complex, which then binds to and regulates the cognate TA promoter. Under stressful conditions, the labile antitoxin is degraded and the complex disintegrates, freeing the stable toxin to facilitate growth arrest. How these events affected the regulation of the TA locus, as well as how the transcription of the operon was subsequently returned to its normal state upon resumption of growth, was not fully understood. Here we show that expression of the NTHi vapBC-1 TA locus is repressed by a complex of VapB-1 and VapC-1 under conditions favorable for growth, and activated by the global transactivator Factor for Inversion Stimulation (Fis) upon nutrient upshift from stationary phase. Further, we demonstrate for the first time that the VapC-1 toxin alone can bind to its cognate TA locus control region and that the presence of VapB-1 directs the binding of the VapBC-1 complex in the transcriptional regulation of vapBC-1.


Towards a global IT system for personalized medicine: the Medicine Safety Code initiative.
The availability of pharmacogenomic data of individual patients can significantly improve physicians' prescribing behavior, lead to a reduced incidence of adverse drug events and an improvement of effectiveness of treatment. The Medicine Safety Code (MSC) initiative is an effort to improve the ability of clinicians and patients to share pharmacogenomic data and to use it at the point of care. The MSC is a standardized two-dimensional barcode that captures individual pharmacogenomic data. The system is backed by a web service that allows the decoding and interpretation of anonymous MSCs without requiring the installation of dedicated software. The system is based on a curated, ontology-based knowledge base representing pharmacogenomic definitions and clinical guidelines. The MSC system performed well in preliminary tests. To evaluate the system in realistic health care settings and to translate it into practical applications, the future participation of stakeholders in clinical institutions, researchers, pharmaceutical companies, genetic testing providers, health IT companies and health insurance organizations will be essential.


Finding meaning in life: an exploration on the experiences with dependence on care of patients with advanced cancer and nurses caring for them.
Patients with advanced cancer are likely to face increasing levels of care dependence. Adult patients who become care dependent on others can experience this condition as one of suffering and humiliation. The nurse-patient relationship plays a key role in the experience of dependence. Understanding patients' and nurses' perceptions of care dependence is crucial to addressing the impact it has on the lives of both. The aim of this study is to explore the experiences of patients with cancer and nurses caring for them. A multicentre qualitative study was conducted in Italy using semi-structured interviews with patients with advanced cancer admitted to 3 hospitals, and 9 focus groups with nurses working in oncology wards of 2 hospitals. Data were analysed with inductive content analysis. Thirty-two patients and 44 nurses participated in the study. Three common themes were identified: within dependence, the relationship is a lifeline; dependence is influenced by internal and external factors and dependence generates changes. Dependence impacts on patients' and nurses' lives and implies a process of personal maturing for both. Patients learn the humility to ask for help by exposing their vulnerability. Nurses become aware that a trusting relationship helps patients to accept dependence, and they learn to self-transcend in order to build it. Striving to build positive relationships implies a change in nurses' and patients' lives. In this way, they come to understand important aspects of life and find meaning in difficult situations. Further studies should explore also homecare settings and patients' families.


An object-based visual attention model for robotic applications.
By extending integrated competition hypothesis, this paper presents an object-based visual attention model, which selects one object of interest using low-dimensional features, resulting that visual perception starts from a fast attentional selection procedure. The proposed attention model involves seven modules: learning of object representations stored in a long-term memory (LTM), preattentive processing, top-down biasing, bottom-up competition, mediation between top-down and bottom-up ways, generation of saliency maps, and perceptual completion processing. It works in two phases: learning phase and attending phase. In the learning phase, the corresponding object representation is trained statistically when one object is attended. A dual-coding object representation consisting of local and global codings is proposed. Intensity, color, and orientation features are used to build the local coding, and a contour feature is employed to constitute the global coding. In the attending phase, the model preattentively segments the visual field into discrete proto-objects using Gestalt rules at first. If a task-specific object is given, the model recalls the corresponding representation from LTM and deduces the task-relevant feature(s) to evaluate top-down biases. The mediation between automatic bottom-up competition and conscious top-down biasing is then performed to yield a location-based saliency map. By combination of location-based saliency within each proto-object, the proto-object-based saliency is evaluated. The most salient proto-object is selected for attention, and it is finally put into the perceptual completion processing module to yield a complete object region. This model has been applied into distinct tasks of robots: detection of task-specific stationary and moving objects. Experimental results under different conditions are shown to validate this model.


Influence of plant diversity and elevated atmospheric carbon dioxide levels on belowground bacterial diversity.
Changes in aboveground plant species diversity as well as variations of environmental conditions such as exposure of ecosystems to elevated concentrations of atmospheric carbon dioxide may lead to changes in metabolic activity, composition and diversity of belowground microbial communities, both bacterial and fungal. We examined soil samples taken from a biodiversity x CO2 grassland experiment where replicate plots harboring 5, 12, or 31 different plant species had been exposed to ambient or elevated (600 ppm) levels of carbon dioxide for 5 years. Analysis of soil bacterial communities in these plots by temporal temperature gradient gel electrophoresis (TTGE) showed that dominant soil bacterial populations varied only very little between different experimental treatments. These populations seem to be ubiquitous. Likewise, screening of samples on a high-resolution level by terminal restriction fragment length polymorphism (T-RFLP) showed that increased levels of carbon dioxide had no significant influence on both soil bacterial community composition (appearance and frequency of operational taxonomic units, OTUs) and on bacterial richness (total number of different OTUs). In contrast, differences in plant diversity levels had a significant effect on bacterial composition but no influence on bacterial richness. Regarding species level, several bacterial species were found only in specific plots and were related to elevated carbon dioxide or varying plant diversity levels. For example, analysis of T-RFLP showed that the occurrence of Salmonella typhimurium was significantly increased in plots exposed to elevated CO2 (P < 0.05). Plant diversity levels are affecting bacterial composition (bacterial types and their frequency of occurrence). Elevated carbon dioxide does not lead to quantitative alteration (bacterial richness), whereas plant diversity is responsible for qualitative changes (bacterial diversity).


HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations.
Memory deficits are characteristic of HIV-associated neurocognitive disorders (HAND) and co-occur with hippocampal pathology. The HIV-1 transactivator of transcription (Tat), a regulatory protein, plays a significant role in these events, but the cellular mechanisms involved are poorly understood. Within the hippocampus, diverse populations of interneurons form complex networks; even subtle disruptions can drastically alter synaptic output, resulting in behavioral dysfunction. We hypothesized that HIV-1 Tat would impair cognitive behavior and injure specific hippocampal interneuron subtypes. Male transgenic mice that inducibly expressed HIV-1 Tat (or non-expressing controls) were assessed for cognitive behavior or had hippocampal CA1 subregions evaluated via interneuron subpopulation markers. Tat exposure decreased spatial memory in a Barnes maze and mnemonic performance in a novel object recognition test. Tat reduced the percentage of neurons expressing neuronal nitric oxide synthase (nNOS) without neuropeptide Y immunoreactivity in the stratum pyramidale and the stratum radiatum, parvalbumin in the stratum pyramidale, and somatostatin in the stratum oriens, which are consistent with reductions in interneuron-specific interneuron type 3 (IS3), bistratified, and oriens-lacunosum-moleculare interneurons, respectively. The findings reveal that an interconnected ensemble of CA1 nNOS-expressing interneurons, the IS3 cells, as well as subpopulations of parvalbumin- and somatostatin-expressing interneurons are preferentially vulnerable to HIV-1 Tat. Importantly, the susceptible interneurons form a microcircuit thought to be involved in feedback inhibition of CA1 pyramidal cells and gating of CA1 pyramidal cell inputs. The identification of vulnerable CA1 hippocampal interneurons may provide novel insight into the basic mechanisms underlying key functional and neurobehavioral deficits associated with HAND.


Failing to deactivate: resting functional abnormalities in autism.
Several regions of the brain (including medial prefrontal cortex, rostral anterior cingulate, posterior cingulate, and precuneus) are known to have high metabolic activity during rest, which is suppressed during cognitively demanding tasks. With functional magnetic resonance imaging (fMRI), this suppression of activity is observed as "deactivations," which are thought to be indicative of an interruption of the mental activity that persists during rest. Thus, measuring deactivation provides a means by which rest-associated functional activity can be quantitatively examined. Applying this approach to autism, we found that the autism group failed to demonstrate this deactivation effect. Furthermore, there was a strong correlation between a clinical measure of social impairment and functional activity within the ventral medial prefrontal cortex. We speculate that the lack of deactivation in the autism group is indicative of abnormal internally directed processes at rest, which may be an important contribution to the social and emotional deficits of autism.


Distributed network organization underlying feeding behavior in the mollusk Lymnaea.
The aim of the work reviewed here is to relate the properties of individual neurons to network organization and behavior using the feeding system of the gastropod mollusk, Lymnaea. Food ingestion in this animal involves sequences of rhythmic biting movements that are initiated by the application of a chemical food stimulus to the lips and esophagus. We investigated how individual neurons contribute to various network functions that are required for the generation of feeding behavior such as rhythm generation, initiation ('decision making'), modulation and hunger and satiety. The data support the view that feeding behavior is generated by a distributed type of network organization with individual neurons often contributing to more than one network function, sharing roles with other neurons. Multitasking in a distributed type of network would be 'economically' sensible in the Lymnaea feeding system where only about 100 neurons are available to carry out a variety of complex tasks performed by millions of neurons in the vertebrate nervous system. Having complementary and potentially alternative mechanisms for network functions would also add robustness to what is a 'noisy' network where variable firing rates and synaptic strengths are commonly encountered in electrophysiological recording experiments.


Ca2+ entry, efflux and release in smooth muscle.
Control of smooth muscle is vital for health. The major route to contraction is a rise in intracellular [Ca2+], determined by the entry and efflux of Ca2+ and release and re-uptake into the sarcoplasmic reticulum (SR). We review these processes in myometrium, to better understand excitation-contraction coupling and develop strategies for preventing problematic labours. The main mechanism of elevating [Ca2+] is voltage-gated L-type channels, due to pacemaker activity, which can be modulated by agonists. The rise of [Ca2+] produces Ca-calmodulin and activates MLCK. This phosphorylates myosin and force results. Without Ca2+ entry uterine contraction fails. The Na/Ca exchanger (NCX) and plasma membrane Ca-ATPase (PMCA) remove Ca2+, with contributions of 30% and 70% respectively. Studies with PMCA-4 knockout mice show that it contributes to reducing [Ca2+] and relaxation. The SR contributes to relaxation by vectorially releasing Ca2+ to the efflux pathways, and thereby increasing their rates. Agonists binding produces IP3 which can release Ca from the SR but inhibition of SR Ca2+ release increases contractions and Ca2+ transients. It is suggested that SR Ca2+ targets K+ channels on the surface membrane and thereby feedback to inhibit excitability and contraction.


Eating patterns and overweight in 9- to 10-year-old children in Telemark County, Norway: a cross-sectional study.
Increasing prevalence of overweight in children is a growing health problem. The aim of this study was to describe the eating patterns of 9- to 10-year-old schoolchildren, and to investigate the relationship between overweight and eating patterns. We recruited 1045 children for a cross-sectional study in Telemark County, Norway. The children's food, snacking and meal frequencies were reported by their parents using a retrospective food frequency questionnaire. Height and weight were measured by health professionals, and body mass index categories were calculated using international standard cutoff points (International Obesity Task Force values). Complete data were obtained for 924 children. Four distinct eating patterns were identified using principal component analysis. We used multiple logistic regression and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for being overweight, and adjusted for parental characteristics and physical activity levels of the children (aORs). Parental characteristics and physical activity were associated with both obesity and eating patterns. Children adhering to a 'junk/convenient' eating pattern had a significantly lower likelihood of being overweight (aOR: 0.6; 95% CI: 0.4, 0.9), whereas children adhering to a 'varied Norwegian' or a 'dieting' eating pattern had a significantly higher likelihood of being overweight (respective values: aOR: 2.1; 95% CI: 1.3, 3.2; aOR: 2.2; 95% CI: 1.4, 3.4). No association with overweight was seen for a 'snacking pattern'. The main finding was that, although family characteristics influenced both the prevalence of overweight and overall dietary behaviour, independent associations were evident between eating patterns and overweight, indicating parental modification of the diets of overweight children.


Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure.
To assess survival time and adverse events related to the administration of pimobendan to cats with congestive heart failure (CHF) secondary to hypertrophic cardiomyopathy (HCM) or hypertrophic obstructive cardiomyopathy (HOCM). Retrospective case-control study. 27 cats receiving treatment with pimobendan and 27 cats receiving treatment without pimobendan. Medical records between 2003 and 2013 were reviewed. All cats with HCM or HOCM treated with a regimen that included pimobendan (case cats) were identified. Control cats (cats with CHF treated during the same period with a regimen that did not include pimobendan) were selected by matching to case cats on the basis of age, sex, body weight, type of cardiomyopathy, and manifestation of CHF. Data collected included signalment, physical examination findings, echocardiographic data, serum biochemical values, and survival time from initial diagnosis of CHF. Kaplan-Meier survival curves were constructed and compared by means of a log rank test. Cats receiving pimobendan had a significant benefit in survival time. Median survival time of case cats receiving pimobendan was 626 days, whereas median survival time for control cats not receiving pimobendan was 103 days. No significant differences were detected for any other variable. The addition of pimobendan to traditional treatment for CHF may provide a substantial clinical benefit in survival time for HCM-affected cats with CHF and possibly HOCM-affected cats with CHF.


Wide-band six-region phase mask coronagraph.
An achromatic six-region phase mask coronagraph, used for the detection of exoplanets, is proposed. The mask has six regions in angular direction and could work in wideband. Furthermore, a six-level phase mask, as an example of the six-region phase mask, is theoretically investigated. According to numerical simulations, this specific mask has a deep elimination of starlight, good performance of achromatism and small inner working angle. As a single phase mask, the ratio of the remaining starlight of the six-level phase mask to the total incident starlight is less than 0.001 when the wavelength is between 500 nm and 600 nm.


Creating room for evidence-based practice: Leader behavior in hospital wards.
The integration (routinizing and sustaining) of evidence-based practice (EBP) into hospital management is a key element for improving patient safety and ensuring better patient outcomes. Hospital managers and clinical leaders play crucial roles in this integration. Interactions between leaders and integration context influence the improvement's quality, but leader-based actions that are effective for improving nursing practice remain unclear. The relationship between leaders could also either hinder or enable this implementation process. The aim of this study was to generate a theory about patterns of leader behavior that leaders are engaged in when attempting to integrate EBP in a clinical setting. We used a classic grounded theory methodology to generate a substantive EBP theory. In this study, through participant observation, we observed 63 nurses (15 specialist, 39 registered, and 9 assistant nurses). From these, five ward leaders (two head nurses, one assistant head nurse, and two teaching nurses) participated in individual interviews, and 18 clinical nurses participated in four focus groups. "Creating room for EBP" emerged as a theory for explaining the way in which the leaders attempted to resolve their main concern: How to achieve EBP treatment and care with tight resources and without overextending the nurses. Creating room for EBP encompasses a process of interactions, including positioning for, executing, and interpreting responses to EBP.


Inhibition of Growth and Metastasis of Breast Cancer in Mice by Milk Fermented With Lactobacillus casei CRL 431.
Breast cancer is the second cause of death in women, who are especially related to uncontrolled metastasis. It was previously demonstrated that the administration of milk fermented by Lactobacillus casei CRL 431 [fermented milk (FM)] delayed the tumor growth in a murine breast cancer model. In this work we evaluated if the administration of FM to mice, starting when the tumor was measurable, can affect not only the tumor growth, but also the extravasation of tumor cells and the lung metastasis. The evaluation of immune cells-infiltrating tumors and lungs was also performed. Tumor volume was calculated. Whole blood, lungs, and liver were processed to count the number of colonies formed by tumor cells. Blood serum was obtained for monocyte chemoattractant protein-1, interleukin (IL)-10, and IL-6 determination, lung tissues for histologic observations, and tumor tissues for angiogenesis determination. Mice that received FM were compared with animals given milk or to the controls without any especial supplementation. The results showed that FM administration to mice decreased or suppressed tumor growth, with less tumor vascularity, extravasation of tumor cells, and lung metastasis. These benefits were associated to modulation of the immune response by decreasing the infiltration of macrophages in both the tumor and the lungs. FM administration maintained an increased antitumor response associated to CD8 lymphocytes, and also increased CD4 lymphocytes that can be involved in the modulation of the immune response. The future evaluation of cytokine profiles will allow knowing more about subpopulation of macrophages and lymphocytes associated to the beneficial effect of this probiotic in the breast cancer model.


Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation.
Operational tolerance (graft acceptance in an immunosuppression (IS)-free environment) after living-donor liver transplantation (LDLT) could occur by our elective protocol in some patients. There is, nevertheless, no reliable parameter to monitor patients who may discontinue IS without a risk of rejection. To identify such parameters, we systemically phenotyped peripheral blood mononuclear cells from operationally tolerant patients. An increase was observed in the frequency of CD4+CD25high+ cells, B cells and Vdelta1/Vdelta2 gammadeltaT-cells ratio in operationally tolerant patients (Gr-tol; n = 12), compared with those from age-matched volunteers (Gr-vol; n = 24) or patients on IS (Gr-IS; n = 19). The frequency of NK cells was decreased in Gr-tol, compared with those in Gr-IS or Gr-vol. The frequency of NKT cells was decreased after LDLT, compared with that in Gr-vol. Although the contribution of those subsets to the tolerant state remains elusive, the results may provide important clues for reliable indicators of tolerance after LDLT.


K-Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines.
Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K-Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback-mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP-competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K-Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.


A randomized controlled trial of a multifaceted integrated complementary-alternative therapy for chronic herpes zoster-related pain.
Our objective was to determine whether a three-week complementary and alternative medicine (CAM) approach integrating several therapies from Traditional Chinese Medicine (TCM) along with neural therapy (injection of 1% procaine as local anesthesia) reduces the level of unresolved pain associated with herpes zoster. The design was a randomized controlled clinical trial in a community-based primary care clinic in Toronto, Ontario. We studied individuals 18 years of age and older with a confirmed diagnosis of herpes zoster of at least 30 days duration and with at least moderate postherpetic neuralgia pain (≥4) on a 10-point Likert scale. The CAM therapies used were acupuncture, neural therapy (1% procaine injection as a local anesthetic), cupping and bleeding, and TCM herbs. An immediate treatment group (n=32) received the CAM intervention once daily, five days per week, for three weeks. A wait-list (delayed treatment) group (n=27) was used as a control and received the same treatment starting three weeks after randomization. This three-week time period, when one group was receiving active CAM treatment and the other was not, was used as basis of comparison for treatment effects between groups. Pain, quality of life, and depression were measured at baseline, and three, six, and nine weeks post-randomization. Patients were followed for up to two years. Participants had a mean age of 69.8 years (SD=11.1) and had had herpes zoster-related pain for a median of 4.8 months (range: 1 month to 15 years). The immediate treatment and control groups had similar pain levels at baseline (treatment = 7.5; control = 7.8; p=0.5; scores based on the 10-point Likert pain scale). At three weeks post-randomization (i.e., after the immediate treatment group completed treatment) pain scores differed significantly (treatment = 2.3; control = 7.2; p<0.001). The observed reduction in pain in the immediate treatment group was maintained at nine weeks and at long-term follow-up (one to two years later). The delayed treatment (control) group also had significant reductions in pain after their integrated CAM treatment was completed. The described CAM protocol was associated with significantly reduced sub-acute and chronic post-herpes zoster neuralgia pain within three weeks of initiating treatment. Improvements persisted for up to two years.


Comparison of real-time PCR and conventional biochemical methods for identification of Staphylococcus lugdunensis.
Staphylococcus lugdunensis is an aggressive, virulent member of the coagulase-negative staphylococci (CoNS) that is responsible for severe, rapidly progressive skin and soft tissue infections and native valve endocarditis. To facilitate prompt identification and appropriate therapy, we describe here a rapid and robust multiplex real-time PCR assay that is able to definitively distinguish S. lugdunensis from other staphylococci. Using melting curve analysis, the assay also identifies Staphylococcus aureus and CoNS other than S. lugdunensis and determines MecA-dependent resistance to methicillin (meticillin). When applied to a panel of well-characterized staphylococcal reference strains, as well as 165 clinical isolates previously identified by conventional methods, the assay was both sensitive and specific for S. lugdunensis, correctly identifying the reference strain and all 47 S. lugdunensis isolates without inappropriate amplification of other staphylococci. Furthermore, rapid biochemical identification using the WEE-TAB system to detect ornithine decarboxylase activity was found to be unsuitable as an alternative to PCR identification, displaying just 31% sensitivity and 77% specificity when tested on a subset (90 isolates) of the clinical strains. We therefore propose that this simple, accurate PCR approach will allow for the routine and timely identification of S. lugdunensis in the clinical microbiology laboratory.


First Report of Stem Rot in Canola Caused by Sclerotinia minor in Western Australia.
Canola (Brassica napus L.) is a significant oilseed break crop in Western Australia. In late October 2012, canola plants (cv. Jackpot) showing typical symptoms of stem rot with bleached appearance and fluffy white fungal growth on the infected tissues were observed in an experimental plot at Katanning, Western Australia. Severely affected plants were lodged with partially filled pods and shriveled seeds. Small, irregular sclerotia (<2 mm) were found inside the plants and were more concentrated in the root and basal stem than in the upper stem regions. Ten sclerotia from three symptomatic plants were surface sterilized with 1.25% NaOCl for 1 minute, rinsed twice in sterile distilled water and plated on potato dextrose agar (PDA) supplemented with 10 mg liter-1 Aureomycin. Plates were incubated under a black light at 22 ± 2°C. Sclerotinia minor Jagger was consistently isolated as identified by colony morphology, abundant sclerotia on PDA, and size of sclerotia <2 mm (3). A pathogenicity test was conducted on six 7-week-old canola plants cv. Tawriffic. Mycelial plugs (5 mm diameter) were excised from the margins of actively growing 3-day-old cultures and attached on to the 2nd and the 4th internodes of the main stem with Parafilm. Three plants inoculated with agar plugs without mycelium served as controls. Following inoculation, the plants were kept in a misting chamber for 48 h and then transferred to a growth room at 18 ± 2°C with a 12-h photoperiod. Typical lesions of stem rot similar to those observed in the field were noticed 3 days after inoculation. Within a week, all the inoculated plants were completely girdled by the lesions with stems breaking off and collapsing at the point of inoculation. Small sclerotia formed within lesions on the outside of the diseased stems. S. minor was reisolated from the stems of symptomatic plants, fulfilling Koch's postulates. No symptoms developed on the control plants. S. minor has previously been reported on host plants other than canola in Western Australia (4), canola petals in New South Wales, Australia (2), and also on canola stems in Argentina (1). To our knowledge, this is the first report of occurrence of S. minor on canola in Western Australia. Although S. sclerotiorum is the predominant species causing stem rot in canola in Western Australia, S. minor has the potential to cause significant yield losses under favorable environmental conditions. Correct identification and monitoring a shift in pathogens is essential for implementing effective management strategies and breeding resistant varieties. References: (1) S. A. Gaetán et al. Plant Dis. 92:172, 2008. (2) T. Hind-Lanoiselet et al. Aust Plant Pathol. 30:289, 2001. (3) L. M. Kohn. Phytopathology 69:881, 1979. (4) R. Shivas. J. Royal. Soc. Western Australia 72:1, 1989.


Cylindrical and spherical ion-acoustic envelope solitons in multicomponent plasmas with positrons.
The nonlinear wave modulation of planar and nonplanar (cylindrical and spherical) ion-acoustic envelope solitons in a collisionless unmagnetized electron-positron-ion plasma with two-electron temperature distributions has been studied. The reductive perturbative technique is used to obtain a modified nonlinear Schrödinger equation, which includes a damping term that accounts for the geometrical effect. The critical wave number threshold Kc, which indicates where the modulational instability sets in, has been determined for various regimes. It is found that an increase in the positron concentration (alpha) leads to a decrease in the critical wave number (Kc) until alpha approaches certain value alphac (critical positron concentration), then further increase in alpha beyond alphac increases the value of Kc. Also, it is found that there is a modulation instability period for the cylindrical and spherical wave modulation, which does not exist in the one-dimensional case.


Long-term outcomes of standard endovascular aneurysm repair in patients with severe neck angulation.
Severe neck angulation is associated with complications after endovascular aneurysm repair (EVAR). Newer endografts may overcome this limitation, but the literature lacks long-term results. We studied the long-term outcomes of EVAR in patients with severe neck angulation. A retrospective case-control study of a prospective multicenter database was performed. All measurements were made with dedicated software with center lumen line reconstruction. A study group including patients with neck length >15 mm, infrarenal angle (β) >75 degrees or suprarenal angle (α) >60 degrees, and neck length 10 to 15 mm with β >60 degrees or α >45 degrees was compared with a control group matched for demographics and other morphologic neck features. The primary end point was type IA endoleak (EL1A). Secondary end points were freedom from neck-related secondary interventions, primary clinical success, and overall survival. Forty-five patients were included in the angulated neck group and compared with 65 matched patients. Median follow-up was 7.4 years (interquartile range, 4.8-8.5 years). In the angulated neck group, mean α was 51.4 degrees (±21.1 degrees) and the mean β was 80.8 degrees (±15.6 degrees); in the nonangulated group, these were 17.9 degrees (±17.0 degrees) and 35.4 degrees (±20.0 degrees), respectively. At 7 years, five patients in the angulated neck group and two nonangulated patients developed EL1A, yielding a freedom from EL1A of 86.1% (n = 14; standard error [SE], 0.069) and 96.6% (n = 34; SE, 0.023), respectively (P = .056). After exclusion of a patient who developed an EL1A secondary to an endograft infection, this difference was significant: 86.1% (n = 14; SE, 0.069) in the angulated neck group and 98.2% (n = 34; SE, 0.018) in the nonangulated group (P = .016). At 7 years, freedom from neck-related secondary interventions was 91.7% (n = 14; SE, 0.059) and 91.6% (n = 29; SE, 0.029), respectively. The 7-year primary clinical success estimates were 41.2% (n = 11; SE, 0.085) and 56.6% (n = 20; SE, 0.072) for the angulated neck and nonangulated groups, respectively (P = .12). The 7-year survival rates were 44.3% (n = 18; SE, 0.076) vs 66.7% (n = 42; SE, 0.059) for the angulated neck and nonangulated groups, respectively (P = .25). Device integrity failure was not observed. Despite satisfactory results early and in the midterm, a higher rate of EL1A was identified among patients with severely angulated necks in the long term. However, mortality was not affected by this difference. These findings suggest that EVAR should be used judiciously in patients with extreme angulation of the proximal neck and highlight the need for close follow-up of EVAR, especially in the long term and in patients treated outside instructions for use.


Hormone-dependent expression of a steroidogenic acute regulatory protein natural antisense transcript in MA-10 mouse tumor Leydig cells.
Cholesterol transport is essential for many physiological processes, including steroidogenesis. In steroidogenic cells hormone-induced cholesterol transport is controlled by a protein complex that includes steroidogenic acute regulatory protein (StAR). Star is expressed as 3.5-, 2.8-, and 1.6-kb transcripts that differ only in their 3'-untranslated regions. Because these transcripts share the same promoter, mRNA stability may be involved in their differential regulation and expression. Recently, the identification of natural antisense transcripts (NATs) has added another level of regulation to eukaryotic gene expression. Here we identified a new NAT that is complementary to the spliced Star mRNA sequence. Using 5' and 3' RACE, strand-specific RT-PCR, and ribonuclease protection assays, we demonstrated that Star NAT is expressed in MA-10 Leydig cells and steroidogenic murine tissues. Furthermore, we established that human chorionic gonadotropin stimulates Star NAT expression via cAMP. Our results show that sense-antisense Star RNAs may be coordinately regulated since they are co-expressed in MA-10 cells. Overexpression of Star NAT had a differential effect on the expression of the different Star sense transcripts following cAMP stimulation. Meanwhile, the levels of StAR protein and progesterone production were downregulated in the presence of Star NAT. Our data identify antisense transcription as an additional mechanism involved in the regulation of steroid biosynthesis.


Evaluating the sustained health impact of household chlorination of drinking water in rural Haiti.
The Jolivert Safe Water for Families program has sold sodium hypochlorite solution (chlorine) and conducted household visits in rural Haiti since 2002. To assess the impact of the program on diarrheal disease, in 2010 we conducted a survey and water quality testing in 201 program participants and 425 control households selected at random. Fifty-six percent of participants (versus 10% of controls) had free chlorine residuals between 0.2 and 2.0 mg/L, indicating correct water treatment. Using intention-to-treat analysis, we found that significantly fewer children < 5 in participant households had an episode of diarrhea in the previous 48 hours (32% versus 52%; P < 0.001) with 59% reduced odds (odds ratio = 0.41, 95% confidence interval = 0.21-0.79). Treatment-on-treated estimates of the odds of diarrhea indicated larger program effects for participants who met more stringent verifications of participation. Diarrheal disease reduction in this long-term program was comparable with that seen in short-term randomized, controlled interventions, suggesting that household chlorination can be an effective long-term water treatment strategy.


Educating nurses to care for military veterans in civilian hospitals: An integrated literature review.
In the UK, military veterans will receive care by civilian nurses in civilian hospitals. We propose that the nurses providing this care require an understanding of the unique experiences and specific health needs of veterans to deliver evidence-based care. To conduct an integrative review of published literature to explore how nursing programmes prepare nurses to care for the military veteran population in civilian hospitals. A systematic search was undertaken of a range of electronic databases, Google Scholar and hand searching of Military and Veteran health journals. Papers that focused on education of civilian nurses about veteran health and included primary research or description of practice-based innovations were included in the review. The search generated sixteen papers that were focused on nurse education in higher education institutions. Several papers focused on simulation as a teaching method for veteran-specific health issues or curriculum developments with educational innovations such as online courses. Six papers focusing in continuing professional education of nurses in the clinical setting were included as supplementary information. All papers reviewed were US focused and dated between January 2011 and September 2015. Our search concluded that there is a gap in knowledge in this subject area within a UK context, therefore our review includes UK background information to support the US findings. Civilian nurses need educational preparation to understand the specific needs of veterans. Educational institutions in the US have responded to nationwide initiatives to undertake that preparation. More empirical studies need to be undertaken to develop, test and evaluate educational innovations for preparing students and nurses delivering care to military veteran in civilian healthcare settings.


LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.
Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%±23% for C-triol and 52%±29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases.


Milk antibodies against Ostertagia ostertagi: relationships with milk IgG and production parameters in lactating dairy cattle.
The present study was carried out to evaluate the relationship between milk optical density ratios (ODRs) from an indirect Ostertagia ostertagi ELISA, total milk IgG levels and milk production and then establish a correction factor to adjust ODR. Five hundred and sixty composite milk samples collected from 358 cows on four dairy herds in June and August 2002 were used in this analysis. The average ODR was 0.34. A positive correlation was found between ODR and IgG values in milk, days in milk, age and log transformed somatic cell counts (SCC). However, ODR was negatively correlated with milk production. The IgG levels and ODR values were constant from 30 to 200 days in milk. However, ODRs increased from 200 days until the end of the lactation. After controlling for age, season, herd and SCC, an increase in milk production of 13 kg/day was associated with a reduction in ODR values of 0.052. The results of the present study suggest that ODR values are not greatly influenced by production factors. ODR follow the same pattern as the IgG variation across lactation and could be adjusted in order to compare ODR values obtained from high producing cows with those obtained from low producing animals.


Occupational health related concerns among surgeons.
The surgeon's daily workload renders him/her susceptible to a variety of the common work-related illness. They are exposed to a number of occupational hazards in their professional work. These hazards include sharp injuries, blood borne pathogens, latex allergy, laser plumes, hazardous chemicals, anesthetic gases, equipment hazards, static postures, and job related stressors. However, many pay little attention to their health, and neither do they seek the appropriate help when necessary. It is observed that occupational hazards pose a huge risk to the personal well-being of surgeons. As such, the importance of early awareness and education alongside prompt intervention is duly emphasized. Therefore, increased attention to the health, economic, personal, and social implications of these injuries is essential for appropriate management and future prevention. These risks are as great as any other occupational hazards affecting surgeons today. The time has come to recognize and address them.


Differentiation between sessile serrated adenoma/polyp and non-sessile serrated adenoma/polyp in large hyper plastic polyp: A Japanese collaborative study.
A hyperplastic polyp (HP) >10 mm is described as a large hyperplastic polyp (LHP). Previous studies have considered LHP and sessile serrated adenoma/polyp (SSA/P) as synonymous. Although HP and SSA/P have previously been morphologically distinguished, differences between LHP and SSA/P have not yet been reported. The present study aimed to define the differences between SSA/P and non-SSA/P in LHP using immunohistochemistry for Ki67. Colorectal serrated lesions (>10 mm) that were completely resected by endoscope and derived from 11 institutions in Japan [Dokkyo Medical University School of Medicine (Mibu), Takahiro Fujii Clinic (Tokyo), Sano Hospital (Kobe), Oda GI Clinic, Hattori GI Endoscopy and Oncology Clinic (Kumamoto), Ohta Clinic (Nagoya), Hiroshima University (Hiroshima), Iwate Medical University (Morioka), Juntendo and Kyorin Universities (Tokyo) as well as Toyama University (Toyama)] affiliated with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) between January 2003 and December 2010 were selected. The histological criteria of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, project meeting; editor-in chief, Takashi Yao) were used to distinguish SSA/P and non-SSA/P from LHP. Non-SSA/P comprises both incomplete SSA/P and HP. A total of 154 samples diagnosed as SSA/P or non-SSA/P from 148 patients were used. This study comprised 107 SSA/P and 47 non-SSA/P cases, whereby lesions were located on the right side of the colon (73.2 and 26.8%, respectively). Ki67-positivity in SSA/Ps was significantly higher compared to non-SSA/Ps. A greater number of SSA/Ps in LHP were located on the right side of the colon compared to the left side. SSA/Ps occurring on the right side of the colon may be precursor lesions of colorectal carcinoma in serrated neoplasia pathways. In conclusion, LHPs and SSA/Ps limited to the right side of the colon are suggested to be clinically treated as the same type of lesions.


Detection of Taura syndrome virus (TSV) strain differences using selected diagnostic methods: diagnostic implications in penaeid shrimp.
Anecdotal industry reports of Taura syndrome (TS) epizootics in a Taura syndrome virus (TSV) tolerant strain of Penaeus stylirostris and collected evidence of field TS epizootics in P. stylirostris suggested that a distinct new TSV strain might have emerged since 1994. The Ecuadorian 1992 TSV genome published in GenBank is virtually identical to the Hawaiian 1994 TSV isolate (HI94TSV) used as reference throughout this investigation. Three other geographic and year isolates of TSV from naturally occurring TS epizootics of cultured penaeid shrimp were obtained from Mexico (SIN98TSV and MX99TSV from P. vannamei and SON2KTSV from P. stylirostris). Selected TSV diagnostic methods set forth by the Office International des Epizooties were utilized as the basis for isolate analysis. By Southern blot, TSV probes P15 and Q1 reacted specifically with all the diagnostic reverse transcription polymerase chain reaction (RT-PCR) fragments. Additionally, labeled RT-PCR amplicons from the TSV isolates amplified by routine diagnostic RT-PCR primers gave positive in situ hybridizations with TSV, indicating that all 4 isolates shared homology. By Western blot, immuno-dot blot, and immunohistochemistry, all TSV-purified isolates reacted with TSV polyclonal antibody (PAb). However, with TSV monoclonal antibody (MAb) 1A1 all isolates, except SIN98TSV, reacted, indicating that the difference in isolate SIN98TSV is within VP1, the target for MAb 1A1. The amino acid (AA) sequence of SIN98TSV VP1, MX99TSV VP1 and SON2KTSV VP1 has a 98% homology with the reference HI94TSV VP1. A span of 12 AAs are identified in SIN98TSV VP1 containing significant AA substitutions which may account for a conformational change of the antigenic epitope sufficient to prevent MAb 1A1 from binding. The implications of these results with respect to the antibody-based diagnosis of TSV are discussed.


Risk factors and outcome of pulmonary aspergillosis in critically ill coronavirus disease 2019 patients-a multinational observational study by the European Confederation of Medical Mycology.
Coronavirus disease 2019 (COVID-19) -associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome. The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centres from nine countries to assess epidemiology, risk factors and outcome of CAPA. CAPA was defined according to the 2020 ECMM/ISHAM consensus definitions. A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31 days) after ICU admission predominantly in older patients (adjusted hazard ratio (aHR) 1.04 per year; 95% CI 1.02-1.06) with any form of invasive respiratory support (HR 3.4; 95% CI 1.84-6.25) and receiving tocilizumab (HR 2.45; 95% CI 1.41-4.25). Median prevalence of CAPA per centre was 10.7% (range 1.7%-26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p < 0.001) and remained an independent negative prognostic variable after adjusting for other predictors of survival (HR 2.14; 95% CI 1.59-2.87, p ≤ 0.001). Prevalence of CAPA varied between centres. CAPA was significantly more prevalent among older patients, patients receiving invasive ventilation and patients receiving tocilizumab, and was an independent strong predictor of ICU mortality.


Catecholamines' enhancement of inducible nitric oxide synthase-induced nitric oxide biosynthesis involves CAT-1 and CAT-2A.
Catecholamines enhance inducible nitric oxide synthase (iNOS) expression that results in nitric oxide (NO) overproduction in lipopolysaccharide (LPS)-stimulated macrophages. L-arginine transport mediated by cationic amino acid transporters (including CAT-1, CAT-2, CAT-2A, and CAT-2B) is crucial in regulating iNOS activity. We sought to assess the effects of catecholamines on L-arginine transport and CAT isozyme expression in stimulated macrophages. Confluent RAW264.7 cells were cultured with LPS with or without catecholamines (epinephrine or norepinephrine, 5 x 10(-6) M) for 18 h. NO production, L-arginine transport, and enzyme expression were determined. Our data revealed that LPS co-induced iNOS, CAT-2, and CAT-2B expression, whereas CAT-1 and CAT-2A expression remained unaffected. Significant increases in NO production and L-arginine transport (approximately eight-fold and three-fold increases, respectively) were found in activated macrophages. Catecholamines significantly enhanced NO production and L-arginine transport (approximately 30% and 20% increases, respectively) in activated macrophages. Catecholamines also enhanced the expression of iNOS, CAT-1, and CAT-2A but not CAT-2 or CAT-2B in LPS-stimulated macrophages. Furthermore, the enhancement effects of catecholamines were inhibited by either dexamethasone or propranolol. We provide the first evidence to indicate that L-arginine transport in activated macrophages could be enhanced by catecholamines. Furthermore, this catecholamine-enhanced L-arginine transport might involve CAT-1 and CAT-2A but not CAT-2 or CAT-2B.


The relative influences of product volume, delivery format and alcohol concentration on dry-time and efficacy of alcohol-based hand rubs.
Alcohol-based hand rubs (ABHR) range in alcohol concentration from 60-95% and are available in a variety of delivery formats, such as rinses, gels, and foams. Recent studies suggest that some ABHR foams dry too slowly, thereby encouraging the use of inadequate volumes. This study investigates the influence of product volume, delivery format, and alcohol concentration on dry-time and antimicrobial efficacy of ABHR foams, gels and rinses. ABHR dry-times were measured using volunteers to determine the influences of product volume, delivery format, and alcohol concentration. ABHR efficacies were evaluated according to the European Standard for Hygienic Hand Disinfection (EN 1500) using 3-mL application volumes rubbed for 30 s, and additionally, using volumes of the products determined to rub dry in 30 s. Volumes of six ABHR determined to rub dry in 30 s ranged from 1.7 mL to 2.1 mL, and the rate of drying varied significantly between products. ABHR dry-times increased linearly with application volume and decreased linearly with increasing alcohol concentration, but were not significantly influenced by product format. An ABHR foam (70% EtOH), rinse (80% EtOH), and gel (90% EtOH) each met EN 1500 efficacy requirements when tested at a volume of 3 mL, but failed when tested at volumes that dried in 30 s. Application volume is the primary driver of ABHR dry-time and efficacy, whereas delivery format does not significantly influence either. Although products with greater alcohol concentration dry more quickly, volumes required to meet EN 1500 can take longer than 30 s to dry, even when alcohol concentration is as high as 90%. Future studies are needed to better understand application volumes actually used by healthcare workers in practice, and to understand the clinical efficacy of ABHR at such volumes.


Superior labral anterior-posterior lesions in rock climbers—primary double tenodesis?
Shoulder problems, especially SLAP (superior labral anterior-posterior) lesions, are frequent in rock climbers. Although various SLAP repair methods demonstrate 75% to 97% good functional outcomes in general population, the results in overhead athletes are inconsistent and the question whether a primary tenodesis is more efficient arises. Prospective cohort study. The patients were treated as inpatient surgical patients, and the follow-up was performed after 6 months and 2 years. Six high-level rock climbers with SLAP lesions and degeneration of the long biceps tendon anchor or additional pulley lesions were surgically treated with primary tenodesis. Primary tenodesis was performed for SLAP lesions in high-level climbers. The postoperative outcome was assessed through physical examination after 6 months and 2 years, Constant-Murley score, re-establishment of initial climbing ability level, and self-perception of the function of the shoulder and climbing ability. All climbers regained their initial climbing level after 6 months. The Constant-Murley score (mean, 97.3%) showed an excellent functional outcome. The self-perception of the shoulder function and climbing ability was 96.8% of normal. The primary biceps tenodesis is proved to be a reliable alternative to arthroscopic SLAP repair in overhead athletes, especially if constant microtrauma persists.


Onset and progression of diabetic glomerulosclerosis; a prospective study based on serial renal biopsies.
Clinical factors related to the development and progression of renal lesions were studied in twenty-three diabetics by the use of serial renal biopsies or autopsy. The results were as follows: Most of the juvenile and intermediate type diabetics were poorly controlled, with the glomerular lesion progressing rather rapidly. In contrast, many cases of the adult type were able to be maintained under good control and the renal lesion neither developed nor progressed. Two of the adult type diabetics with poor control showed slowly and slightly progressing renal lesions. The progression of glomerular lesions was significantly related to the control of blood glucose, type of diabetes, age at onset, type of treatment, and degree of obesity, but not to the duration of diabetes or the length of the follow-up period. There was a significant correlation between the type of diabetes and the control of blood glucose over the years. Arteriolar lesions developed concurrently with the progression of the glomerular lesion. Retinopathy also had a tendency to develop in proportion to the progress of glomerular lesions although it was not statistically significant. We have discussed the clinical factors responsible for the progression of diabetic glomerulosclerosis and have suggested that the type of diabetes rather than the degree of control of blood glucose might be more important in determining the development and progression of diabetic glomerulosclerosis. Nevertheless, the possibility remains that successful control of blood glucose may prevent or retard the development of diabetic glomerulosclerosis.


Exact ionization potentials from wavefunction asymptotics: the extended Koopmans' theorem, revisited.
A simple explanation is given for the exactness of the extended Koopmans' theorem, (EKT) for computing the removal energy of any many-electron system to the lowest-energy ground state ion of a given symmetry. In particular, by removing the electron from a "removal orbital" of appropriate symmetry that is concentrated in the asymptotic region, one obtains the exact ionization potential and the exact Dyson orbital for the corresponding state of the ion. It is argued that the EKT is not restricted to many-electron systems but holds for any finite many-body system, provided that the interaction vanishes for increasing interparticle distance. A necessary and sufficient condition for the validity of the EKT for any state (not just the lowest-energy states of a given symmetry) in terms of the third-order reduced density matrix is stated and derived.


Alternative pathway regulation by factor H modulates Streptococcus pneumoniae induced proinflammatory cytokine responses by decreasing C5a receptor crosstalk.
Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection.


Skeletal blood flow in Paget's disease of bone and its response to calcitonin therapy.
1. Blood flow to the skeleton was measured by the 18F clearance method of Wooton, Reeve & Veall (1976) in 24 patients with untreated Paget's disease. In every patient but one, resting skeletal blood flow was increased. There was a significant positive correlation between skeletal blood flow and serum alkaline phosphatase and between skeletal blood flow and urinary total hydroxyproline excretion. 2. Fourteen patients were re-studied after they had received short-term (7 days or less) or long-term (7 weeks or more) calcitonin. Skeletal blood flow, alkaline phosphatase and urinary hydroxy-proline excretion fell towards normal in every case. There was some evidence from the short-term studies that calcitonin produced a more rapid fall in skeletal blood flow than in alkaline phosphatase. 3. Glomerular filtration rate appeared to increase transiently in response to calcitonin.


Prediction methods of maxillary canine impaction: a systematic review.
To describe and assess the available evidence of prediction methods of maxillary canine impaction (MCI). A systematic search was conducted through PubMed, Cochrane Library, Embase, EBSCOhost, Scopus, ScienceDirect, Bireme and Scielo until December 2020. This systematic review was conducted according to the PRISMA statement. The methodology of the selected studies was assessed using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2). A total of 2391 articles were identified in the first approach and after a 2-phase selection, 11 studies were included in qualitative analysis. Prediction methods were constructed using equation-based models, geometric measurements and computational methods from clinical and imaging data to predict palatal/buccal MCI. The quality of evidence was low to moderate due to the presence of risk of bias in most of the studies included. Three cohort studies with the best methodological quality proposed prediction models based on geometric measurements, canine position and facial growth pattern that would allow predicting MCI from CBCT, lateral and panoramic radiographs. The evidence is limited and most of the studies present a low methodological quality. However, it is possible to suggest that some prediction methods based on the position of the canine and facial growth pattern could predict palatal/buccal MCI in mixed dentition. Cohort studies with better methodological quality and long-term follow-up are needed to better validate a prediction model.


QSPR Modeling of Bioconcentration Factors of Nonionic Organic Compounds.
The terms bioaccumulation and bioconcentration refer to the uptake and build-up of chemicals that can occur in living organisms. Experimental measurement of bioconcentration is time-consuming and expensive, and is not feasible for a large number of chemicals of potential regulatory concern. A highly effective tool depending on a quantitative structure-property relationship (QSPR) can be utilized to describe the tendency of chemical concentration organisms represented by, the important ecotoxicological parameter, the logarithm of Bio Concentration Factor (log BCF) with molecular descriptors for a large set of non-ionic organic compounds. QSPR models were developed using multiple linear regression, partial least squares and neural networks analyses. Linear and non-linear QSPR models to predict log BCF of the compounds developed for the relevant descriptors. The results obtained offer good regression models having good prediction ability. The descriptors used in these models depend on the volume, connectivity, molar refractivity, surface tension and the presence of atoms accepting H-bonds.


A mixed integer linear programming model to reconstruct phylogenies from single nucleotide polymorphism haplotypes under the maximum parsimony criterion.
Phylogeny estimation from aligned haplotype sequences has attracted more and more attention in the recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from medical research, to drug discovery, to epidemiology, to population dynamics. The literature on molecular phylogenetics proposes a number of criteria for selecting a phylogeny from among plausible alternatives. Usually, such criteria can be expressed by means of objective functions, and the phylogenies that optimize them are referred to as optimal. One of the most important estimation criteria is the parsimony which states that the optimal phylogeny T∗for a set H of n haplotype sequences over a common set of variable loci is the one that satisfies the following requirements: (i) it has the shortest length and (ii) it is such that, for each pair of distinct haplotypes hi,hj∈H, the sum of the edge weights belonging to the path from hi to hj in T∗ is not smaller than the observed number of changes between hi and hj. Finding the most parsimonious phylogeny for H involves solving an optimization problem, called the Most Parsimonious Phylogeny Estimation Problem (MPPEP), which is NP-hard in many of its versions. In this article we investigate a recent version of the MPPEP that arises when input data consist of single nucleotide polymorphism haplotypes extracted from a population of individuals on a common genomic region. Specifically, we explore the prospects for improving on the implicit enumeration strategy of implicit enumeration strategy used in previous work using a novel problem formulation and a series of strengthening valid inequalities and preliminary symmetry breaking constraints to more precisely bound the solution space and accelerate implicit enumeration of possible optimal phylogenies. We present the basic formulation and then introduce a series of provable valid constraints to reduce the solution space. We then prove that these constraints can often lead to significant reductions in the gap between the optimal solution and its non-integral linear programming bound relative to the prior art as well as often substantially faster processing of moderately hard problem instances. We provide an indication of the conditions under which such an optimal enumeration approach is likely to be feasible, suggesting that these strategies are usable for relatively large numbers of taxa, although with stricter limits on numbers of variable sites. The work thus provides methodology suitable for provably optimal solution of some harder instances that resist all prior approaches.


Clinical application of liver stiffness measurement using transient elastography: a surgical perspective.
Liver biopsy (LB) remains the gold standard for assessing the severity of liver fibrosis; however, LB is often limited by its invasiveness, sampling error, and intra-/inter-observer variability in histological interpretation. Furthermore, repeated LB examinations within a short time interval are ineligible in real clinical practice. Thus, due to the pressing need for non-invasive surrogates, over the past decade, significant progress has been made in non-invasively assessing liver fibrosis. Of the methods now available, transient elastography (TE) appears to be an excellent tool for assessing liver fibrosis and also has some prognostic value in surgical settings. Recent studies have proposed the extended role of TE in the surgical field, based on the concept that TE values show significant correlations with portal hypertension and hepatocellular carcinoma development. TE appears promising in predicting postoperative short-term outcomes such as hepatic insufficiency or complications and long-term outcomes such as recurrence or liver-related death. Furthermore, TE may be useful in predicting the severity of liver fibrosis progression due to recurrence of hepatitis C virus infection or other underlying liver diseases after transplantation. TE cannot completely replace other tests accompanied with hepatic surgical treatments, including LB, endoscopic examination, hepatic venous pressure gradient evaluation, or the indocyanine green retention test. However, TE represents an important non-invasive tool that enables more efficient and tailored management strategies for patients who were treated with liver resection or transplantation. This review discusses extended TE applications in the surgical setting, such as hepatic resection or transplantation.


The future: putting Humpty-Dumpty together again.
Successful biological analysis requires that we understand the functional interactions between key components of cells, organs and systems, and how these interactions change in disease. This information resides neither in the genome nor in the individual proteins that genes encode. It lies at the level of protein interactions within the context of sub-cellular, cellular, tissue, organ and system structures. There is therefore no alternative to copying Nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases, models of cells, tissues and organs, and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. Systems biology of the 21st century is set to become highly quantitative, and therefore one of the most computer-intensive disciplines.


Coevolution of the mammalian middle ear and neocortex.
Phylogenetic analysis with x-ray computed tomography of fossilized and recent crania implicates differential growth of the neocortex in the evolution and development of the mammalian middle ear. In premammalian tetrapods, the middle ear evolved as a chain of bones attached to the mandible and cranium, but in adult mammals the chain is detached from the mandible and lies behind it. The neocortex evolved concurrently with detachment of the chain. In mammalian development the auditory chain arises connected to the mandible but later detaches, recapitulating the phylogenetic transformation. In modern didelphid development, the auditory chain reaches mature size by the third week after birth and is then separated from the jaw and displaced caudally as the neocortex grows for another 9 weeks.


Mathematical extrapolation of image spectrum for constraint-set design and set-theoretic superresolution.
Several powerful iterative algorithms are being developed for the restoration and superresolution of diffraction-limited imagery data by use of diverse mathematical techniques. Notwithstanding the mathematical sophistication of the approaches used in their development and the potential for resolution enhancement possible with their implementation, the spectrum extrapolation that is central to superresolution comes in these algorithms only as a by-product and needs to be checked only after the completion of the processing steps to ensure that an expansion of the image bandwidth has indeed occurred. To overcome this limitation, a new approach of mathematically extrapolating the image spectrum and employing it to design constraint sets for implementing set-theoretic estimation procedures is described. Performance evaluation of a specific projection-onto-convex-sets algorithm by using this approach for the restoration and superresolution of degraded images is outlined. The primary goal of the method presented is to expand the power spectrum of the input image beyond the range of the sensor that captured the image.


Dietary factors associated with wheezing and allergic rhinitis in children.
The effect of dietary factors on asthma is controversial. This study examined food consumption and the use of fats in relation to wheezing and allergic rhinitis in children. Baseline questionnaire data on individual and family characteristics were recorded by parents of 5,257 children aged 6-7 yrs living in central Italy participating in the International Study on Asthma and Allergies in Childhood study. A total of 4,104 children (78.1%) were reinvestigated after 1 yr using a second parental questionnaire to record occurrence of respiratory symptoms over the intervening 12 months. Consumption of foods rich in antioxidants, such as vitamins C and E, animal fats, and food containing omega-3 fatty acids were investigated using a food-frequency questionnaire. Frequency of use of fats was also evaluated. Wheezing, shortness of breath with wheeze, and symptoms of allergic rhinitis in the past 12 months were considered. Intake of cooked vegetables, tomatoes, and fruit were protective factors for any wheeze in the last 12 months and shortness of breath with wheeze. Consumption of citrus fruit had a protective role for shortness of breath with wheeze. Consumption of bread and margarine was associated with an increased risk of wheeze, while bread and butter was associated with shortness of breath with wheeze. Dietary antioxidants in vegetables may reduce wheezing symptoms in childhood, whereas both butter and margarine may increase the occurrence of such symptoms.


Formation of nitrogenous disinfection by-products from pre-chloramination.
A sampling survey investigated the formation of nitrogenous disinfection by-products (N-DBPs) and carbonaceous DBPs (C-DBPs) from pre-chloramination, an increasingly common treatment strategy in China for regulated C-DBP control, followed by subsequent conventional water treatment processes, i.e., coagulation, sedimentation, and filtration. Dihalogenated N-DBPs typically peaked in the summer and early autumn with a relatively higher temperature, with the maximum levels of dichloroacetamide (DCAcAm), dichloroacetonitrile (DCAN), bromochloroacetonitrile, dibromoacetonitrile and dichloroacetone at 1.8, 6.3, 6.0, 2.6 and 1.8μgL(-1) in the finished water, respectively. Also, the levels of all the dichlorinated N-DBPs were correlated with the ratio of dissolved organic nitrogen (DON) to dissolved organic carbon, implying autochthonous DON played an essential role in the formation of these DBPs. In contrast, the yields of trihalogenated DBPs [chloroform (CF), trichloronitromethane (TCNM) and trichloroacetone (TCAce)] appeared not to be significantly affected by seasons. CF and DCAN were the dominant species in trihalomethanes (THMs) and dihaloacetonitriles (DHANs), respectively. Bromine was more readily incorporated into DHANs to form brominated DBPs than THMs during pre-chloramination. Although pre-chloramination can ensure the finished water to meet with the current Chinese THM regulatory limits, the increased levels of TCNM and TCAce may be a new water quality concern.


Predicting oral contraceptive continuation using the transtheoretical model of health behavior change.
Improved continuation of oral contraceptive use may decrease the incidence of unintended pregnancy. Therefore, identifying predictors of continuation is important to informing targeted interventions. A survey conducted in 2003-2005 collected data from young women who sought oral contraceptives at three family planning clinics in New York, Dallas and Atlanta. Cluster analysis of data from 1,245 women was used to identify three distinct groups on the basis of baseline responses to items measuring constructs from the transtheoretical model of health behavior change: perceived advantages of pill use, perceived disadvantages and self-confidence in ability to sustain use. Logistic regression was used to assess the likelihood of continuation among the clusters. Participants who were confident in their ability to use the pill and who considered both its advantages and its disadvantages important were more likely to continue use for six months than were those who gave low scores to the method's advantages and their ability to use it (odds ratio, 1.4). The same appeared to be true for those who gave high scores to the pill's advantages and their ability to use it, but a low score to the method's disadvantages (1.3); however, this finding was only marginally significant. Demographic variables were not significant after adjustment for cluster membership. Cluster membership based on transtheoretical model constructs helps predict oral contraceptive continuation. Women who undervalue the advantages of pill use and have low confidence in their ability to use the method represent a target for interventions and future research.


Transendothelial transport of serum albumin: a quantitative immunocytochemical study.
The steady-state distribution of endogenous albumin in mouse diaphragm was determined by quantitative postembedding protein A-gold immunocytochemistry using a specific anti-mouse albumin antibody. Labeling density was recorded over vascular lumen, endothelium, junctions, and subendothelial space. At equilibrium, the volume density of interstitial albumin was 18% of that in circulation. Despite this large difference in albumin concentration between capillary lumen and interstitium, plasmalemmal vesicles labeling was uniformly distributed across the endothelial profile. 68% of the junctions displayed labeling for albumin, which was however low and confined to the luminal and abluminal sides. The scarce labeling of the endothelial cell surface did not confirm the fiber matrix theory. The kinetics of albumin transcytosis was evaluated by injecting radioiodinated and DNP-tagged BSA. At 3, 10, 30, and 60 min, and 3, 5, and 24 h circulation time, blood radioactivity was measured and diaphragms were fixed and embedded. Anti-DNP antibodies were used to map the tracer in aforementioned compartments. A linear relationship between blood radioactivity and vascular labeling density was found, with a detection sensitivity approaching 1 gold particle per DNP-BSA molecule. Tracer presence over endothelial vesicles reached rapidly (10 min) a saturation value; initially localized near the luminal front, it evolved towards a uniform distribution across endothelium during the first hour. An hour was also needed to reach the saturation limit within the subendothelial space. Labeling of the junctions increased slowly, out of phase with the inferred transendothelial albumin fluxes. This suggests that they play little, if any, role in albumin transcytosis, which rather seems to proceed through the vesicular way.


The Primary Care Assessment Survey: tests of data quality and measurement performance.
The authors examine the data quality and measurement performance of the Primary Care Assessment Survey (PCAS), a patient-completed questionnaire that operationalizes formal definitions of primary care, including the definition recently proposed by the Institute of Medicine Committee on the Future of Primary Care. The PCAS measures seven domains of care through 11 summary scales: accessibility (organizational, financial), continuity (longitudinal, visit-based), comprehensiveness (contextual knowledge of patient, preventive counseling), integration, clinical interaction (clinician-patient communication, thoroughness of physical examinations), interpersonal treatment, and trust. Data from a study of Massachusetts state employees (n = 6094) were used to evaluate key measurement properties of the 11 PCAS scales. Analyses were performed on the combined population and for each of the 16 subgroups defined according to sociodemographic and health characteristics. The 11 PCAS scales demonstrated consistently strong measurement characteristics across all subgroups of this adult population. Tests of scaling assumptions for summated rating scales were well satisfied by all Likert-scaled measures. Assessment of data completeness, scale score dispersion characteristics, and inter-scale correlations provide strong evidence for the soundness of all scales, and for the value of separately measuring and interpreting these concepts. With public and private sector policies increasingly emphasizing the importance of primary care, the need for tools to evaluate and improve primary care performance is clear. The PCAS has excellent measurement properties, and performs consistently well across varied segments of the adult population. Widespread application of an assessment methodology, such as the PCAS, will afford an empiric basis through which to measure, monitor, and continuously improve primary care.


Effects of Strength Training Using Unstable Surfaces on Strength, Power and Balance Performance Across the Lifespan: A Systematic Review and Meta-analysis.
The effectiveness of strength training on unstable surfaces (STU) versus stable surfaces (STS) or a control condition (CON; i.e., no training or regular training only) for strength, power and balance performance across the lifespan has not yet been investigated in a systematic review and meta-analysis. The aims of this systematic review and meta-analysis were to determine the general effects of STU versus STS or CON on muscle strength, power and balance in healthy individuals across the lifespan and to investigate whether performance changes following STU are age specific. A computerized systematic literature search was performed in the electronic databases PubMed and Web of Science from January 1984 up to February 2015. Initially, 209 articles were identified for review. Only controlled trials were included if they investigated STU in healthy individuals and tested at least one measure of maximal strength, strength endurance, muscle power, or static/dynamic balance. In total, 22 studies met the inclusion criteria. The included studies were coded for the following criteria: age, sex, training status, training modality, exercise and test modality. Effect size measures included within-subject standardized mean differences (SMDw) and weighted between-subject standardized mean differences (SMDb). Heterogeneity between studies was assessed using I2 and χ2 statistics. The methodological quality of each study was assessed using the Physiotherapy Evidence Database (PEDro) Scale. Our search failed to identify studies that examined the effects of STU versus STS or CON in children and middle-aged adults. However, four studies were identified that investigated the effects of STU versus CON or STS in adolescents, 15 studies were identified in young adults and three studies were identified in old adults. Compared with CON, STU produced medium effects on maximal strength in young adults and no effects to medium effects in old adults. In addition, large effects were detected on strength endurance in adolescents and in young adults; in old adults, a small effect was found. With regard to muscle power, medium effects were observed in young adults and small effects were observed in old adults. Further, large effects were found for static and dynamic balance in old adults, but only a small effect was found for dynamic balance in young adults. The comparison of STU and STS revealed inconsistent results as indicated by training-induced changes in favour of STU, as well as STS. Small to medium effects were found for maximal strength in adolescents in favour of STS, and small effects were found in young adults in favour of STU. With regard to strength endurance, large effects were found in adolescents in favour of STS and small effects were found in favour of STU. Additionally, we detected small effects in young adults in favour of STU. In terms of muscle power, no effects were observed in adolescents but medium effects were found in favour of STS in young adults. With regard to balance, small effects were detected in adolescents for static and dynamic balance in favour of STU. In young adults, small effects were found for static balance in favour of STS. With regard to dynamic balance, the analysis revealed small effects in young adults in favour of STU. The quality of the included studies was rather low, with mean PEDro scores of 5.8, 4.0 and 5.0 for studies including adolescents, young adults and old adults, respectively. Further, trivial to considerable heterogeneity between studies (i.e., 0% ≤ I2 ≤ 96%) was detected. Compared with CON, STU is effective in improving muscle strength, power and balance in adolescents, young adults and old adults. However, inconsistent results were particularly found in adolescents and young adults when the specific effects of STU were compared with those of STS. We conclude that the performance of STU compared with STS has limited extra effects on muscle strength, power and balance performance in healthy adolescents and young adults. Given that our systematic search did not identify studies that examined the effects of STU versus STS in children, middle-aged adults and old adults, further research of high methodological quality is needed to determine whether there are additive effects of STU as compared with STS in those age groups.


Scattering by two rayleigh-debye spheres.
The Rayleigh-Gans approximation theory is applied to the problem of scattering by two neighboring spherical particles. For simplicity, we have examined in detail the case of two identical uniform spheres. Differential intensities for any arbitrary location of the particle pair relative to the incident wave, mean intensities, and mean scattering cross sections for randomly oriented particles are considered. The results show good agreement with the exact theory. Some numerical results are presented for the particular case of touching spheres (dumbbells), which are either at random, or are at specific, orientation relative to the direction of polarization of the incident wave. It is observed that for small spheres at random orientation, the scattering cross section is four times the value for that of a single sphere. This factor is two for large particles. We also observe that both the intensity and dissymmetry patterns for two spheres are totally different from the single particle ones.


A description of eosinophilic esophagitis in the Southwestern state of Nevada.
Eosinophilic esophagitis (EoE) is a rare immune-mediated esophageal disorder that has been documented worldwide. Prior to this study, eosinophilic esophagitis had not been described in the Southwestern state of Nevada. Records containing positive eosinophilic esophagitis diagnosis codes were extracted from a large hospital utilization database and yielded over 2,000 records over 5 years (2013-2017). Descriptive statistics were used to identify the overall population demography. Logistic regression was used to determine the factors associated with an eosinophilic esophagitis event in Nevada. Males were 2.93 times more likely (95% CI: 2.53, 3.41; p < 0.001) to have had an eosinophilic esophagitis event when compared to females. Older age was also significant; for each additional year in age the odds of having an eosinophilic esophagitis visit increased by 30% (95% CI: 1.28, 1.31; p < 0.001). Finally, individuals living in the Northern region had 1.95 higher odds of an eosinophilic esophagitis event than their Southern counterparts (OR = 1.95, 95% CI: 1.68, 2.26; p < 0.001). The climate in Nevada makes this study novel, as the climate is unlike other studies reporting EoE disease prevalence. Previous atopic studies in Nevada report that warmer, drier weather leads to increased atopic illness and perennial pollen, which ultimately may be contributing to the higher than expected number of EoE records identified. Given the well-documented relationship between EoE and atopy, Nevada may be a susceptible region for this condition and an ideal location for future studies.


Restricted diffusion in the brain of transgenic mice with cerebral amyloidosis.
A prominent hallmark of Alzheimer's disease pathology is cerebral amyloidosis. However, it is not clear how extracellular amyloid-beta peptide (A beta) deposition and amyloid formation compromise brain function and lead to dementia. It has been argued that extracellular amyloid deposition is neurotoxic and/or that soluble A beta oligomers impair synaptic function. Amyloid deposits, by contrast, may affect diffusion properties of the brain interstitium with implications for the transport of endogenous signalling molecules during synaptic and/or extrasynaptic transmission. We have used diffusion-weighted magnetic resonance imaging to study diffusion properties in brains of young (6-month-old) and aged (25-month-old) APP23 transgenic mice and control littermates. Our results demonstrate that fibrillar amyloid deposits and associated gliosis in brains of aged APP23 transgenic mice are accompanied by a reduction in the apparent diffusion coefficient. This decrease was most pronounced in neocortical areas with a high percentage of congophilic amyloid and was not significant in the caudate putamen, an area with only modest and diffuse amyloid deposition. These findings suggest that extracellular deposition of fibrillar amyloid and/or associated glial proliferation and hypertrophy cause restrictions to interstitial fluid diffusion. Reduced diffusivity within the interstitial space may alter volume transmission and therefore contribute to the cognitive impairment in Alzheimer's disease.