Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance.
We investigated whether 6 wk of antioxidant supplementation (AS) would enhance 30 km time trial (TT) cycling performance. Eleven elite male cyclists completed a randomized, double-blind, cross-over study to test the effects of twice daily AS containing essential vitamins plus quercetin (FRS), and AS minus quercetin (FRS-Q) versus a baseline TT (B). MANOVA analysis showed that time to complete the 30 km TT was improved by 3.1% on FRS compared to B (P < 0.01), and by 2% over the last 5 km (P < 0.05). Absolute and relative (%HRmax) heart rates and percent VO2max were not different between trials, but average and relative power (% peak power) was higher on FRS (P < or = 0.01). Rates of carbohydrate and fat oxidation were not different between trials. Thus, FRS supplementation significantly improved high-intensity cycling TT performance through enhancement of power output. Further study is needed to determine the potential mechanism(s) of the antioxidant efficacy.


High intensity focused ultrasound as first line salvage therapy in prostate cancer local relapse after radical prostatectomy: 4-year follow-up outcomes.
Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. Despite the primary treatments, 20-30% of patients experience a recurrence. The main objective of this study was to evaluate the clinical efficacy of salvage high intensity focused ultrasound (HIF U) after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir. Twenty two patients with local recurrence of Pca after radical prostatectomy underwent HIFU as first-line salvage therapy. Considering that in all HIFU experiences, PSA nadir and PSA failure are different and PSA definition of BFSR is unknown, we defined treatment success as a PSA nadir ≤0.4 ng/mL 3 months after treatment. All early and late medical and surgical complications were recorded. Ten of the 22 patients (45.5%) were classified as "success" three months after HIFU, showing a nadir PSA≤0.4 ng/mL; 12/22 patients (54.5%) were classified as "failure" during follow-up (median follow-up: 48 months). Seventeen of 22 (77%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in 5 cases (early onset) after treatment. A case of vesicoureteral anastomotic stenosis was treated, endoscopically through cold urethrotomy. We did not observe cases of recto-urinary fistula or persistent lower urinary tract symptoms. Two sevenths of the patients complained about de novo erectile dysfunction after HIFU. The positive oncologic outcomes in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm these promising preliminary results.


Why breeding time has not responded to selection for earlier breeding in a songbird population.
A crucial assumption underlying the breeders' equation is that selection acts directly on the trait of interest, and not on an unmeasured environmental factor which affects both fitness and the trait. Such an environmentally induced covariance between a trait and fitness has been repeatedly proposed as an explanation for the lack of response to selection on avian breeding time. We tested this hypothesis using a long-term dataset from a Dutch great tit (Parus major) population. Although there was strong selection for earlier breeding in this population, egg-laying dates have changed only marginally over the last decades. Using a so-called animal model, we quantified the additive genetic variance in breeding time and predicted breeding values for females. Subsequently, we compared selection at the phenotypic and genetic levels for two fitness components, fecundity and adult survival. We found no evidence for an environmentally caused covariance between breeding time and fitness or counteracting selection on the different fitness components. Consequently, breeding time should respond to selection but the expected response to selection was too small to be detected.


Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia.
Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.


Development of Sponge Microspicule Cream as a Transdermal Delivery System for Protein and Growth Factors from Deer Antler Velvet Extract.
Sponge spicules are needle-like structures and used for dermabrasive treatment of the skin. This research aimed to develop an effective delivery system by using sponge spicules for enhancing skin permeation of bioactive proteins and growth factors from deer antler velvet (DAV). DAV was extracted by sonication and bioactivity studies were evaluated. The size of microspicules (MSs) was reduced and mixed with DAV extract cream. In vitro skin permeation was analyzed by using bovine serum albumin-fluorescein isothiocyanate conjugate (BSA-FITC) as a model macromolecular compound. For in vivo study, DAV extract formulations were applied on the skin of healthy humans, and effects were evaluated. Results showed that DAV extract containing proteins and growth factors increased the proliferation and migration of skin fibroblast cells. This extract was homogeneously mixed with spicule cream. Without blending, MS was 11.89 µm wide and 176.77 µm long; blending time exhibited short and broken MSs (MBs) for short blending (30 s) and fine powder (MF) for long blending (10 min). MS cream showed the highest permeation of BSA-FITC through the skin (2.26-fold enhancement), but it resulted in skin irritation. Therefore, MB cream that increased the permeation of BSA-FITC by 1.94-fold was not significantly different from MS formulations chosen for in vivo study. Applying DAV-containing MB cream on the skin for 14 d decreased the melanin content and erythema value but increased elasticity and hydration. Therefore, the MB-containing cream can enhance the macromolecule delivery through the skin, improve the skin properties, and avoid skin irritation.


Molecular Dynamics Study of the Conformation, Ion Adsorption, Diffusion, and Water Structure of Soluble Polymers in Saline Solutions.
Polymers have interesting physicochemical characteristics such as charge density, functionalities, and molecular weight. Such attributes are of great importance for use in industrial purposes. Understanding how these characteristics are affected is still complex, but with the help of molecular dynamics (MD) and quantum calculations (QM), it is possible to understand the behavior of polymers at the molecular level with great consistency. This study was applied to polymers derived from polyacrylamide (PAM) due to its great use in various industries. The polymers studied include hydrolyzed polyacrylamide (HPAM), poly (2-acrylamido-2-methylpropanesulfonate) (PAMPS), polyacrylic acid (PAA), polyethylene oxide polymer (PEO), and guar gum polysaccharide (GUAR). Each one has different attributes, which help in understanding the effects on the polymer and the medium in which it is applied along a broad spectrum. The results include the conformation, diffusion, ion condensation, the structure of the water around the polymer, and interatomic polymer interactions. Such characteristics are important to selecting a polymer depending on the environment in which it is found and its purpose. The effect caused by salinity is particular to each polymer, where polymers with an explicit charge or polyelectrolytes are more susceptible to changes due to salinity, increasing their coiling and reducing their mobility in solution. This naturally reduces its ability to form polymeric bridges due to having a polymer with a smaller gyration radius. In contrast, neutral polymers are less affected in their structure, making them favorable in media with high ionic charges.


Is a longer time interval between recombinant human deoxyribonuclease (dornase alfa) and chest physiotherapy better? A multi-center, randomized crossover trial.
Although the benefits of recombinant human deoxyribonuclease (dornase alfa) in patients with cystic fibrosis (CF) are established, its optimal timing in relation to physiotherapy is unknown. As its enzymatic effect lasts for 6-11 hr, dornase alfa may be more efficacious if the time interval between inhalation and chest physiotherapy is increased. The aim of this study was to investigate if a longer time interval between dornase alfa nebulization and chest physiotherapy improves clinical outcomes of subjects with CF. A single-blind randomized cross-over trial was conducted on subjects with CF from outpatients of four hospitals. Subjects were in stable health and studied over 6 weeks (utilizing 14-day blocks of morning or evening dornase alfa administration with 14 days washout). Usual regimens for physiotherapy and exercise were unaltered. Thus changing the times altered the dwell time of dornase alfa prior to physiotherapy. Long interval was defined as dwell time of >6 hr and short as < or =6 hr. Outcomes were measured at pre and post each regimen. Twenty subjects aged 7-40 years completed the study. At end of long interval regimen, (median interval = 11.1 hr), FEF(25-75%) and CF-specific quality of life significantly improved compared to baseline values and to short interval regimen (median interval = 0.25 hr) outcomes. FVC, FEV(1), sputum weights, and adherence were similar in both regimens. A longer time interval between dornase alfa and physiotherapy is more efficacious than short interval. Administration timing of dornase alfa based on patient choice to incorporate longer interval time is likely to be the best regimen for patients previously established on dornase alfa nebulization.


Insulin resistance: Genetic associations with depression and cognition in population based cohorts.
Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition.


Methicillin-resistant Staphylococcus aureus in palliative care: A prospective study of Methicillin-resistant Staphylococcus aureus prevalence in a hospital-based palliative care unit.
Methicillin-resistant Staphylococcus aureus is a common organism in hospitals worldwide and is associated with morbidity and mortality. However, little is known about the prevalence in palliative care patients. Furthermore, there is no standardized screening protocol or treatment for patients for whom therapy concentrates on symptom control. Examining the prevalence of methicillin-resistant Staphylococcus aureus in palliative care patients as well as the level of morbidity and mortality. We performed a prospective study where methicillin-resistant Staphylococcus aureus screening was undertaken in 296 consecutive patients within 48 h after admission to our palliative care unit. Medical history was taken, clinical examination was performed, and the Karnofsky Performance Scale and Palliative Prognostic Score were determined. Prevalence of Methicillin-resistant Staphylococcus aureus was compared to data of general hospital patients. In total, 281 patients were included in the study having a mean age of 69.7 years (standard deviation = 12.9 years) and an average Karnofsky Performance Scale between 30% and 40%. The mean length of stay was 9.7 days (standard deviation = 7.6 days). A total of 24 patients were methicillin-resistant Staphylococcus aureus positive on the first swab. Median number of swabs was 2. All patients with a negative methicillin-resistant Staphylococcus aureus swab upon admission remained Methicillin-resistant Staphylococcus aureus negative in all subsequent swabs. Our study suggests that the prevalence of Methicillin-resistant Staphylococcus aureus among patients in an in-hospital palliative care unit is much higher than in other patient populations.


Growth and development of the placenta in the capybara (Hydrochaeris hydrochaeris).
The guinea pig is an attractive model for human pregnancy and placentation, mainly because of its haemomonochorial placental type, but is rather small in size. Therefore, to better understand the impact of body mass, we studied placental development in the capybara which has a body mass around 50 kg and a gestation period of around 150 days. We paid attention to the development of the lobulated arrangement of the placenta, the growth of the labyrinth in the course of gestation, the differentiation of the subplacenta, and the pattern of invasion by extraplacental trophoblast. Material was collected from six animals at pregnancy stages ranging from the late limb bud stage to mid gestation. Methods included latex casts, standard histology, immunohistochemistry for cytokeratin, vimentin, alpha-smooth muscle actin, and proliferating cell nuclear antigen as well as transmission electron microscopy. At the limb bud stage, the placenta was a pad of trophoblast covered by a layer of mesoderm from which fetal vessels were beginning to penetrate at folds in the surface. By 70 days, the placenta comprised areas of labyrinth (lobes) separated by interlobular areas. Placental growth resulted predominantly from proliferation of cellular trophoblast situated in nests at the fetal side of the placenta and along internally directed projections on fetal mesenchyme. Additional proliferation was demonstrated for cellular trophoblast within the labyrinth.Already at the limb bud stage, there was a prominent subplacenta comprising cellular and syncytial trophoblast with mesenchyme and associated blood vessels. At 90 days, differentiation was complete and similar to that seen in other hystricognath rodents. Overlap of fetal vessels and maternal blood lacunae was confirmed by latex injection of the vessels. At all stages extraplacental trophoblast was associated with the maternal arterial supply and consisted of cellular trophoblast and syncytial streamers derived from the subplacenta. All important characteristics of placental development and organization in the capybara resembled those found in smaller hystricognath rodents including the guinea pig. These features apparently do not dependent on body size. Clearly, placentation in hystricognaths adheres to an extraordinarily stable pattern suggesting they can be used interchangeably as models of human placenta.


Total and distributed plantar loading in subjects with stage II tibialis posterior tendon dysfunction during terminal stance.
In subjects with stage II tibialis posterior tendon dysfunction (TPTD), the function of the tibialis posterior muscle is altered and may be associated with a change in total and distributed loading. Thirty subjects with a diagnosis of stage II TPTD and 15 matched control subjects volunteered to participate in a study to examine the total and distributed plantar loading under the foot during the terminal stance phase of gait. Plantar loading, measured as the subject walked barefoot, was assessed using instrumented flexible insoles. A secondary analysis was done to explore the contribution of flatfoot kinematics to plantar loading patterns. Overall, there was reduced total plantar loading in subjects with stage II TPTD compared with controls. Accounting for differences in total loading, the presence of clinically measured weakness in subjects with TPTD was associated with reduced lateral forefoot loading. Medial longitudinal arch height was significantly correlated with loading patterns but explained only 21% of the variance in observed loading patterns. Subjects with TPTD who are strong exhibited loading patterns similar to controls. Changes in total and distributed loading during terminal stance suggest there are altered ankle mechanics at push-off during the functional task of gait. Strength, in the presence of TPTD, may be important to stabilize the midfoot during gait and might be important in rehabilitation protocols.


Socio-economic determinants of casualty and NHS Direct use.
There is limited evidence on the social determinants of A&E use and concerns over the equity of NHS Direct utilization. We analysed data from the 2004-05 British General Household Survey, which included 20,421 participants. Logistic regression was used to examine individual casualty use in the last 3 months and household NHS Direct use in the last year. Casualty use was higher for individuals living in rented accommodation or without car access, lower income groups, unskilled manual workers, current smokers and for individuals with limiting illness. In contrast, NHS Direct use was lower in households with older residents, low income, no car access and where the head of household was from a manual occupational group, a minority ethnic group or born outside the UK. The odds ratio for use of NHS Direct for households in the lowest equivalized income quintile was 0.67 (0.55-0.81). Adjustment for limiting illness increased the effect of socio-economic factors on NHS Direct use. Reduced access to A&E services will disproportionately affect poorer individuals, whereas increased investment in telephone services will benefit affluent populations. Current national policy may widen inequities in access to emergency care.


The effect of aprotinin on the absorption of subcutaneously injected regular insulin in normal subjects.
The effect of aprotinin on the absorption of regular insulin was assessed in normal man. Ten units of Actrapid insulin were subcutaneously injected together with 1.4 mg aprotinin (i.e., 0.5 ml of Trasylol) or an equivalent volume of physiologic saline (controls) into the thighs of overnight-fasted normal subjects. Aprotinin caused an increase in the rate of insulin entry into the circulation; the absolute amount of insulin that was detected in the circulation during the course of the experiment was also higher. In addition, the onset of the hypoglycemic action of exogenous insulin was significantly accelerated when insulin was administered together with aprotinin. These data suggest that aprotinin increases the absorption rate of subcutaneously injected insulin from its depot into the circulation, possibly by an inhibition of the local degradation of exogenous insulin at the injection site.


Patterns of information-seeking for cancer on the internet: an analysis of real world data.
Although traditionally the primary information sources for cancer patients have been the treating medical team, patients and their relatives increasingly turn to the Internet, though this source may be misleading and confusing. We assess Internet searching patterns to understand the information needs of cancer patients and their acquaintances, as well as to discern their underlying psychological states. We screened 232,681 anonymous users who initiated cancer-specific queries on the Yahoo Web search engine over three months, and selected for study users with high levels of interest in this topic. Searches were partitioned by expected survival for the disease being searched. We compared the search patterns of anonymous users and their contacts. Users seeking information on aggressive malignancies exhibited shorter search periods, focusing on disease- and treatment-related information. Users seeking knowledge regarding more indolent tumors searched for longer periods, alternated between different subjects, and demonstrated a high interest in topics such as support groups. Acquaintances searched for longer periods than the proband user when seeking information on aggressive (compared to indolent) cancers. Information needs can be modeled as transitioning between five discrete states, each with a unique signature representing the type of information of interest to the user. Thus, early phases of information-seeking for cancer follow a specific dynamic pattern. Areas of interest are disease dependent and vary between probands and their contacts. These patterns can be used by physicians and medical Web site authors to tailor information to the needs of patients and family members.


Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.
Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4-/- mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4-/- mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4-/- mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4-/- mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure.


Elevated serum alpha-1 antitrypsin is a major component of GlycA-associated risk for future morbidity and mortality.
GlycA is a nuclear magnetic resonance (NMR) spectroscopy biomarker that predicts risk of disease from myriad causes. It is heterogeneous; arising from five circulating glycoproteins with dynamic concentrations: alpha-1 antitrypsin (AAT), alpha-1-acid glycoprotein (AGP), haptoglobin (HP), transferrin (TF), and alpha-1-antichymotrypsin (AACT). The contributions of each glycoprotein to the disease and mortality risks predicted by GlycA remain unknown. We trained imputation models for AAT, AGP, HP, and TF from NMR metabolite measurements in 626 adults from a population cohort with matched NMR and immunoassay data. Levels of AAT, AGP, and HP were estimated in 11,861 adults from two population cohorts with eight years of follow-up, then each biomarker was tested for association with all common endpoints. Whole blood gene expression data was used to identify cellular processes associated with elevated AAT. Accurate imputation models were obtained for AAT, AGP, and HP but not for TF. While AGP had the strongest correlation with GlycA, our analysis revealed variation in imputed AAT levels was the most predictive of morbidity and mortality for the widest range of diseases over the eight year follow-up period, including heart failure (meta-analysis hazard ratio = 1.60 per standard deviation increase of AAT, P-value = 1×10-10), influenza and pneumonia (HR = 1.37, P = 6×10-10), and liver diseases (HR = 1.81, P = 1×10-6). Transcriptional analyses revealed association of elevated AAT with diverse inflammatory immune pathways. This study clarifies the molecular underpinnings of the GlycA biomarker's associated disease risk, and indicates a previously unrecognised association between elevated AAT and severe disease onset and mortality.


Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.
The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.


Differential diagnosis in dementia using the cerebral blood flow agent 99mTc HM-PAO: a SPECT study.
One of the potential clinical uses of the new cerebral blood flow agent 99mTc-hexamethylpropyleneamineoxime (HM-PAO) is the investigation of dementia, in particular to differentiate between dementia of the Alzheimer type (DAT) and multiinfarct dementia (MID). In this study 27 patients, 17 with DAT and 10 with MID, and three normal volunteers were imaged both with single photon emission CT and magnetic resonance. The HM-PAO perfusion deficits were much more common in the DAT group than in the MID group, especially in the temporoparietooccipital (TPO) regions. The two groups of patients were found to be significantly different (p less than 0.02), as regards the frequency of occurrence of bilateral TPO perfusion deficits. Four of the 17 DAT patients did not have bilateral TPO deficits but these included the three least impaired patients as assessed by psychometric testing.


Coinage metal complexes of a boron-substituted soft scorpionate ligand.
An improved synthesis of lithium phenyltris(methimazolyl)borate, Li[PhTm(Me)], (methimazole = 1-methylimidazole-2-thione) is described, and the structure of the methanol-solvated [Li(OHMe)4][PhTm(Me)] has been determined. The syntheses and characterization of complexes [M(PhTm(Me))(PR3)] (M = Cu, Ag, Au; R = Et, Ph;) are reported, and the complexes [Cu(PhTm(Me))(PPh3)], [Ag(PhTm(Me))(PEt3)] and [Au(PhTm(Me))(PEt3)] are crystallographically characterized, showing a progression from pseudo-tetrahedral geometry (copper, S3P coordination) to trigonal planar geometry (silver, S2P coordination) to linear geometry (gold, SP coordination). In addition, the copper(I) and silver(I) triphenylphosphine complexes of the adventitiously formed phenylhydrobis(methimazolyl)borate ligand, [M(PhBm(Me))(PPh3)], have been crystallographically characterized, showing both species to have a trigonal planar primary coordination sphere, with a secondary M...H-B interaction. Finally, reaction of copper(II) chloride with Li[PhTm(Me)] results in formation of a compound analyzing as [Cu(II)(PhTm(Me))Cl], although its extreme insolubility and marked instability have precluded its complete characterization. Attempts to prepare this by ultra-slow diffusion of the reactants through solvent blanks has led to isolation of a mixed-valence copper(I/II) methimazolate cluster, [Cu(I)10Cu(II)2(mt)12Cl2] and a copper(I) dimeric complex [Cu2(PhTm(Me))2], indicating that copper(II) ions oxidatively decompose the phenyltris(methimazolyl)borate anion.


Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys.
In vitro evidence of the involvement of the endoplasmic reticulum (ER) during drug-induced renal toxicity is accumulating. ER stress and ER-mediated cell death markers have been reported after exposure of renal cells to model toxicants and nephrotoxic drugs in various in vitro models, but in vivo experiments with clinically relevant nephrotoxic compounds are lacking. In order to determine the relevance of the in vitro findings, markers of ER stress (XBP1 messenger RNA processing and protein expression; GRP78 and GRP94 upregulation) and ER-mediated cell death (caspase-12 and calpain activation) were examined in kidney tissue of rats exposed to nephrotoxic doses of cisplatin (CIS), gentamicin (GEN), and p-aminophenol (PAP), a nephrotoxic metabolite of acetaminophen. XBP1 signaling was observed with all three drugs and was associated with increased expression of GRP94 and GRP78 in GEN- and PAP-treated animals, but surprisingly not after CIS exposure. m-Calpain expression was increased after 7 days of CIS treatment, whereas it was decreased in PAP-treated rats. Caspase-12 cleavage products were increased after CIS, GEN, and PAP administration. The results of this study demonstrate that three clinically relevant nephrotoxic drugs are all associated with changes in markers of ER stress and ER-mediated cell death in vivo. Further investigation is warranted to determine the role of the ER, the calpain system, and caspase-12 in drug-induced renal cell death.


Technical Note: Defining cyclotron-based clinical scanning proton machines in a FLUKA Monte Carlo system.
Cyclotron-based pencil beam scanning (PBS) proton machines represent nowadays the majority and most affordable choice for proton therapy facilities, however, their representation in Monte Carlo (MC) codes is more complex than passively scattered proton system- or synchrotron-based PBS machines. This is because degraders are used to decrease the energy from the cyclotron maximum energy to the desired energy, resulting in a unique spot size, divergence, and energy spread depending on the amount of degradation. This manuscript outlines a generalized methodology to characterize a cyclotron-based PBS machine in a general-purpose MC code. The code can then be used to generate clinically relevant plans starting from commercial TPS plans. The described beam is produced at the Provision Proton Therapy Center (Knoxville, TN, USA) using a cyclotron-based IBA Proteus Plus equipment. We characterized the Provision beam in the MC FLUKA using the experimental commissioning data. The code was then validated using experimental data in water phantoms for single pencil beams and larger irregular fields. Comparisons with RayStation TPS plans are also presented. Comparisons of experimental, simulated, and planned dose depositions in water plans show that same doses are calculated by both programs inside the target areas, while penumbrae differences are found at the field edges. These differences are lower for the MC, with a γ(3%-3 mm) index never below 95%. Extensive explanations on how MC codes can be adapted to simulate cyclotron-based scanning proton machines are given with the aim of using the MC as a TPS verification tool to check and improve clinical plans. For all the tested cases, we showed that dose differences with experimental data are lower for the MC than TPS, implying that the created FLUKA beam model is better able to describe the experimental beam.


Tolerance to naloxone-induced suppression of intake: learning and cross-tolerance to cholecystokinin in rats.
Experiments were conducted to evaluate the contribution of conditioning to tolerance to the meal-suppressive effect of naloxone (Nx) in rats. The results indicated (a) Nx suppresses consumption in a dose-dependent manner; (b) tolerance to this suppression of intake is "contingent" (the rat must eat in conjunction with drug administration for tolerance to develop); (c) tolerance is displayed only in the context of environmental cues previously associated with Nx; (d) Nx-tolerant rats overeat when presented with cues previously associated with the drug; (e) Nx-tolerant rats display cross-tolerance to cholecystokinin. The results are consistent with C.X. Poulos and H. Cappell's (1991) "homeostatic" theory of tolerance, as well as with the results of other experiments indicating that conditioning contributes to tolerance to many effects of various drugs.


Leveraging input and output structures for joint mapping of epistatic and marginal eQTLs.
As many complex disease and expression phenotypes are the outcome of intricate perturbation of molecular networks underlying gene regulation resulted from interdependent genome variations, association mapping of causal QTLs or expression quantitative trait loci must consider both additive and epistatic effects of multiple candidate genotypes. This problem poses a significant challenge to contemporary genome-wide-association (GWA) mapping technologies because of its computational complexity. Fortunately, a plethora of recent developments in biological network community, especially the availability of genetic interaction networks, make it possible to construct informative priors of complex interactions between genotypes, which can substantially reduce the complexity and increase the statistical power of GWA inference. In this article, we consider the problem of learning a multitask regression model while taking advantage of the prior information on structures on both the inputs (genetic variations) and outputs (expression levels). We propose a novel regularization scheme over multitask regression called jointly structured input-output lasso based on an ℓ(1)/ℓ(2) norm, which allows shared sparsity patterns for related inputs and outputs to be optimally estimated. Such patterns capture multiple related single nucleotide polymorphisms (SNPs) that jointly influence multiple-related expression traits. In addition, we generalize this new multitask regression to structurally regularized polynomial regression to detect epistatic interactions with manageable complexity by exploiting the prior knowledge on candidate SNPs for epistatic effects from biological experiments. We demonstrate our method on simulated and yeast eQTL datasets. Software is available at http://www.sailing.cs.cmu.edu/.


Cow's Milk and Immune Function in the Respiratory Tract: Potential Mechanisms.
During the last decades, the world has witnessed a dramatic increase in allergy prevalence. Epidemiological evidence shows that growing up on a farm is a protective factor, which is partly explained by the consumption of raw cow's milk. Indeed, recent studies show inverse associations between raw cow's milk consumption in early life and asthma, hay fever, and rhinitis. A similar association of raw cow's milk consumption with respiratory tract infections is recently found. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections. However, for ethical reasons, it is not possible to conduct controlled studies with raw cow's milk in infants, so formal proof is lacking to date. Because viral respiratory tract infections and aeroallergen exposure in children may be causally linked to the development of asthma, it is of interest to investigate whether cow's milk components can modulate human immune function in the respiratory tract and via which mechanisms. Inhaled allergens and viruses trigger local immune responses in the upper airways in both nasal and oral lymphoid tissue. The components present in raw cow's milk are able to promote a local microenvironment in which mucosal immune responses are modified and the epithelial barrier is enforced. In addition, such responses may also be triggered in the gut after exposure to allergens and viruses in the nasal cavity that become available in the GI tract after swallowing. However, these immune cells that come into contact with cow's milk components in the gut must recirculate into the blood and home to the (upper and lower) respiratory tract to regulate immune responses locally. Expression of the tissue homing-associated markers α4β7 and CCR9 or CCR10 on lymphocytes can be influenced by vitamin A and vitamin D3, respectively. Since both vitamins are present in milk, we speculate that raw milk may influence homing of lymphocytes to the upper respiratory tract. This review focuses on potential mechanisms via which cow's milk or its components can influence immune function in the intestine and the upper respiratory tract. Unraveling these complex mechanisms may contribute to the development of novel dietary approaches in allergy and asthma prevention.


Oxidative burst elicited by Bacillus mycoides isolate Bac J, a biological control agent, occurs independently of hypersensitive cell death in sugar beet.
Response of sugar beet cultivars C40 and USH11 to syringe infiltration of live and dead Bacillus mycoides isolate Bac J, a biological control agent, and virulent and avirulent isolates of Erwinia carotovora pv. betavasculorum was measured by monitoring systemic acquired resistance control of Cercospora beticola, specific activity of chitinase and beta-glucanase, the oxidative burst, and hypersensitive cell death at the infiltration site. Priming sugar beet with B. mycoides Bac J (1 x 10(8) cells/ml) and avirulent isolates of E. carotovora pv. betavasculorum (1 x 10(6) cells/ml) reduced C. beticola symptoms by nearly 70% on distal, untreated leaves. Systemic resistance responses elicited by live B. mycoides Bac J and avirulent E. carotovora pv. betavasculorum isolates, measured by assays for chitinase and beta-glucanase, were statistically equivalent, and biphasic hydrogen peroxide production was observed. Although similar in timing, the second hydrogen peroxide burst was twofold lower for B. mycoides Bac J than for avirulent E. carotovora pv. betavasculorum. Hypersensitive cell death was elicited by avirulent E. carotovora pv. betavasculorum but not B. mycoides Bac J. An oxidative burst was elicited by spray-applied B. mycoides Bac J under both light and green light conditions, indicating that the signal produced by B. mycoides Bac J was not reliant on the stomata for entry into sugar beet. A working model for signal delivery and systemic resistance induction by B. mycoides Bac J in sugar beet is proposed.


The application of gene expression microarray technology to kinetoplastid research.
Protozoan parasites in the order Kinetoplastida cause severe disease primarily in tropical and subtropical areas. Vaccines to control these diseases have shown some promise, but none are in active clinical use. Drug treatments are available for all of the acute infections, but the emergence of resistance and an unresponsive chronic phase are current problems. Rapid advances in genomic technology open the possibility of discovering new genes that can contribute to vaccine initiatives or serve as targets for development of new drugs. The DNA microarray is a genomic technology, which is being applied to new gene discovery in kinetoplastid parasites. Both cDNA and genomic microarrays for Leishmania major have identified a number of new genes that are expressed in a stage-specific fashion and preliminary results from a L. donovani genomic microarray also demonstrated new gene discovery. A microarray of Trypanosoma brucei genomic fragments identified new genes whose expression differs between the insect borne stage and the human infectious stage of the parasite. The next few years, building on this foundational work, should witness the most exciting stage as microarrays are applied to questions such as the basis of drug resistance, post kala azar dermal leishmaniasis, the regulation of differentiation to infectious stages, linking coordinately regulated pathways of genes and development of genetically defined parasites that may have potential as live attenuated vaccines.


Decreased plasma tryptophan levels in major depression.
Total plasma tryptophan was significantly lower in 12 depressed patients than in 12 normal controls. The ratio of total tryptophan to neutral amino acids was also decreased in the depressed patients suggesting that tryptophan availability to the brain might be reduced. There was no correlation between basal tryptophan concentrations in the depressed subjects and the subsequent neuroendocrine response to intravenous tryptophan.


Baseline Levels of Rapid Eye Movement Sleep May Protect Against Excessive Activity in Fear-Related Neural Circuitry.
Sleep, and particularly rapid eye movement sleep (REM), has been implicated in the modulation of neural activity following fear conditioning and extinction in both human and animal studies. It has long been presumed that such effects play a role in the formation and persistence of posttraumatic stress disorder, of which sleep impairments are a core feature. However, to date, few studies have thoroughly examined the potential effects of sleep prior to conditioning on subsequent acquisition of fear learning in humans. Furthermore, these studies have been restricted to analyzing the effects of a single night of sleep-thus assuming a state-like relationship between the two. In the current study, we used long-term mobile sleep monitoring and functional neuroimaging (fMRI) to explore whether trait-like variations in sleep patterns, measured in advance in both male and female participants, predict subsequent patterns of neural activity during fear learning. Our results indicate that higher baseline levels of REM sleep predict reduced fear-related activity in, and connectivity between, the hippocampus, amygdala and ventromedial PFC during conditioning. Additionally, skin conductance responses (SCRs) were weakly correlated to the activity in the amygdala. Conversely, there was no direct correlation between REM sleep and SCRs, indicating that REM may only modulate fear acquisition indirectly. In a follow-up experiment, we show that these results are replicable, though to a lesser extent, when measuring sleep over a single night just before conditioning. As such, baseline sleep parameters may be able to serve as biomarkers for resilience, or lack thereof, to trauma.SIGNIFICANCE STATEMENT Numerous studies over the past two decades have established a clear role of sleep in fear-learning processes. However, previous work has focused on the effects of sleep following fear acquisition, thus neglecting the potential effects of baseline sleep levels on the acquisition itself. The current study provides the first evidence in humans of such an effect. Specifically, the results of this study suggest that baseline rapid eye movement (REM) sleep may serve a protective function against enhanced fear encoding through the modulation of connectivity between the hippocampus, amygdala, and the ventromedial PFC. Building on this finding, baseline REM measurements may serve as a noninvasive biomarker for resilience to trauma or, conversely, to the potential development of posttraumatic stress disorder following trauma.


Cross-country comparison of strategies for building consumer trust in food.
Consumer trust in the modern food system is essential given its complexity. Contexts vary across countries with regard to food incidents, regulation and systems. It is therefore of interest to compare how key actors in different countries might approach (re)building consumer trust in the food system; and particularly relevant to understanding how food systems in different regions might learn from one another. The purpose of this paper is to explore differences between strategies for (re)building trust in food systems, as identified in two separate empirical studies, one conducted in Australia, New Zealand and the UK (Study 1) and another on the Island of Ireland (Study 2). Interviews were conducted with media, food industry and food regulatory actors across the two studies (n = 105 Study 1; n = 50 Study 2). Data were coded into strategy statements, strategies describing actions to (re)build consumer trust. Strategy statements were compared between Studies 1 and 2 and similarities and differences were noted. The strategy statements identified in Study 1 to (re)build consumer trust in the food system were shown to be applicable in Study 2, however, there were notable differences in the contextual factors that shaped the means by which strategies were implemented. As such, the transfer of such approaches across regions is not an appropriate means to addressing breaches in consumer trust. Notwithstanding, our data suggest that there is still capacity to learn between countries when considering strategies for (re)building trust in the food system but caution must be exercised in the transfer of approaches.


Evaluation of time-series data sets using the Pearson product-moment correlation coefficient.
The Pearson product-moment correlation has been used by researchers to compare time series data sets to assess the temporal similarities. Computer generated data, vertical ground reaction force (VGRF) data and hybrid data (constructed by combining features of computer generated and VGRF data) were used to investigate the influence of timing and amplitude differences on the effectiveness of this technique. Under a specific set of conditions the correlation coefficient is a valid and reliable indicator of temporal similarity. Deviations from these conditions, however, result in interactive effects between timing and amplitude components with subsequent reductions in the value of the coefficient. Although GRF data were evaluated, the results apply equally to other types of curves as well. The correlation coefficient is easy to use and can be used to evaluate the entire curve as opposed to discrete data points. Its usefulness is jeopardized, however, since it can be influenced by timing and amplitude differences as well as the characteristics of the curves being analyzed. A high coefficient is always indicative of temporal similarity but a lesser value does not guarantee a lack of temporal similarity.


Typology of Social Network Structures and Late-Life Depression in Low- and Middle-Income Countries.
Rapid social changes and youth migration ensures a continuous drain on the social networks of the elderly in Low- and Middle-Income Countries (LMICs). We reviewed available literature on the relationship between social network structures and depression among community dwelling older persons in LMICs with a view to identifying patterns that might provide information for designing preventive psychosocial interventions. We searched the MEDLINE database through Pubmed, extracted information on the typologies of social network structures in LMICs and identified dimensions with the strongest systematic association with late-life depression, by weight, using the inverse of variance method. All analyses were conducted using the Cochrane review manager version 5.3. Fourteen community-based surveys drawn from 16 LMIC contexts met criteria for syntheses. They included a total of 37,917 mostly female (58.8%) participants with an average age of 73.2 years. Social network size, contact with network, diversity of network, co-residency with own child, having more friends than family in the network, and prestigious standing of persons in the social network were protective structures against late-life depression. Conversely, low network diversity contributed 44.2% of the weight of all social network structures that are predictive of late-life depression. Recommendations are made for the design of new measures of social network structures in LMICs that captures the key dimensions identified. Epidemiological studies using such tools will provide more precise information for planning and prioritization of scarce resources for the prevention of late-life depression in LMICs.


Spatially resolved photochemical coding of reversibly anchored cysteine-rich domains.
We present a novel methodology to generate recodable surfaces using cysteine-rich domains (CRD) via a combination of photolithography and reversible covalently peptide-driven disulfide formation. Therefore, two 21mer CRD peptide derivatives were synthesized, one bearing an electron deficient fumarate group for immobilization via nitrile imine-ene mediated cycloaddition (NITEC) to a tetrazole-functional surface. Secondly, a bromine moiety is introduced to the CRD for analytic labelling purposes to detect surface encoding. The photolithography is conducted by selectively passivating the surface with a polyethylene glycol (PEG)-fumarate via NITEC using a photomask in a dotted pattern. Consecutively, the CRD-fumarate is immobilized via NITEC adjacent to the PEG-functional areas to the unaffected tetrazole covered surface layer. Subsequently, the CRD-bromide is covalently linked to the CRD-fumarate by forming disulfide bonds under mild reoxidative conditions in a buffer solution. The CRD-bromide is released from the surface upon reduction to recover the prior state of the surface without the bromine marker. The analysis of the CRD precursors is based on electrospray ionization mass spectrometry (ESI-MS). The surface analytics were carried out via time-of-flight secondary ion mass spectrometry (ToF-SIMS), unambiguously verifying the successful immobilization as well as coding and decoding of the CRD-bromide on the surface based on dynamically reversible disulfide bond formation.


Pushing NMR sensitivity limits using dynamic nuclear polarization with closed-loop cryogenic helium sample spinning.
We report a strategy to push the limits of solid-state NMR sensitivity far beyond its current state-of-the-art. The approach relies on the use of dynamic nuclear polarization and demonstrates unprecedented DNP enhancement factors for experiments performed at sample temperatures much lower than 100 K, and can translate into 6 orders of magnitude of experimental time-savings. This leap-forward was made possible thanks to the employment of cryogenic helium as the gas to power magic angle sample spinning (MAS) for dynamic nuclear polarization (DNP) enhanced NMR experiments. These experimental conditions far exceed what is currently possible and allows currently reaching sample temperatures down to 30 K while conducting experiments with improved resolution (thanks to faster spinning frequencies, up to 25 kHz) and highly polarized nuclear spins. The impressive associated gains were used to hyperpolarize the surface of an industrial catalyst as well as to hyperpolarize organic nano-assemblies (self-assembling peptides in our case), for whom structures cannot be solved using diffraction techniques. Sustainable cryogenic helium sample spinning significantly enlarges the realm and possibilities of the MAS-DNP technique and is the route to transform NMR into a versatile but also sensitive atomic-level characterization tool.


CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice.
CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell-dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4⁺CD25⁺ Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy.


Cytomegalovirus-specific cytotoxic T lymphocytes can be efficiently expanded from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell products ex vivo and safely transferred to stem cell transplantation recipients to facilitate immune reconstitution.
Uncontrolled cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation causes significant morbidity and mortality. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) is a promising therapy to treat reactivation and prevent viral disease. In this article, we describe the generation of clinical-grade CMV-specific CTLs directly from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell (G-HPC) products collected for transplantation. This method requires less than 2.5% of a typical G-HPC product to reproducibly expand CMV-specific CTLs ex vivo. Comparison of 11 CMV CTL lines generated from G-HPC products with 52 CMV CTL lines generated from nonmobilized peripheral blood revealed similar expansion kinetics and phenotype. G-HPC-derived CTLs produced IFN-γ after reexposure to CMVpp65 antigen and exhibited CMV-directed cytotoxicity but no alloreactivity against transplantation recipient-derived cells. Seven patients received CMV-specific CTL lines expanded from G-HPC products in a prophylactic adoptive immunotherapy phase I/II clinical trial. Use of G-HPC products will facilitate integration of CTL generation into established quality systems of transplantation centers and more rapid inclusion of T cell therapies into routine clinical care.


[Relationship between morphological and functional changes in the stomach with aging].
The authors investigated the relationship between morphological changes and functional changes of the stomach with ageing, especially in term of change of gastric emptying in 92 healthy subjects. We checked the difference in chronological age and the stomach age in these subjects (in order to assess these subjects). The morphological change was evaluated by extent of atrophic gastritis in endoscopical atrophic border and histological findings of biopsy specimens, and the functional change was evaluated by maximal acid output in gastric secretion. Atrophic gastritis was expanded and maximal acid output was significantly reduced with ageing. From these results we confirmed that there was no difference between the chronological age and the stomach age and the quality of these subjects was very good. Gastric emptying was investigated by the acetaminophen method. In spite of ageing, gastric emptying was almost constant in these healthy subjects.


Antibacterial Activity of In Situ Prepared Chitosan/Silver Nanoparticles Solution Against Methicillin-Resistant Strains of Staphylococcus aureus.
Investigation of new effective drugs against the methicillin-resistant strains of Staphylococcus aureus (MRSA) is an urgent issue of modern medicine. Antiseptics as an alternative of antibiotics are strong, sustained, and active preparations against resistant strains and do not violate microbiocenosis. The activity of in situ prepared chitosan-Ag nanoparticles (Ag NPs) solution with different component ratio was tested against MRSA isolated from patients. Ag NPs were synthesized via chemical reduction method using green chemistry approach. In order to improve antimicrobial activity and dispersibility of Ag NPs, surface modification of Ag NPs by cetrimonium bromide (CTAB) was performed. Ag NPs and chitosan-Ag NPs solution were characterized using X-ray diffraction, transmission electron microscopy, infrared spectroscopy, and spectrophotometric measurements. The results of XRD, FTIR, UV-Vis, and TEM measurements confirmed the chemical composition of chitosan and Ag NPs and their high purity. Chitosan-AgNPs solutions have shown their superior antimicrobial efficacy compared to its pure forms. At the same time, in situ preparation of chitosan-Ag NPs solution (chitosan powder 6.0 μg/ml, Ag/CTAB NPs) was not possible due to the precipitation of the components. This result is very promising and may be considered as an effective solution in fighting against drug-resistant bacteria.


Solenoid Driven Pressure Valve System: Toward Versatile Fluidic Control in Paper Microfluidics.
As paper-based diagnostics has become predominantly driven by more advanced microfluidic technology, many of the research efforts are still focused on developing reliable and versatile fluidic control devices, apart from improving sensitivity and reproducibility. In this work, we introduce a novel and robust paper fluidic control system enabling versatile fluidic control. The system comprises a linear push-pull solenoid and an Arduino Uno microcontroller. The precisely controlled pressure exerted on the paper stops the flow. We first determined the stroke distance of the solenoid to obtain a constant pressure while examining the fluidic time delay as a function of the pressure. Results showed that strips of grade 1 chromatography paper had superior reproducibility in fluid transport. Next, we characterized the reproducibility of the fluidic velocity which depends on the type and grade of paper used. As such, we were able to control the flow velocity on the paper and also achieve a complete stop of flow with a pressure over 2.0 MPa. Notably, after the actuation of the pressure driven valve (PDV), the previously pressed area regained its original flow properties. This means that, even on a previously pressed area, multiple valve operations can be successfully conducted. To the best of our knowledge, this is the first demonstration of an active and repetitive valve operation in paper microfluidics. As a proof of concept, we have chosen to perform a multistep detection system in the form of an enzyme-linked immunosorbent assay with mouse IgG as the target analyte.


Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension.
To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (beta=-1.25-/+0.17), whereas BN.GH2 (beta=0.66-/+0.09) and BN.GH18 (beta=0.71-/+0.07) had significantly decreased responses to ANGII from those observed in the BN (beta=0.88-/+0.08). The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.


Spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic severity going from high mortality within the first year for SMA type 1 to no mortality for the chronic and later onset forms.


[The impairing head-injured child (author's transl)].
Among 1,572 cases of children's head injuries, we have noted in 9 p. cent a secundary impairment of the neurological condition. 1) After a lucid interval, an intracranial hematoma (4 p. cent), much more after extradural than subdural, it can suddenly break out. Bradycardia and anemia are very evocative of it. 2) Without a real lucid interval (0.8 p. cent) the diagnosis of cortical contusion with oedema is settled after having eliminated an hematoma. 3) The so called baby's hemiconvulsion-hemiplegia syndrome (4.2 p. cent) is very particular in itself and its favorable evolution. In conclusion, clinical survey goes first. In emergency further investigations take place on account of the clinical findings: skull-X ray, carotid angiography and CT-Scanner.


Despite variation in volume, Veterans Affairs hospitals show consistent outcomes among patients with non-postoperative mechanical ventilation.
To assess the relationship between volume of nonoperative mechanically ventilated patients receiving care in a specific Veterans Health Administration hospital and their mortality. Retrospective cohort study. One-hundred nineteen Veterans Health Administration medical centers. We identified 5,131 hospitalizations involving mechanically ventilated patients in an intensive care unit during 2009, who did not receive surgery. None. We extracted demographic and clinical data from the VA Inpatient Evaluation Center. For each hospital, we defined volume as the total number of nonsurgical admissions receiving mechanical ventilation in an intensive care unit during 2009. We examined the hospital contribution to 30-day mortality using multilevel logistic regression models with a random intercept for each hospital. We quantified the extent of interhospital variation in 30-day mortality using the intraclass correlation coefficient and median odds ratio. We used generalized estimating equations to examine the relationship between volume and 30-day mortality and risk-adjusted all models using a patient-level prognostic score derived from clinical data representing the risk of death conditional on treatment at a high-volume hospital. Mean age for the sample was 65 (SD 11) yrs, 97% were men, and 60% were white. The median VA hospital cared for 40 (interquartile range 19-62) mechanically ventilated patients in 2009. Crude 30-day mortality for these patients was 36.9%. After reliability and risk adjustment to the median patient, adjusted hospital-level mortality varied from 33.5% to 40.6%. The intraclass correlation coefficient for the hospital-level variation was 0.6% (95% confidence interval 0.1, 3.4%), with a median odds ratio of 1.15 (95% confidence interval 1.06, 1.38). The relationship between hospital volume of mechanically ventilated and 30-day mortality was not statistically significant: each 50-patient increase in volume was associated with a nonsignificant 2% decrease in the odds of death within 30 days (odds ratio 0.98, 95% confidence interval 0.87-1.10). Veterans Health Administration hospitals caring for lower volumes of mechanically ventilated patients do not have worse mortality. Mechanisms underlying this finding are unclear, but, if elucidated, may offer other integrated health systems ways to overcome the disadvantages of small-volume centers in achieving good outcomes.


Further evidence for visual landmark involvement in the pigeon's familiar area map
In previous experiments suggesting that previewing visual landscapes speeds homing from familiar release sites, restricted access to olfactory cues may have artefactually encouraged homing pigeons, Columba liviato resort to visual landmark orientation. Since evidence for the role of visual landmarks in wide-ranging avian orientation is still equivocal, Braithwaite & Guilford's (1991, Proc. R. Soc. Lond. Ser. B245, 183-186) 'previewing' experiments were replicated: birds were allowed or denied visual access to a familiar site prior to release, but allowed ample access to olfactory cues. In experiment 1, allowing birds to preview familiar sites for 5 min prior to release enhanced homing speeds by about 12%. In experiment 2, modified to reduce between-day effects on variation, previewing enhanced homing speeds by about 16%. These experiments support the conclusion that visual landmarks remote from sight of the loft are an important component of the familiar area map, although the nature of the landmarks and how they are encoded remain to be determined.


Pseudoloma neurophilia infections in zebrafish Danio rerio: effects of stress on survival, growth, and reproduction.
Pseudoloma neurophilia (Microsporidia) is a common disease of zebrafish Danio rerio, including those used as research models. We conducted a study comprised of 4 separate experiments to determine the effects of husbandry stress on preexisting and experimental P. neurophilia infections and the subsequent effects on survival, infection onset and intensity, fish growth, and reproduction. In fish (AB strain) with preexisting infections, stress or feeding cortisol significantly increased mortality over 7 wk compared to no stress or cortisol treatment. In contrast, no mortality was observed in fish (TL strain) experimentally exposed to P. neurophilia over 10 wk. A third experiment involved experimental exposure of AB fish to P. neurophilia and exposure to crowding and handling stressors. No mortality was associated with P. neurophilia regardless of stress treatment over a period of 20 wk. However, the onset of infection occurred sooner in stress-treated fish. Stress significantly increased the mean intensity of infection (described as xenoma area/spinal cord area in histological sections) at Week 20 post-exposure (PE). In fish with preexisting infections, myositis was significantly greater in stressed and cortisol-treated fish than those not stressed. With experimental exposure of AB fish, stressed and infected groups weighed significantly less than the control group at Week 20 PE. Regarding fecundity, the number of larvae hatched at 5 d post fertilization was negatively associated with mean infection intensity among P. neurophilia-infected and stressed AB fish. These experiments are the first to show empirically that P. neurophilia can be associated with reduced weight and fecundity, and that stress can exacerbate the severity of the infection.


Orange Carotenoid Protein as a Control Element in an Antenna System Based on a DNA Nanostructure.
Taking inspiration from photosynthetic mechanisms in natural systems, we introduced a light-sensitive photo protective quenching element to an artificial light-harvesting antenna model to control the flow of energy as a function of light intensity excitation. The orange carotenoid protein (OCP) is a nonphotochemical quencher in cyanobacteria: under high-light conditions, the protein undergoes a spectral shift, and by binding to the phycobilisome, it absorbs excess light and dissipates it as heat. By the use of DNA as a scaffold, an antenna system made of organic dyes (Cy3 and Cy5) was constructed, and OCP was assembled on it as a modulated quenching element. By controlling the illumination intensity, it is possible to switch the direction of excitation energy transfer from the donor Cy3 to either of two acceptors. Under low-light conditions, energy is transferred from Cy3 to Cy5, and under intense illumination, energy is partially transferred to OCP as well. These results demonstrate the feasibility of controlling the pathway of energy transfer using light intensity in an engineered light-harvesting system.


Neutrophilic dermatoses: a review of current treatment options.
Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis are neutrophilic dermatoses - conditions that have an inflammatory infiltrate consisting of mature polymorphonuclear leukocytes. The neutrophils are usually located within the dermis in Sweet syndrome and pyoderma gangrenosum; however, in subcorneal pustular dermatosis, they are found in the upper layers of the epidermis. Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by pyrexia, elevated neutrophil count, painful erythematous cutaneous lesions that have an infiltrate of mature neutrophils typically located in the upper dermis, and prompt clinical improvement following the initiation of systemic corticosteroid therapy. Classical, malignancy-associated, and drug-induced variants of Sweet syndrome exist. Pyoderma gangrenosum is characterized by painful, enlarging necrotic ulcers with bluish undermined borders surrounded by advancing zones of erythema; its clinical variants include: ulcerative or classic, pustular, bullous or atypical, vegetative, peristomal, and drug-induced. Subcorneal pustular dermatosis is an uncommon relapsing symmetric pustular eruption that involves flexural and intertriginous areas; it can be idiopathic or associated with cancer, infections, medications, and systemic diseases. Since Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis share not only the same inflammatory cell but also similar associated systemic diseases, it is not surprising that the concurrent or sequential development of these neutrophilic dermatoses has been observed in the same individual. Also, it is not unexpected that several of the effective therapeutic interventions - including systemic drugs, topical agents, and other treatment modalities - for the management of these dermatoses are the same. The treatment of choice for Sweet syndrome and idiopathic pyoderma gangrenosum is systemic corticosteroids; however, for subcorneal pustular dermatosis, dapsone is the drug of choice. Yet, tumor necrosis factor-alpha antagonists are becoming the preferred choice when pyoderma gangrenosum is accompanied by inflammatory bowel disease or rheumatoid arthritis. Potassium iodide and colchicine are alternative first-line therapies for Sweet syndrome and indomethacin (indometacin), clofazimine, cyclosporine (ciclosporin), and dapsone are second-line treatments. Cyclosporine is effective in the acute management of pyoderma gangrenosum; however, when tapering the drug, additional systemic agents are necessary for maintaining the clinical response. In some patients with subcorneal pustular dermatosis, systemic corticosteroids may be effective; yet, systemic retinoids (such as etretinate and acitretin) have effectively been used for treating this neutrophilic dermatosis - either as monotherapy or in combination with dapsone or as a component of phototherapy with psoralen and UVA radiation. Topical agents can have an adjuvant role in the management of these neutrophilic dermatoses; however, high-potency topical corticosteroids may successfully treat localized manifestations of Sweet syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis. Intralesional corticosteroid therapy for patients with Sweet syndrome and pyoderma gangrenosum, hyperbaric oxygen and plasmapheresis for patients with pyoderma grangrenosum, and phototherapy for patients with subcorneal pustular dermatosis are other modalities that have been used effectively for treating individuals with these neutrophilic dermatoses.


Osteopontin Fragments with Intact Thrombin-Sensitive Site Circulate in Cervical Cancer Patients.
We investigated whether circulating osteopontin (OPN) could be used as a biomarker for cervical cancer. We employed a monoclonal antibody (mAb 659) specific for the unique and intact thrombin-sensitive site in OPN using an inhibition ELISA. We found significantly higher levels of OPN in 33 cervical cancer patients in both the plasma (mean +/- SD, 612 +/- 106 ng/mL) and serum (424 +/- 121 ng/mL) compared to healthy subjects [409 +/- 56 ng/mL, from 31 plasma samples (P < 0.0001), and 314 +/- 98 ng/mL, from 32 serum samples (P = 0.0002), respectively]. Similar results were obtained when the plasma from a bigger group (147 individuals) of cervical cancer patients (560 +/- 211 ng/mL) were compared with the same plasma samples of the healthy individuals (P = 0.0014). More significantly, the OPN level was highest in stage III-IV disease (614 +/- 210 ng/mL, from 52 individuals; P = 0.0001) and least and non-discriminatory in stage I (473 +/- 110 ng/mL, from 40 individuals; P = 0.5318). No such discrimination was found when a mAb of a different specificity (mAb 446) was used in a similar inhibition ELISA to compare the two groups in the first study; a commercial capture ELISA also failed. The possibility that the target epitope recognized by the antibody probe in these assays was absent from the circulating OPN due to protein truncation was supported by gel fractionation of the OPN found in patients' plasma: 60-64 kDa fragments were found instead of the presumably full-length OPN (68 kDa) seen in healthy people. How these fragments are generated and what possible role they play in cancer biology remain interesting questions.


The Structural Burden of Caregiving: Shared Challenges in the United States and Canada.
In contrasting health care structures, we each served as caregivers to elderly parents where a shared and unexpected theme in our experiences was the substantial burden of negotiating and managing long-term care (LTC) services within our respective health and social care systems. In this article, we introduce and elucidate an under recognized source of caregiver burden in the United States and Canada: the structural burden of caregiving. We draw on shared and unique experiences cross-nationally, along with the literature, to illustrate that (a) today's caregiving is increasingly characterized by interactions with formal health and social systems in negotiating and managing services, (b) these systems are hampered by discontinuous and fragmented care which increase caregiver stress, and (c) this structural burden likely exacerbates inequity for both care recipients and caregivers. In conclusion, we call for theoretical models of caregiving to highlight health and social systems as creating burden and for measurement of caregiver burden to explicitly consider the time and stress stemming from interactions with formal health and social systems. Finally, we call for future policy evaluation to incorporate structural burden as an additional outcome in considering changes to LTC provisions and funding.


The use of person-centered language in scientific research articles focusing on alcohol use disorder.
Worldwide, alcohol use disorder (AUD) is one of the most common substance use disorders, yet often goes undertreated. One major barrier that prevents adequate treatment of AUD is the high stigmatization the disorder receives, including from the scientific community. Thus, we evaluated the current use of patient-centered language (PCL) among AUD-related, journal publications. This cross-sectional analysis included a systematic search of PubMed AUD-related articles from May 2018 to April 2020. All journals with 20 or more AUD-related, PubMed indexed items with human subjects and available in English were included, resulting in 3445 articles from 49 journals. A random sample of 500 publications were screened and examined for inclusion of pre-specified, non- PCL terminology.. After excluding editorials and commentaries, 292 were retained. We found 59 (20.1 %) publications adhered to PCL. Among articles with non-PCL, labeling occurred in 198 (67.8 %) articles, and emotional language implying helplessness was identified in 123 (42.1 %). We found no difference in PCL adherence with journal ranking nor authorship guidelines requiring AMA/ICMJE adherence. Our investigation showed that a majority of current AUD literature does not conform to PCL standards. PCL carries a positive connotation and is recommended by multiple professional groups. In continuing the shift toward reducing stigma and increasing advocacy for individuals with AUD, it is necessary for the sources of information that guide clinical practice adhere to PCL. This study is not intended to impede the autonomy of individuals to label themselves or influence terms purposefully used in support programs.


Automated protein turnover calculations from 15N partial metabolic labeling LC/MS shotgun proteomics data.
Protein turnover is a well-controlled process in which polypeptides are constantly being degraded and subsequently replaced with newly synthesized copies. Extraction of composite spectral envelopes from complex LC/MS shotgun proteomics data can be a challenging task, due to the inherent complexity of biological samples. With partial metabolic labeling experiments this complexity increases as a result of the emergence of additional isotopic peaks. Automated spectral extraction and subsequent protein turnover calculations enable the analysis of gigabytes of data within minutes, a prerequisite for systems biology high throughput studies. Here we present a fully automated method for protein turnover calculations from shotgun proteomics data. The approach enables the analysis of complex shotgun LC/MS 15N partial metabolic labeling experiments. Spectral envelopes of 1419 peptides can be extracted within an hour. The method quantifies turnover by calculating the Relative Isotope Abundance (RIA), which is defined as the ratio between the intensity sum of all heavy (15N) to the intensity sum of all light (14N) and heavy peaks. To facilitate this process, we have developed a computer program based on our method, which is freely available to download at http://promex.pph.univie.ac.at/protover.


Phase II study of gemcitabine and vinorelbine combination chemotherapy in patients with non-small-cell lung cancer not responding to previous chemotherapy.
Both gemcitabine and vinorelbine are new anticancer drugs that have shown activity in the treatment of chemonaïve non-small-cell lung cancer (NSCLC). Their role in the second-line treatment of NSCLC is less clear. We conducted a phase II study of gemcitabine and vinorelbine combination chemotherapy in patients with NSCLC who had not responded to previous platinum-based chemotherapy, to assess the response and toxicity of this regimen. Seventeen patients were enrolled from September 1998 to February 2001. Treatment consisted of vinorelbine 20 mg/m2 and gemcitabine 800 mg/m2 intravenous infusion on days 1, 8, and 15 every 4 weeks. Sixty-five cycles of treatment were given, with a median of four cycles. All patients were evaluable for the toxicity profile, and 16 patients were evaluable for the response rate. The major toxicity was myelosuppression. Grade III or IV neutropenia occurred in 9 patients (52.9%) during treatment. Febrile neutropenia occurred in only 1 patient (5.9%). Grade III anemia and thrombocytopenia occurred in two and three patients, respectively. Other toxicities were few and mild in severity. After 2 cycles of treatment, 5 of 16 patients (31.3%) had a partial response (95% CI 8.6-64%). The median time to disease progression was 4.6 months and the median survival was 8.3 months. The 1-year survival rate was 34.3%. In conclusion, gemcitabine and vinorelbine salvage chemotherapy produces a relatively high response rate, low toxicity profile, and good survival in Chinese patients with NSCLC who have not responded to previous platinum-based chemotherapy. Further study is needed to confirm its activity.


Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3β Signaling Pathway.
Demand is increasing for safer inhalational anesthetics for use in pediatric anesthesia. In this regard, researchers have debated whether isoflurane is more toxic to the developing brain than desflurane. In the present study, we compared the effects of postnatal exposure to isoflurane with those of desflurane on long-term cognitive performance and investigated the role of the Akt/GSK3β signaling pathway. Postnatal day 6 (P6) mice were exposed to either isoflurane or desflurane, after which the phosphorylation levels of Akt/GSK3β and learning and memory were assessed at P8 or P31. The phosphorylation levels of Akt/GSK3β and learning and memory were examined after intervention with lithium. We found that isoflurane, but not desflurane, impaired spatial learning and memory at P31. Accompanied by behavioral change, only isoflurane decreased p-Akt (ser473) and p-GSK3β (ser9) expressions, which led to GSK3β overactivation. Lithium prevented GSK3β overactivation and alleviated isoflurane-induced cognitive deficits. These results suggest that isoflurane is more likely to induce developmental neurotoxicity than desflurane in context of multiple exposures and that the Akt/GSK3β signaling pathway partly participates in this process. GSK3β inhibition might be an effective way to protect against developmental neurotoxicity.


Quantitative and Specific Detection of Exosomal miRNAs for Accurate Diagnosis of Breast Cancer Using a Surface-Enhanced Raman Scattering Sensor Based on Plasmonic Head-Flocked Gold Nanopillars.
MicroRNAs in exosomes (exosomal miRNAs) have attracted increased attention as cancer biomarkers for early diagnosis and prognosis owing to their stability in body fluids. Since strong association exists between exosomal miRNA expression levels and breast cancer, the development of effective methods that can monitor exosomal miRNA expression both over broad concentration ranges and in ultralow amounts is critical. Here, a surface-enhanced Raman scattering (SERS)-based sensing platform is developed for the quantitative determination of exosomal miRNAs. Ultrasensitive exosomal miRNA detection with single-nucleotide specificity is obtained from enhanced SERS signals from a uniform plasmonic head-flocked gold nanopillar substrate, which generates multiple hotspots and enables hybridization between short oligonucleotides, i.e., miRNAs and locked nucleic acid probes. The proposed SERS sensor shows an extremely low detection limit without any amplification process, a wide dynamic range (1 am to 100 nm), multiplex sensing capability and sound miRNA recovery in serum. Furthermore, this sensor allows reliable observation of exosomal miRNA expression patterns from breast cancer cell lines and can discriminate breast cancer subtype based on the difference between these patterns. The results suggest that this sensor can be used for universal cancer diagnosis and further biomedical applications through the quantitative measurement of exosomal miRNAs in bodily fluids.


Epidemiology of neural tube defects.
Neural tube defects (NTDs)-malformations secondary to abnormal neural tube closure between the third and fourth weeks of gestational age-have a complex and imperfectly understood etiology in which both genetic and environmental factors appear to be involved. A number of specific chromosomal or single-gene disorders, presumably not affected by environmental influences, are associated with the development of NTDs, but such syndromal cases account for a small proportion of NTDs in live-born infants. Analysis of recurrence patterns within families and of twin-concordance data provides evidence of a genetic influence in nonsyndromal cases, but factors such as socioeconomic status and geographic area (independent of race or ethnicity) are also associated with variations in the incidence of NTDs. The prevalence at birth of both anencephaly and spina bifida has decreased, but the advent of antenatal diagnosis and elective termination of affected pregnancies has undermined the reliability of birth prevalence rate as an estimate of incidence. Some occupational and other exposures, including maternal use of antiepileptic drugs (AEDs), are associated with increased risk for NTDs. Among women who have had an NTD-affected pregnancy, recurrence risk is markedly higher than the risk for a first NTD-affected pregnancy in the general population. There is strong evidence, overall, for a protective effect of adequate folate consumption. In some high-risk groups, however, such as women taking AEDs, folate supplementation has not been proven to reduce NTD risk.


Polytene chromosomal maps of 11 Drosophila species: the order of genomic scaffolds inferred from genetic and physical maps.
The sequencing of the 12 genomes of members of the genus Drosophila was taken as an opportunity to reevaluate the genetic and physical maps for 11 of the species, in part to aid in the mapping of assembled scaffolds. Here, we present an overview of the importance of cytogenetic maps to Drosophila biology and to the concepts of chromosomal evolution. Physical and genetic markers were used to anchor the genome assembly scaffolds to the polytene chromosomal maps for each species. In addition, a computational approach was used to anchor smaller scaffolds on the basis of the analysis of syntenic blocks. We present the chromosomal map data from each of the 11 sequenced non-Drosophila melanogaster species as a series of sections. Each section reviews the history of the polytene chromosome maps for each species, presents the new polytene chromosome maps, and anchors the genomic scaffolds to the cytological maps using genetic and physical markers. The mapping data agree with Muller's idea that the majority of Drosophila genes are syntenic. Despite the conservation of genes within homologous chromosome arms across species, the karyotypes of these species have changed through the fusion of chromosomal arms followed by subsequent rearrangement events.


Pancreatic tropism of metastatic renal cell carcinoma.
Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.


Topological edge states in high-temperature superconductiving FeSe/SrTiO3 films with Te substitution.
Using first principles theory, we investigated the behavior of the one-dimensional (1D) topological edge states of high temperature superconductiviing FeSe/SrTiO3 films with Te atoms substitution to Se atoms in the bottom (top) layer in single-layer FeSe, as a function of strain. It was discovered that the 1D topological edge states are present in single-unit-cell FeSe film on SrTiO3, but are absent when more than 50% Se atoms are replaced by Te atoms. Stress induced displacive phase transformation exists in FeSe/SrTiO3 film when Te atoms substitute Se atoms in the bottom (top) layer in single-layer FeSe under 3% strain respectively. The 1D topological edge states are present under 3% (1.8%) strain in FeSe/SrTiO3 films with Te substitution Se in the bottom (top) layer in single-layer FeSe, even up to 5%, respectively. This indicates that the bonding angle of Se-Fe-Se (Te) and the distance of Te (or Se) atoms to the Fe plane are correlated with the topological edge states. Our findings provide an effective interface system that provides both superconducting and topological states, opening a new route for realizing 2D topological superconductors with proximity effect.


A Web-Based Public Health Intervention to Reduce Functional Impairment and Depressive Symptoms in Adults With Type 2 Diabetes (The SpringboarD Trial): Randomized Controlled Trial Protocol.
Depressive symptoms are common in people with type 2 diabetes and contribute to adverse health consequences that substantially impact social and vocational function. Despite the existence of effective depression treatments, the majority of people with type 2 diabetes do not access these when needed. Web-based alternatives to more traditional psychotherapies offer a potential solution to reducing the personal and economic burdens of type 2 diabetes. This paper outlines the protocol for a randomized controlled trial (RCT) of myCompass, a Web-based public health psychotherapy intervention, in people with type 2 diabetes. Fully automated, interactive, and delivered via the Internet without clinician support, myCompass teaches cognitive behavioral therapy-based skills and supports symptom monitoring to improve daily functioning and reduce mild-to-moderate mental health symptoms. A two-arm RCT will be conducted. People with type 2 diabetes and mild-to-moderately severe depressive symptoms will be recruited from the community and general practice settings. Screening and enrollment is via an open-access website. Participants will be randomized to use either myCompass or an active placebo program for 8 weeks, followed by a 4-week tailing-off period. The placebo program is matched to myCompass on mode of delivery, interactivity, and duration. Outcomes will be assessed at baseline and at 3-month, 6-month, and 12-month follow-up. The primary study outcome is work and social functioning. Secondary study outcomes include depressive and anxious symptoms, diabetes-related distress, self-care behaviors, and glycemic control. Nationwide recruitment is currently underway with the aim of recruiting 600 people with type 2 diabetes. Recruitment will continue until October 2017. This is the first known trial of a Web-based psychotherapy program that is not diabetes specific for improving social and vocational function in people with type 2 diabetes and mild-to-moderately severe depressive symptoms. With the increasing prevalence of type 2 diabetes and depression, a potentially scalable public health intervention could play a very large role in reducing unmet mental health need and ameliorating the personal and societal impact of illness comorbidity. Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12615000931572; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368109 (Archived by WebCite at http://www.webcitation.org/ 6rh3imVMh).


Treatment of nocturia symptoms with acupuncture.
Nocturia is a common symptom in the elderly. It causes sleeping disorders and is also associated with a higher risk of falling and increased mortality. The majority of nocturia patients prescribed desmopressin although it may cause significant hyponatremia which is a serious life threatening side effect. There is a need to use safer alternative treatment strategies specialy for older nocturia patients. We aim to examine the effect of acupuncture treatment on nocturia patients as a safe alternative treatment option. 35 nocturia patients have been joined to our study aged between 28 to 72. Among those patients in the study, 23 were female while 12 were male. Acupuncture treatment were applied in every 2 days totaling 10 sessions and each treatment session has lasted for 20 minutes. Nocturia frequency of the patients were recorded 1 to 6 before acupuncture treatment sessions. We have observed that nocturia symptoms recovered completely in 60% of the patients at the end of 10 sessions of the treatment while nocturia frequency were reduced to one per night in 37% of the patients. On the other hand nocturia sypmtoms in 2.8% of the patients were not changed at all. As a result 97% of the patients have responded to acupuncture treatment positively which applied bilaterally to Yintang point, Ki 3, Liv 3, Sp 9, L.I. 4, Ht 7, Sp 6, Lu 9, Sp 3, P 6 points. According to our results we conclude that acupuncture treatment should be widely used in nocturia patients of older ages as well as relatively younger adults.


Stable feature selection based on the ensemble L 1 -norm support vector machine for biomarker discovery.
Lately, biomarker discovery has become one of the most significant research issues in the biomedical field. Owing to the presence of high-throughput technologies, genomic data, such as microarray data and RNA-seq, have become widely available. Many kinds of feature selection techniques have been applied to retrieve significant biomarkers from these kinds of data. However, they tend to be noisy with high-dimensional features and consist of a small number of samples; thus, conventional feature selection approaches might be problematic in terms of reproducibility. In this article, we propose a stable feature selection method for high-dimensional datasets. We apply an ensemble L 1 -norm support vector machine to efficiently reduce irrelevant features, considering the stability of features. We define the stability score for each feature by aggregating the ensemble results, and utilize backward feature elimination on a purified feature set based on this score; therefore, it is possible to acquire an optimal set of features for performance without the need to set a specific threshold. The proposed methodology is evaluated by classifying the binary stage of renal clear cell carcinoma with RNA-seq data. A comparison with established algorithms, i.e., a fast correlation-based filter, random forest, and an ensemble version of an L 2 -norm support vector machine-based recursive feature elimination, enabled us to prove the superior performance of our method in terms of classification as well as stability in general. It is also shown that the proposed approach performs moderately on high-dimensional datasets consisting of a very large number of features and a smaller number of samples. The proposed approach is expected to be applicable to many other researches aimed at biomarker discovery.