Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons.
Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase--null (gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced rotenone neurotoxicity. In neuron--glia cultures, dopaminergic neurons from gp91phox-/- mice were more resistant to rotenone neurotoxicity than those from gp91phox+/+ mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91phox+/+ mice but not from gp91phox-/- mice to neuron-enriched cultures markedly increased rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91phox+/+ mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.


Molecular cloning and functional characterization of a monoterpene synthase isolated from the aromatic wild shrub Thymus albicans.
The essential oil of Thymus albicans Hoffmanns. & Link, a native shrub from the Iberian Peninsula, is mainly composed of monoterpenes. In this study, a 1,8-cineole synthase was isolated from the 1,8-cineole chemotype. A partial sequence that lacked the complete plastid transit peptide but contained an extended C-terminal when compared to other related terpene synthases was generated by PCR and Rapid Amplification of cDNA Ends (RACE). The predicted mature polypeptide was 593 amino acids in length and shared 78% and 77% sequence similarity with the homologue 1,8-cineole synthase from Rosmarinus officinalis and Salvia officinalis, respectively. The putative protein possessed the characteristic conserved motifs of plant monoterpene synthases including the RRx8W and DDxxD motifs and phylogenetic analysis indicated that the amplified 1,8-cineole synthase bears greater sequence similarity with other 1,8-cineole synthases from Lamiaceae family relative to the terpene synthases from the genus Thymus. Functional expression of the recombinant protein in Escherichia coli revealed that in the presence of geranyl diphosphate (GPP) 1,8-cineole was the major product but that its production was too low for robust quantification. Other minor conversion products included α-pinene, β-pinene, sabinene and β-myrcene suggesting the isolated 1,8-cineole synthase may be a multi-product enzyme. To our knowledge, this is the first report of a functionally characterized monoterpene synthase from Thymus albicans.


A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes.
High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D. Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL2 and HDL3 by rapid ultracentrifugation. Carotenoids were measured in serum, HDL2 and HDL3 by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL2 and HDL3 by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL2 and HDL3 by a fluorometric assay. In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL2 and particularly HDL3, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL3 (p = 0.006 and 0.044, respectively). To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein. ISRCTN21676269.


Twist again: Dynamically and reversibly controllable chirality in liquid crystalline elastomer microposts.
Photoresponsive liquid crystalline elastomers (LCEs) constitute ideal actuators for soft robots because their light-induced macroscopic shape changes can be harnessed to perform specific articulated motions. Conventional LCEs, however, do not typically exhibit complex modes of bending and twisting necessary to perform sophisticated maneuvers. Here, we model LCE microposts encompassing side-chain mesogens oriented along a magnetically programmed nematic director, and azobenzene cross-linkers, which determine the deformations of illuminated posts. On altering the nematic director orientation from vertical to horizontal, the post's bending respectively changes from light-seeking to light-avoiding. Moreover, both modeling and subsequent experiments show that with the director tilted at 45°, the initially achiral post reversibly twists into a right- or left-handed chiral structure, controlled by the angle of incident light. We exploit this photoinduced chirality to design "chimera" posts (encompassing two regions with distinct director orientations) that exhibit simultaneous bending and twisting, mimicking motions exhibited by the human musculoskeletal system.


Messenger RNA expression of IL-8, FOXP3, and IL-12beta differentiates latent tuberculosis infection from disease.
Differentiation of active from latent tuberculosis (TB) is a major challenge in the control of TB. In this study, PBMC from latent TB-infected subjects, TB patients, and tuberculin skin test-negative donors stimulated with the Mycobacterium tuberculosis (Mtb)-specific Ag, early secretory antigenic target 6, and mRNA for 45 immune-related genes was measured by quantitative real-time PCR. Univariate analysis showed significant differences in the expression of 10 genes (IFN-gamma, FOXP3, IL-1alpha, IL-1beta, IL-2, IL-6, IL-8, IL-12alpha, IL-12beta, and IL-24) in PBMC from TB patients vs latent TB-infected subjects (p < 0.01). Multivariate logistic regression and classification and regression tree analyses revealed that expression of three genes, IL-8, FOXP3, and IL-12beta, is predictive for TB vs latent Mtb infection. Thus, measurement of Ag-specific expression of these three genes may offer a specific and noninvasive means of differentiating between latent Mtb infection and TB.


Comparison of fenofibrate and pioglitazone effects on patients with nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is known to be a health-related problem; there is no proven treatment for NAFLD. However, a wide range of possible therapies have been proposed and studied. In the current study, we aimed to compare the therapeutic effects of fenofibrate and pioglitazone on NAFLD. In this randomized clinical trial study (ethic number: ZUMS.REC.1393.133), patients with NAFLD and alanine aminotransferase in range of 1-1.5 folds of normal and BMI (25-35) were studied. Blood lipids and liver enzymes were measured. The patients were divided randomly into three groups (recipient of fenofibrate, pioglitazone, and exercise). After the patients completed the course of treatment, liver enzymes were measured. According to the results of this study, 90 patients with NAFLD were divided into three groups of 30 patients. All variables at the beginning of the study showed no significant difference among the three groups, but after the treatment period, the results showed that the levels of alanine aminotransferase, aspartate transaminase, systolic blood pressure, diastolic blood pressure, and BMI changed significantly: the levels decreased in all groups. This study showed beneficial effects of fenofibrate and pioglitazone in patients with fatty liver. Further studies with larger study populations on the effects of these drugs on fatty liver, lipid profile, blood glucose, and insulin are suggested.


Recent and temporal trends (1975 to 1999) in the treatment, hospital, and long-term outcomes of Hispanic and non-Hispanic white patients hospitalized with acute myocardial infarction: a population-based perspective.
Extremely limited population-based data are available describing recent and temporal trends in the characteristics, treatment, and outcomes of Hispanic and non-Hispanic white patients hospitalized with acute myocardial infarction (AMI). This was a community-based, observational study of 9649 greater Worcester residents hospitalized in all hospitals serving the Worcester, Massachusetts, metropolitan area in 12 one-year periods between 1975 and 1999. In the total study sample, 171 (2%) patients were Hispanic. Hispanic patients were matched with 395 non-Hispanic white patients on the basis of age, sex, and year of hospitalization. Hispanics were more likely to present to greater Worcester hospitals with a history of diabetes as compared with non-Hispanic whites. Hispanics were less likely to have an initial, Q-wave AMI during the index hospitalization. After controlling for a limited number of known potentially confounding factors, Hispanics were at lower risk for development of heart failure (OR, 0.63; 95% CI, 0.41, 0.96). Both Hispanics (13% vs 11%) and non-Hispanic whites (28% vs 9%), however, had declines in hospital case-fatality rates between 1975 and 1999. An overall similar treatment pattern and increasing trends in the use of effective cardiac medications over time were observed in both patient groups. However, Hispanics were significantly less likely to be treated with coronary angioplasty during the acute hospitalization. Trends of a worse long-term survival for discharged Hispanic patients were observed over a 10-year follow-up period. The results of this community-wide study suggest encouraging hospital outcomes in Hispanic and non-Hispanic white patients hospitalized with AMI. Enhanced secondary prevention efforts remain needed to improve the hospital and long-term outcomes of patients with AMI, irrespective of race or ethnicity.


Quantitative "magnetic resonance immunohistochemistry" with ligand-targeted (19)F nanoparticles.
Unstable atherosclerotic plaques exhibit microdeposits of fibrin that may indicate the potential for a future rupture. However, current methods for evaluating the stage of an atherosclerotic lesion only involve characterizing the level of vessel stenosis, without delineating which lesions are beginning to rupture. Previous work has shown that fibrin-targeted, liquid perfluorocarbon nanoparticles, which carry a high payload of gadolinium, have a high sensitivity and specificity for detecting fibrin with clinical (1)H MRI. In this work, the perfluorocarbon content of the targeted nanoparticles is exploited for the purposes of (19)F imaging and spectroscopy to demonstrate a method for quantifiable molecular imaging of fibrin in vitro at 4.7 T. Additionally, the quantity of bound nanoparticles formulated with different perfluorocarbon species was calculated using spectroscopy. Results indicate that the high degree of nanoparticle binding to fibrin clots and the lack of background (19)F signal allow accurate quantification using spectroscopy at 4.7 T, as corroborated with proton relaxation rate measurements at 1.5 T and trace element (gadolinium) analysis. Finally, the extension of these techniques to a clinically relevant application, the evaluation of the fibrin burden within an ex vivo human carotid endarterectomy sample, demonstrates the potential use of these particles for uniquely identifying unstable atherosclerotic lesions in vivo.


Monocyte-dependent fibroblast CXCL8 secretion occurs in tuberculosis and limits survival of mycobacteria within macrophages.
CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 +/- 88 ng/ml vs 48.6 +/- 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF-alpha or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-kappaB, C/EBP, and JNK dependent. Sustained NF-kappaB activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma.


[Computer-assisted smoking cessation].
Though the prevalence of cigarette smoking has declined it still remains the leading cause of premature death from chronic disease. In the prevention of tobacco associated disease the promotion of smoking cessation is a key strategy. This article presents a smoking cessation program based on the transtheoretical model, an empirical model distinguishing five stages of behavioral change. Specific interventions are matched to the current stage of change. Smokers in the intervention program repeatedly fill in questionnaires about their smoking habits, attitudes and strategies in the smoking cessation process. The individual questionnaires are analyzed by a computerized expert system which creates letters with comments on the smoking cessation process and suggestions for further steps from a pool of feedback paragraphs. A further component of the program are five stage-matched brochures. The efficacy of the expert system and its potential impact on Public Health are discussed.


Dual regulation of the anaphase promoting complex in human cells by cyclin A-Cdk2 and cyclin A-Cdk1 complexes.
In mammalian somatic cells, the Anaphase Promoting Complex (APC) is inactivated during S phase by active cyclin A-Cyclin dependent kinase (Cdk) 2 complexes promoting accumulation of mitotic regulators, such as cyclin B and Polo like kinase 1 (Plk1). However, mitotic entry does not appear to be perturbed in some human cancer cells or in normal mouse cells following Cdk2 RNA interference (i) or deletion of the Cdk2 gene. These results suggest functional complementation of APC regulation by a compensatory kinase. Using Plk1 protein level as readout of APC activity, we show that APC is inactivated during S phase in human cells by both cyclin A-Cdk2 and cyclin A-Cdk1 complexes. Expression of a dominant negative mutant of Cdk2 or Cdk2 RNAi in early S phase destabilizes Plk1 as it begins to accumulate. However, this effect wanes in late S phase, where destabilization of Plk1 also requires Cdk1 RNAi. Although Cdk2 is the dominant partner of cyclin A in these settings, cyclin A also binds Cdk1. Both complexes bind the APC targeting factor Cdh1, but Cdk1 complexes are inactive in early S phase, accounting for the stronger regulation of APC function by Cdk2. These results provide further evidence that cyclin A-Cdk2 and -Cdk1 complexes display overlapping and partially redundant roles in preparing cells for mitosis, through regulation of the APC.


Data-driven parcellation and graph theory analyses to study adolescent mood and anxiety symptoms.
Adolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms-salient features across psychiatric conditions. As reward circuitry matures considerably during adolescence, we examined both Whole Brain and three task-derived reward networks. Subjects were 87 psychotropic-medication-free adolescents (age = 12-20) with diverse psychiatric conditions (n = 68) and healthy controls (n = 19). All completed diagnostic interviews, dimensional clinical assessments, and 3T resting-state fMRI (10 min/2.3 mm/TR = 1 s). Following high-quality Human Connectome Project-style preprocessing, multimodal surface matching (MSMAll) alignment, and parcellation via the Cole-Anticevic Brain-wide Network Partition, weighted graph theoretical metrics (Strength Centrality = CStr; Eigenvector Centrality = CEig; Local Efficiency = ELoc) were estimated within each network. Associations with symptom severity and clinical status were assessed non-parametrically (two-tailed pFWE < 0.05). Across subjects, depression scores correlated with ventral striatum CStr within the Reward Attainment network, while anticipatory anhedonia correlated with CStr and ELoc in the subgenual anterior cingulate, dorsal anterior cingulate, orbitofrontal cortex, caudate, and ventral striatum across multiple networks. Group differences and associations with anxiety were not detected. Using detailed functional and clinical measures, we found that adolescent depression and anhedonia involve increased influence and communication efficiency in prefrontal and limbic reward areas. Resting-state network properties thus reflect positive valence system anomalies related to discrete reward sub-systems and processing phases early in the course of illness.


Cover cropping to reduce nitrate loss through subsurface drainage in the northern U.S. corn belt.
Despite the use of best management practices for nitrogen (N) application rate and timing, significant losses of nitrate nitrogen (NO3(-)-N) in drainage discharge continue to occur from row crop cropping systems. Our objective was to determine whether a autumn-seeded winter rye (Secale cereale L.) cover crop following corn (Zea mays L.) would reduce NO3(-)-N losses through subsurface tile drainage in a corn-soybean [Glycine mar (L.) Merr.] cropping system in the northern Corn Belt (USA) in a moderately well-drained soil. Both phases of the corn-soybean rotation, with and without the winter rye cover crop following corn, were established in 1998 in a Normania clay loam (fine-loamy, mixed, mesic Aquic Haplustoll) soil at Lamberton, MN. Cover cropping did not affect subsequent soybean yield, but reduced drainage discharge, flow-weighted mean nitrate concentration (FWMNC), and NO3(-)-N loss relative to winter fallow, although the magnitude of the effect varied considerably with annual precipitation. Three-year average drainage discharge was lower with a winter rye cover crop than without (p = 0.06). Over three years, subsurface tile-drainage discharge was reduced 11% and NO3(-)-N loss was reduced 13% for a corn-soybean cropping system with a rye cover crop following corn than with no rye cover crop. We estimate that establishment of a winter rye cover crop after corn will be successful in one of four years in southwestern Minnesota. Cover cropping with rye has the potential to be an effective management tool for reducing NO3(-)-N loss from subsurface drainage discharge despite challenges to establishment and spring growth in the north-central USA.


Primary oral health service provision in Aboriginal Medical Services-based dental clinics in Western Australia.
Australians living in rural and remote areas have poorer access to dental care. This situation is attributed to workforce shortages, limited facilities and large distances to care centres. Against this backdrop, rural and remote Indigenous (Aboriginal) communities in Western Australia seem to be more disadvantaged because evidence suggests they have poorer oral health than non-Indigenous people. Hence, provision of dental care for Aboriginal populations in culturally appropriate settings in rural and remote Western Australia is an important public health issue. The aim of this research was to compare services between the Aboriginal Medical Services (AMS)-based clinics and a typical rural community clinic. A retrospective analysis of patient demographics and clinical treatment data was undertaken among patients who attended the dental clinics over a period of 6 years from 1999 to 2004. The majority of patients who received dental care at AMS dental clinics were Aboriginal (95.3%), compared with 8% at the non-AMS clinic. The rate of emergency at the non-AMS clinic was 33.5%, compared with 79.2% at the AMS clinics. The present study confirmed that more Indigenous patients were treated in AMS dental clinics and the mix of dental care provided was dominated by emergency care and oral surgery. This indicated a higher burden of oral disease and late utilisation of dental care services (more focus on tooth extraction) among rural and remote Indigenous people in Western Australia.


[Role of magnetic resonance imaging in the early diagnosis of cognitive impairments in patients with type 1 diabetes mellitus].
To assess the role of brain magnetic resonance imaging (MRI) in patients with type 1 diabetes mellitus (DMI) in relation to clinical, metabolic, and psychoneurological disorders. Fifty-eight patients aged 16 to 30 years with DM1 were examined; a control group consisted of 29 healthy young people matched by gender and age. Their examination involved clinical, metabolic, and psychological testing. The quality of life was assessed using the general Medical Outcomes Study Short Form (MOS SF-36) and the specific Audit-Dependent Quality of Life (AdDQoL). The Montreal Cognitive Assessment (MoCa test) was employed to screen for cognitive impairments. All the patients were advised by a neurologist. Brain MRI using a 1.0 T Siemens Magnetom scanner was carried out to evaluate structural changes in the central nervous system. The examination of the patients with DM1 revealed the signs of grey matter atrophy, enlarged Virchow-Robin spaces, white matter injury, which correlated with the presence of chronic hyperglycemia, cognitive impairments, and microvascular complications. Routine brain MRI is best carried out in patients with DMI and poor disease control to timely implement therapeutic-and-prophylactic measures for preventing cognitive impairments and improving the quality of life.


Running-specific, periodized strength training attenuates loss of stride length during intense endurance running.
The purpose of this study was to determine the effects of a running-specific, periodized strength training program (performed over the specific period [8 weeks] of a 16-week macrocycle) on endurance-trained runners' capacity to maintain stride length during running bouts at competitive speeds. Eighteen well-trained middle-distance runners completed the study (personal bests for 1500 and 5000 m of 3 minutes 57 seconds +/- 12 seconds and 15 minutes 24 seconds +/- 36 seconds). They were randomly assigned to each of the following groups (6 per group): periodized strength group, performing a periodized strength training program over the 8-week specific (intervention) period (2 sessions per week); nonperiodized strength group, performing the same strength training exercises as the periodized group over the specific period but with no week-to-week variations; and a control group, performing no strength training at all during the specific period. The percentage of loss in the stride length (cm)/speed (m.s) (SLS) ratio was measured by comparing the mean SLS during the first and third (last) group of the total repetitions, respectively, included in each of the interval training sessions performed at race speeds during the competition period that followed the specific period. Significant differences (p < 0.05) were found in mean percentage of SLS loss between the 3 study groups, with the periodized strength group showing no significant SLS change (0.36 +/- 0.95%) and the 2 other groups showing a moderate or high SLS loss (-1.22 +/- 1.5% and -3.05 +/- 1.2% for the nonperiodized strength and control groups, respectively). In conclusion, periodized, running-specific strength training minimizes the loss of stride length that typically occurs in endurance runners during fatiguing running bouts.


Atypical antipsychotics cause an acute increase in cutaneous hand blood flow in patients with schizophrenia and schizoaffective disorder.
Clinical studies suggest resting thermoregulatory cutaneous vasomotor tone could be increased in schizophrenia, resulting in reduced hand blood flow. In animal models, atypical antipsychotics including clozapine potently inhibit sympathetic neural outflow to the thermoregulatory cutaneous vascular beds. We have now determined whether antipsychotic medication administration is associated with an acute increase in hand blood flow in patients with schizophrenia and schizoaffective disorder, and whether this increase correlates with clinical status. Hand temperature was measured with an infrared camera in 12 patients with chronic schizophrenia or schizoaffective disorder 30 min prior to, then 30 and 60 min following medication. Clinical status was assessed via the Brief Psychiatric Rating Scale (BPRS). Results were compared using regression and repeated measures analysis of variance. A robust and significant increase in hand temperature (p < 0.001) was observed following antipsychotic administration. The mean increase after 60 min was 4.1 ± 2.4°C. This increase was significantly associated with colder hand temperature prior to medication (p < 0.05; suggestive of increased resting vasoconstriction) and with more severe psychiatric symptoms (p < 0.05). Atypical antipsychotics were associated with increased hand blood flow, consistent with inhibition of thermoregulatory sympathetic outflow to the cutaneous vascular bed in patients with schizophrenia and schizoaffective disorder. This increase correlated with symptom severity. Hand temperature increase following antipsychotic medication may therefore be a simple and informative physiological marker of disease activity and potential response in patients with schizophreniform disorders. Given that antipsychotics also inhibit sympathetic outflow to brown adipose tissue, which normally converts energy to heat, future studies should examine whether antipsychotic-induced hand temperature increase is associated with antipsychotic-induced weight gain.


Who Benefits--Or Does not--From South Africa's Old Age Pension? Evidence from Characteristics of Rural Pensioners and Non-Pensioners.
Social protection grants play a critical role in survival and livelihoods of elderly individuals in South Africa. Rarely is it possible to assess how well a social program reaches its target population. Using a 2010 survey and Agincourt Health Demographic Surveillance System census data we conduct multivariate logistic regression to predict pension receipt in rural South Africa. We find only 80% of age-eligible individuals report pension receipt. Pension non-recipients tend to be male, have poor socio-economic status, live in smaller households, be of Mozambican origin, and have poorer physical function; while older persons living in households receiving other grants are more likely to report pension receipt. We conclude that a reservoir of older persons exists who meet eligibility criteria but who are not yet receiving pensions. Ensuring that they and their households are properly linked to all available social services--whether for child or old-age social grants--is likely to have beneficial and synergistic effects.


Renal Metastasis of Small Cell Lung Cancer With Urothelial Carcinoma of the Bladder Misdiagnosed as Renal Cell Carcinoma.
Metastases to the kidney from lung cancer are very rare and are usually therefore recognized at autopsy. A 71-year-old man visited the urology department due to symptoms of worsening hematuria. An abdominal computed tomography scan showed a right renal mass. After a nephrectomy, he was diagnosed with small cell lung carcinoma, and further investigation showed small cell lung cancer in the central area of the left upper lobe with hepatic, bone and brain metastases. But his hematuria was unchanged. Therefore, we additionally diagnosed urothelial cell carcinoma in the bladder by transurethral resection of the bladder tumor. He was treated with etoposide and cisplatin chemotherapy. This is a unique antemortem case report in the literature of small cell lung cancer metastasizing to the contralateral kidney, liver, bone and brain diagnosed concurrently with urothelial cell carcinoma in the bladder.


Development of a ReaxFF reactive force field for glycine and application to solvent effect and tautomerization.
Tautomerization of amino acids between the neutral form (NF) and the zwitterionic form (ZW) in water has been extensively studied, often using glycine as a model to understand this fundamental process. In spite of many advanced studies, the tautomerization reaction remains poorly understood because of the intrinsic complexities of the system, including multiple accessible reaction pathways, charge transfer, and variations of solvation structure. To establish an accurate model that can be used for molecular dynamics simulations, a ReaxFF reactive force field has been developed for glycine. A training set for the ReaxFF hydrocarbon potential was augmented with several glycine conformers and glycine-water complexes. The force field parameters were optimized to reproduce the quantum mechanically derived energies of the species in the training set. The optimized potential could accurately describe the properties of gas-phase glycine. It was applied to investigate the effect of solvation on the conformational distribution of glycine. Molecular dynamics simulations indicated significant differences in the dominant conformers in the gas phase and in water. This suggests that the tautomerization of glycine occurs through a conformational isomerization followed by the proton transfer event. The direct reaction mechanism of the NF → ZW proton transfer reaction in water, as well as mechanisms mediated by one or two water molecules, were investigated using molecular dynamics simulations. The results suggest that the proton transfer reaction is most likely mediated by a single water molecule. The ReaxFF potential developed in this work provides an accurate description of proton transfer in glycine and thus provides a useful methodology for simulating proton transfer reactions in organic molecules in the aqueous environment.


Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction.
Antithrombotic treatment is indicated for use in patients after myocardial infarction (MI); however, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) could pose safety concerns. To examine the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed. Using nationwide administrative registries in Denmark (2002-2011), we studied patients 30 years or older admitted with first-time MI and alive 30 days after discharge. Subsequent treatment with aspirin, clopidogrel, or oral anticoagulants and their combinations, as well as ongoing concomitant NSAID use, was determined. Use of NSAIDs with ongoing antithrombotic treatment after first-time MI. Risk of bleeding (requiring hospitalization) or a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke) according to ongoing NSAID and antithrombotic therapy, calculated using adjusted time-dependent Cox regression models. We included 61,971 patients (mean age, 67.7 [SD, 13.6] years; 63% men); of these, 34% filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2%). A total of 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%) occurred. The crude incidence rates of bleeding (events per 100 person-years) were 4.2 (95% CI, 3.8-4.6) with concomitant NSAID treatment and 2.2 (95% CI, 2.1-2.3) without NSAID treatment, whereas the rates of cardiovascular events were 11.2 (95% CI, 10.5-11.9) and 8.3 (95% CI, 8.2-8.4). The multivariate-adjusted Cox regression analysis found increased risk of bleeding with NSAID treatment compared with no NSAID treatment (hazard ratio, 2.02 [95% CI, 1.81-2.26]), and the cardiovascular risk was also increased (hazard ratio, 1.40 [95% CI, 1.30-1.49]). An increased risk of bleeding and cardiovascular events was evident with concomitant use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use. Among patients receiving antithrombotic therapy after MI, the use of NSAIDs was associated with increased risk of bleeding and excess thrombotic events, even after short-term treatment. More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.


Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy.
To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26-8.69, P = 0.65). Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.


The effect of retrospective sampling on binary regression models for clustered data.
Recently a great deal of attention has been given to binary regression models for clustered or correlated observations. The data of interest are of the form of a binary dependent or response variable, together with independent variables X1,...., Xk, where sets of observations are grouped together into clusters. A number of models and methods of analysis have been suggested to study such data. Many of these are extensions in some way of the familiar logistic regression model for binary data that are not grouped (i.e., each cluster is of size 1). In general, the analyses of these clustered data models proceed by assuming that the observed clusters are a simple random sample of clusters selected from a population of clusters. In this paper, we consider the application of these procedures to the case where the clusters are selected randomly in a manner that depends on the pattern of responses in the cluster. For example, we show that ignoring the retrospective nature of the sample design, by fitting standard logistic regression models for clustered binary data, may result in misleading estimates of the effects of covariates and the precision of estimated regression coefficients.


Streptococcal toxic shock syndrome in a patient with community-acquired pneumonia. Impact of rapid diagnostics on patient management.
Here we describe a community-acquired pneumonia with Streptococcus pyogenes , group A following a common cold caused by human metapneumovirus. The patient, a 58-year-old woman with no prior medical history, developed respiratory failure and multi-organ dysfunction caused by streptococcal toxic shock syndrome. The patient was admitted to the intensive care unit and treated with supportive care. The definitive diagnosis was made by BioFire FilmArray by Biomerieux (multiplex PCR) 12 h before positive blood culture, thus enabling the clinician to add clindamycin and intravenous immunoglobulin to the treatment. The patient was discharged fully recovered after 23 days. Streptococci group A is a rare pathogen of severe pneumonia and rapid diagnostics by syndromic testing, potentially performed in a near patient setting, is crucial for early implementation of targeted antimicrobial treatment.


Prioritizing islands for the eradication of invasive vertebrates in the United Kingdom overseas territories.
Invasive alien species are one of the primary threats to native biodiversity on islands worldwide. Consequently, eradicating invasive species from islands has become a mainstream conservation practice. Deciding which islands have the highest priority for eradication is of strategic importance to allocate limited resources to achieve maximum conservation benefit. Previous island prioritizations focused either on a narrow set of native species or on a small geographic area. We devised a prioritization approach that incorporates all threatened native terrestrial vertebrates and all invasive terrestrial vertebrates occurring on 11 U.K. overseas territories, which comprise over 2000 islands ranging from the sub-Antarctic to the tropics. Our approach includes eradication feasibility and distinguishes between the potential and realistic conservation value of an eradication, which reflects the benefit that would accrue following eradication of either all invasive species or only those species for which eradication techniques currently exist. We identified the top 25 priority islands for invasive species eradication that together would benefit extant populations of 155 native species including 45 globally threatened species. The 5 most valuable islands included the 2 World Heritage islands Gough (South Atlantic) and Henderson (South Pacific) that feature unique seabird colonies, and Anegada, Little Cayman, and Guana Island in the Caribbean that feature a unique reptile fauna. This prioritization can be rapidly repeated if new information or techniques become available, and the approach could be replicated elsewhere in the world.


Smoking and Parkinson's disease. An age-dependent risk effect? The EUROPARKINSON Study Group.
We studied the association between smoking and Parkinson's disease (PD) through a case-control study. Several studies have shown an inverse association between smoking and PD. This association has been interpreted as spurious by some investigators, and as real and causal by others. Several other studies did not confirm the inverse association. We included 193 prevalent cases of PD ascertained in five European prevalence surveys that followed a two-phase design of screening and clinical examination. Each case was matched by center, age (+/- 2 years), and gender to three control subjects drawn from the same populations (N = 579). Information on smoking was obtained through direct or proxy interview. Overall, there was no association between ever smoking and PD (odds ratio = 1.1; p = 0.6). Analyses stratified by age showed that ever smoking was associated with a decreased risk of PD in the younger individuals (odds ratio = 0.4; p = 0.03) and with a significant trend of increasing risk with advancing age (p = 0.003). The risk of PD in relation to smoking is strongly modified by age; smoking may be protective in the younger cases but not in the older cases. This finding may explain the conflicting results from previous studies.


Representation of less-developed countries in Pharmacology journals: an online survey of corresponding authors.
Scientists from less-developed countries (LDC) perceive that it is difficult to publish in international journals from their countries. This online survey was conducted with the primary aim of determining the opinion of corresponding authors of published papers in international Pharmacology journals regarding the difficulties in publications and their possible solutions. The titles of all Pharmacology journals were retrieved from Pubmed. 131 journals were included in study. The latest issue of all journals was reviewed thoroughly. An online survey was conducted from the corresponding authors of the published papers who belonged to LDC. 584 out 1919 papers (30.4%) originated from the LDC. 332 responses (response rate; 64.5%) were received from the authors. Approximately 50% the papers from LDC were published in journals with impact factor of less than 2. A weak negative correlation (r = -0.236) was observed between journal impact factor and the percentage of publications emanating from LDC. A significant majority of the corresponding authors (n = 254; 76.5%) perceived that it is difficult to publish in good quality journals from their countries. According to their opinion, biased attitude of editors and reviewers (64.8%) is the most important reason followed by the poor writing skills of the scientists from LDC (52.8%). The authors thought that well-written manuscript (76.1%), improvement in the quality of research (69.9%) and multidisciplinary research (42.9%) are important determinants that may improve the chances of publications. The LDC are underrepresented in publications in Pharmacology journals. The corresponding authors of the published articles think that biased attitude of the editors as well as the reviewers of international journals and the poor writing skills of scientists are the major factors underlying the non-acceptance of their results. They also think that the improvement in the writing skills and quality of research will increase the chances of acceptance of their works in international journals.


Structural differences in envelope glycoproteins associated with rat leukaemia virus produced by Novikoff hepatocellular carcinoma and spontaneously transformed Wistar rat embryo cells.
Immunochemical and immunocytochemical techniques have been used to characterize viral glycoproteins and endogenous rat leukaemia viruses (RaLV) produced both by Novikoff hepatocellular carcinoma cells and spontaneously transformed Wistar rat embryo cells (WRC). Results from immunocytochemical analysis demonstrated that RaLV produced by Novikoff and WRC cells could be distinguished by their unique patterns of reactivity with xenoantisera raised against virus particles or viral glycoproteins. This differential labelling was unexpected since all the antisera tested had been shown by immunoprecipitation and immunodepletion analysis to be reactive with viral glycoproteins expressed on the cell surface. Since no significant differences in cell surface-associated viral glycoproteins and those shed from the cell surface were detected by pulse iodination analysis, it was concluded that the apparent discrepancy between immunoferritin labelling and immunoprecipitation analysis resulted from differences in antigen accessibility on intact virions caused by structural differences in the viral glycoproteins expressed on Novikoff and WRC cells. This conclusion was supported by results from ferritin-lectin labelling, affinity chromatography and neuraminidase digestion studies which demonstrated differences in the saccharide moieties on both virion and cell surface-associated viral glycoproteins. Further evidence of structural differences was provided by limited digestion with trypsin and V8 protease of the Mr 64 000 (Nov gp64) and Mr 68 000 (WRC gp68) viral glycoproteins immunoprecipitated from Novikoff and WRC cells, respectively, with either monospecific anti-Rauscher murine leukaemia virus anti-gp70 serum or monospecific antiserum against Nov gp64 (anti-gp64). Results from digestion studies showed that all the major cleavage fragments from WRC gp68 were of higher molecular weight than their Nov gp64-derived counterparts. Evidence that Nov gp64 and WRC gp68 both share structural homology with other murine viral gp70s was suggested by results from immunoprecipitation analysis with anti-gp70 and anti-gp64 sera under reducing and non-reducing conditions which demonstrated the presence of an interchain disulphide bond in both glycoproteins and showed that at least some of these molecules exist on the cell surface as disulphide-linked heterodimers of Mr 78 000 and 82 000.


Lived-Experience of Women's Well-Being in the Cyclone Shelters of Coastal Bangladesh.
Bangladesh is repeatedly threatened by tropical storms and cyclones, exposing one-third of the total population of the country. As a preparedness measure, several cyclone shelters have been constructed, yet a large proportion of the coastal population, especially women, are unwilling to use them. Existing studies have demonstrated a range of concerns that discourage women from evacuating and have explored the limitations of the shelters, but the experiences of female evacuees have not been apparent in these stories. This study explores the lived-experiences of women in the cyclone shelters of Bangladesh and discusses their health and well-being as evacuees in the shelters. Nineteen women from three extremely vulnerable districts of coastal Bangladesh were interviewed. Seven research themes were identified from the participants' narratives using van Manen's thematic analysis process. The most salient theme, being understood (as a woman), portrayed the quintessential image of these women, which subsequently influenced their vulnerability as evacuees. The next themes-being a woman during crisis, being in a hostile situation, being fearful, being uncertain, being faithful, and being against the odds-focused on the incidents they lived through which affected their physical and mental health and the emotions they felt as evacuees. The paper offers a deep inquiry into women's experiences of well-being in the shelters and recognizes the significance of women's voices to improve their experiences as evacuees.


Thymectomy versus tumor resection for early-stage thymic malignancies: a Chinese Alliance for Research in Thymomas retrospective database analysis.
To evaluate the surgical outcomes of tumor resection with or without total thymectomy for thymic epithelial tumors (TETs) using the Chinese Alliance for Research in Thymomas (ChART) retrospective database. Patients without preoperative therapy, who underwent surgery for early-stage (Masaoka-Koga stage I and II) tumors, were enrolled for the study. They were divided into thymectomy and thymomectomy groups according to the resection extent of the thymus. Demographic and surgical outcomes were compared between the two patients groups. A total of 1,047 patients were enrolled, with 796 cases in the thymectomy group and 251 cases in the thymomectomy group. Improvement rate of myasthenia gravis (MG) was higher after thymectomy than after thymomectomy (91.6% vs. 50.0%, P<0.001). Ten-year overall survival was similar between the two groups (90.9% after thymectomy and 89.4% after thymomectomy, P=0.732). Overall, recurrence rate was 3.1% after thymectomy and 5.4% after thymomectomy, with no significant difference between the two groups (P=0.149). Stratified analysis revealed no significant difference in recurrence rates in Masaoka-Koga stage I tumors (3.2% vs. 1.4%, P=0.259). However in patients with Masaoka-Koga stage II tumors, recurrence was significantly less after thymectomy group than after thymomectomy (2.9% vs. 14.5%, P=0.001). Thymectomy, instead of tumor resection alone, should still be recommended as the surgical standard for thymic malignancies, especially for stage II tumors and those with concomitant MG.


Uterine smooth muscle tumor of uncertain malignant potential: a three-case report.
Based on the degree of cytologic atypia, mitotic activity, and other features, uterine smooth muscle tumors have historically been grouped into two classes: benign leiomyomas and malignant leiomyosarcomas. However, this separation holds true more in principle than in practice because the tumor's biological potential may not always be determined with certainty, complicating diagnosis, and therapy. We report three cases of patients with uterine smooth muscle tumors of uncertain malignant potential. Surgery was radical in two and conservative in one. During the follow-up, one patient developed diffuse lung metastases. The two other patients have not shown any signs of relapse to date. Uterine smooth muscle tumors of uncertain malignant potential may have an unpredictable clinical course and may metastasize to seemingly low-grade neoplasms in distant sites even after several years and even in the absence of important negative prognostic predictors, such as coagulative tumor cell necrosis. At present, no final consensus has been reached on the choice of the best strategy for surgery and adjuvant therapy.


A systematic literature review of the assessment of treatment burden experienced by patients and their caregivers.
Many older adults with multiple chronic conditions, particularly those who are functionally impaired, spend considerable time juggling the competing demands of managing their conditions often assisted by caregivers. We examined methods of assessing the treatment burden experienced by this population as a first step to identifying strategies to reduce it. Systematic searches were performed of the peer-reviewed and grey-literature (PubMed, Cochrane library, CINAHL, EMBASE, Web of Science, SCOPUS, New York Academy of Medicine Grey Literature Review, NLM catalog and ProQuest Digital Theses and Dissertations). After title and abstract screening, both qualitative and quantitative articles describing approaches to assessment of treatment burden were included. Forty-five articles from the peer reviewed and three items from the grey literature were identified. Most articles (34/48) discussed treatment burden associated with a specific condition. All but one examined the treatment burden experienced by patients and six addressed the treatment burden experienced by caregivers. Qualitative studies revealed many aspects of treatment burden including the burdens of understanding the condition, juggling, monitoring and adjusting treatments, efforts to engage with others for support as well as financial and time burdens. Many tools to assess treatment burden in different populations were identified through the qualitative data. The most commonly used instrument was the Treatment Burden Questionnaire. Many instruments are available to assess treatment burden, but no one standardized assessment method was identified. Few articles examined approaches to measuring the treatment burden experienced by caregivers. As people live longer with more chronic conditions healthcare providers need to identify patients and caregivers burdened by treatment and engage in approaches to ameliorate treatment burden. A standard and validated assessment method to measure treatment burden in the clinical setting would help to enhance the care of people with multiple chronic conditions, allow comparison of different approaches to reducing treatment burden, and foster ongoing evaluation and monitoring of burden across conditions, patient populations, and time.


The natural course of preneoplastic lesions in bronchial epithelium.
To study the natural history of preneoplastic lesions in the bronchial mucosa of the individuals at risk. White light and autofluorescence bronchoscopy examinations have been done in 52 individuals harboring 134 preneoplastic lesions (WHO criteria). End points were the development of carcinoma in situ (CIS) or squamous cell cancer (SCC) or the highest category of dysplasia up until March 1, 2003 for the remaining preneoplastic lesions. Distribution and outcome of preneoplastic lesions have been found to be unrelated to various risk factors such as smoking history, past history of cancer, or chronic obstructive pulmonary disease. Nonstepwise changes of preneoplastic lesions are seen. Regression rate has been 54%. Progression to CIS/SCC has been 13.4% (18 of 134) and was for severe dysplasia, significantly higher (P < 0.003) than preneoplastic lesions showing lower-grade dysplasia (squamous metaplasia, mild and moderate dysplasia). Time to progression was not significantly different. However, when analyzed per individual, no significant difference of progression rate between individuals with or without severe dysplasia was seen (39% versus 26%; P = 0.36). The 54% regression rate of all preneoplastic lesions, 26% to 39% progression rate to CIS/SCC of individuals with lower-grade dysplasia or severe dysplasia with no significant difference in progression rate and time to progression combined with nonstepwise histologic changes unrelated to the initial histologic grading indicate that one cannot differentiate the potentially more malignant preneoplastic lesions among the many preneoplastic lesions present in the bronchial mucosa. The initial WHO classification of any preneoplastic lesion cannot be reliably used for accurate risk assessment of field carcinogenesis.


Poly(A) polymerase distribution in normal and malignant lymphoid cells.
The incorporation of ATP on poly(A) primers catalyzed by poly(A) polymerase was investigated in normal and neoplastic lymphoid cells from animal and human sources. High levels of the enzyme were found in mouse thymus, in chicken bursa and thymus, as well as in neoplastic cells from patients affected by lymphoblastic and Burkitt's lymphomas. Low or very low quantities were found in peripheral blood lymphocytes, chronic lymphocytic leukemia cells, normal lymph nodes and solid lymphoid tissues of Hodgkin's disease. In general, the enzymatic content of neoplastic lymphoid cells reflected those of their normal counterpart. No effect of fasting or cortisone treatment on poly(A) polymerase in mouse spleen, thymus or liver was found. No particular relationships with B, T or non-T, non-B lineages were observed, but some relationship with DNA polymerase alpha was found. Therefore, it may be that poly(A) polymerase levels are related to the proliferative activity of the cellular populations.


RETOUCHING OF RADIOGRAPHS.
Underexposed or underdeveloped radiographs which could have been used for teaching or publication were treated prior to photographing with a technique similar to that used for photographic negative retouching. This method enables these radiographs to be used for diagnostic demonstration, where before they would have been condemned as unsuitable for reproduction. The method is simple and requires very little experience or equipment.


Antifungal effects of carvacrol, the main volatile compound in Origanum vulgare L. essential oil, against Aspergillus flavus in postharvest wheat.
Plant volatile organic compounds (VOCs) with antimicrobial activity could potentially be extremely useful fumigants to prevent and control the fungal decay of agricultural products postharvest. In this study, antifungal effects of volatile compounds in essential oils extracted from Origanum vulgare L. against Aspergillus flavus growth were investigated using transcriptomic and biochemical analyses. Carvacrol was identified as the major volatile constituent of the Origanum vulgare L. essential oil, accounting for 66.01 % of the total content. The minimum inhibitory concentrations of carvacrol were 0.071 and 0.18 μL/mL in gas-phase fumigation and liquid contact, respectively. Fumigation with 0.60 μL/mL of carvacrol could completely inhibit A. flavus proliferation in wheat grains with 20 % moisture, showing its potential as a biofumigant. Scanning electron microscopy revealed that carvacrol treatment caused morphological deformation of A. flavus mycelia, and the resulting increased electrolyte leakage indicates damage to the plasma membrane. Confocal laser scanning microscopy confirmed that the carvacrol treatment caused a decrease in mitochondrial membrane potential, reactive oxygen species accumulation, and DNA damage. Transcriptome analysis revealed that differentially expressed genes were mainly associated with fatty acid degradation, autophagy, peroxisomes, the tricarboxylic acid cycle, oxidative phosphorylation, and DNA replication in A. flavus mycelia exposed to carvacrol. Biochemical analyses of hydrogen peroxide and superoxide anion content, and catalase, superoxide dismutase, and glutathione S-transferase activities showed that carvacrol induced oxidative stress in A. flavus, which agreed with the transcriptome results. In summary, this study provides an experimental basis for the use of carvacrol as a promising biofumigant for the prevention of A. flavus contamination during postharvest grain storage.


Screening for Syphilis Infection in Nonpregnant Adolescents and Adults: US Preventive Services Task Force Reaffirmation Recommendation Statement.
Syphilis is a sexually transmitted infection that can progress through different stages (primary, secondary, latent, and tertiary) and cause serious health problems if left untreated. Reported cases of primary and secondary syphilis in the US increased from a record low of 2.1 cases per 100 000 population in 2000 and 2001 to 11.9 cases per 100 000 population in 2019. Men account for the majority of cases (83% of primary and secondary syphilis cases in 2019), and rates among women nearly tripled from 2015 to 2019. To reaffirm its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update focusing on targeted key questions evaluating the performance of risk assessment tools and the benefits and harms of screening for syphilis in nonpregnant adolescents and adults. Asymptomatic, nonpregnant adolescents and adults who have ever been sexually active and are at increased risk for syphilis infection. Using a reaffirmation process, the USPSTF concludes with high certainty that there is a substantial net benefit of screening for syphilis infection in nonpregnant persons who are at increased risk for infection. The USPSTF recommends screening for syphilis infection in persons who are at increased risk for infection. (A recommendation).


Hyperbaric oxygen therapy and osteoradionecrosis.
Osteoradionecrosis of the mandible is a potentially devastating complication of head and neck radiation. Radiation causes progressive vascular occlusion with tissue hypoxia, tissue death, and failure of healing. Hyperbaric oxygen therapy is an accepted treatment for osteoradionecrosis. This article reviews the history of hyperbaric oxygen therapy, its physiologic mechanisms, its use in the management of osteoradionecrosis, and its complications and contraindications.


Cirrhosis and insulin resistance: current knowledge, pathophysiological mechanisms, complications and potential treatments.
End-stage chronic liver diseases are often associated with insulin resistance (IR) and diabetes mellitus (DM). Indeed, to quantify insulin sensitivity the euglycemic clamp technique was utilized, allowing the following to be stated: in small groups of patients, an IR in almost all cirrhotic patients can be observed, compared with a control group. Additionally, it has been demonstrated that IR in cirrhosis is linked to a decreased peripheral (muscle) glucose uptake rather than an increased liver glucose production. The homoeostasis model of IR (HOMA-IR) technique, devised only later, was then exploited to assess this same phenomenon in a larger sample population. The research established that even in patients with preserved liver function, cirrhosis is associated with significant alterations in glucose homoeostasis levels. The purpose of the present paper is to present the current research around the affiliation of cirrhosis and IR, discuss potential mechanisms explaining the association between cirrhosis and IR (i.e. endocrine perturbation, liver inflammation, altered muscle mass and composition, altered gut microbiota and permeability), complications that can arise as well as treatment options, through a critical review of the literature surrounding this subject. This research will also be investigating the beneficial impact, if there is any, of identifying and curing IR in patients with cirrhosis.


Identification by computer-simulated RFLP of phytoplasmas associated with eggplant giant calyx representative of two subgroups, a lineage of 16SrIII-J and the new subgroup 16SrIII-U.
Symptoms resembling giant calyx, a graft-transmissible disease, were observed on 1-5 % of eggplant (aubergine; Solanum melongena L.) plants in production fields in Sao Paulo state, Brazil. Phytoplasmas were detected in 12 of 12 samples from symptomatic plants that were analysed by a nested PCR assay employing 16S rRNA gene primers R16mF2/R16mR1 followed by R16F2n/R16R2. RFLP analysis of the resulting rRNA gene products (1.2 kb) indicated that all plants contained similar phytoplasmas, each closely resembling strains previously classified as members of RFLP group 16SrIII (X-disease group). Virtual RFLP and phylogenetic analyses of sequences derived from PCR products identified phytoplasmas infecting eggplant crops grown in Piracicaba as a lineage of the subgroup 16SrIII-J, whereas phytoplasmas detected in plants grown in Bragança Paulista were tentatively classified as members of a novel subgroup 16SrIII-U. These findings confirm eggplant as a new host of group 16SrIII-J phytoplasmas and extend the known diversity of strains belonging to this group in Brazil.


A bovine macrophage cell line supports bovine herpesvirus-4 persistent infection.
Although bovine herpesvirus-4 (BHV-4), a gammaherpesvirus lacking a clear disease association, has been demonstrated in many tissues during persistent BHV-4 infection, a likely site of virus persistence is in cells of the monocyte/macrophage lineage. To establish an in vitro model of persistent infection potentially useful for examining the molecular mechanisms of BHV-4 persistence/latency, we infected the bovine macrophage cell line BOMAC. Following extensive cell death, surviving cells were found to be persistently infected, maintaining the viral genome over many passages and producing low levels of infectious virus. Although selection was unnecessary for the maintenance of the viral genome, cells persistently infected with recombinant BHV-4 containing a neomycin-resistance gene could be selected with geneticin, thus confirming that persistent BHV-4 infection was compatible with cell survival and replication. Furthermore, persistent BHV-4 infection caused no decrease in the growth rate of BOMAC cells. Sodium butyrate, which reactivates latent gammaherpesviruses in vitro, or dexamethasone, which reactivates latent BHV-4 in vivo, increased viral DNA by 10- to 15-fold in persistently infected BOMAC cells. This suggests that reactivation of latent BHV-4 by dexamethasone in vivo might involve direct action of dexamethasone on latently infected cells.


Predictors of discontinuing exclusive breastfeeding before six months among mothers in Kinshasa: a prospective study.
Although breastfeeding is common in Democratic Republic of the Congo, the proportion of women who exclusively breastfeed their babies up to 6 months remains low. This study aimed at identifying predictors of discontinuing exclusive breastfeeding before six months among mothers in Kinshasa. A prospective study was carried out from October 2012 to July 2013 among 422 mother-child pairs recruited shortly after discharge from twelve maternities in Kinshasa and followed up to six months. Interviews were conducted at each woman's house during the first week after birth, and at one, two, three, four, five and six months. Collected data included history of child's feeding and mother's socio-demographic and psychosocial characteristics. The Cox Proportional Model was used to identify predictors of discontinuing exclusive breastfeeding before six months. The median duration of exclusive breastfeeding was 10.9 weeks (Inter Quartile Range 4.3 to 14.9). At six months, 2.8 % of infants were exclusively breastfed. The factors independently associated with the discontinuation of exclusive breastfeeding before six months were: not confident in the ability to breastfeed [Adjusted hazard ratio (AHR) = 3.90; 95 % CI 1.66, 9.16)], no plan on the duration of EBF (AHR = 2.86; 95 % CI 1.91, 4.28), breastfeeding problems during the first week (AHR = 1.54; 95 % CI 1.13, 2.11), low level of breastfeeding knowledge (AHR = 1.52; 95 % CI 1.08, 2.15), and experienced less than five Baby-friendly practices during the maternity stay (AHR = 1.47; 95 % CI 1.05, 2.06). Confidence in the ability to breastfeed and intention to exclusively breastfeed were the most important predictors of discontinuing exclusive breastfeeding before six months. To have a greater impact on the duration of exclusive breastfeeding, interventions should focus on these factors.


A 25-Hydroxycholecalciferol-Fortified Dairy Drink Is More Effective at Raising a Marker of Postprandial Vitamin D Status than Cholecalciferol in Men with Suboptimal Vitamin D Status.
Background: One strategy for improving population vitamin D status is consumption of fortified foods. However, the effects of dairy products fortified with different vitamin D isoforms on postprandial vitamin D status and metabolic outcomes have not been addressed.Objective: We investigated whether consumption of dairy drinks fortified with either 25-hydroxycholecalciferol [25(OH)D3] or cholecalciferol (vitamin D3) had differential effects on 24-h circulating plasma 25(OH)D3 concentration (a marker of vitamin D status) and cardiometabolic risk markers.Methods: A randomized, controlled, 3-way crossover, double-blind, postprandial study was conducted in 17 men with suboptimal vitamin D status [mean ± SEM age: 49 ± 3 y; body mass index (in kg/m2): 26.4 ± 0.6; and plasma 25(OH)D3 concentration: 31.7 ± 3.4 nmol/L]. They were randomly assigned to consume 3 different test meals (4.54 MJ, 51 g fat, 125 g carbohydrate, and 23 g protein), which contained either a nonfortified dairy drink (control), 20 μg 25(OH)D3-fortified (+HyD3) dairy drink, or 20 μg vitamin D3-fortified (+D3) dairy drink with toasted bread and jam on different occasions, separated by a 2-wk washout. Plasma 25(OH)D3 concentrations and cardiometabolic risk markers, including vascular stiffness, serum lipids, and inflammatory markers, were measured frequently within 8 h postprandially and 24 h after the dairy drink was consumed.Results: Plasma 25(OH)D3 concentrations (the primary outcome) were significantly higher after the +HyD3 dairy drink was consumed compared with +D3 and control (P = 0.019), which was reflected in the 1.5-fold and 1.8-fold greater incremental area under the curve for the 0-8 h response, respectively. The change in plasma 25(OH)D3 concentrations from baseline to 24 h for the +HyD3 dairy drink was also 0.9-fold higher than the +D3 dairy drink and 4.4-fold higher than the control (P < 0.0001), which were not significantly different from each other.Conclusion: The dairy drink fortified with 25(OH)D3 was more effective at raising plasma 25(OH)D3 concentrations postprandially than was the dairy drink fortified with vitamin D3 in men with suboptimal vitamin D status. This trial was registered at clinicaltrials.gov as NCT02535910.


Re-creation of historical chrysotile-containing joint compounds.
Chrysotile-containing joint compound was commonly used in construction of residential and commercial buildings through the mid 1970s; however, these products have not been manufactured in the United States for more than 30 years. Little is known about actual human exposures to chrysotile fibers that may have resulted from use of chrysotile-containing joint compounds, because few exposure and no health-effects studies have been conducted specifically with these products. Because limited amounts of historical joint compounds are available (and the stability or representativeness of aged products is suspect), it is currently impossible to conduct meaningful studies to better understand the nature and magnitude of potential exposures to chrysotile that may have been associated with historical use of these products. Therefore, to support specific exposure and toxicology research activities, two types of chrysotile-containing joint compounds were produced according to original formulations from the late 1960s. To the extent possible, ingredients were the same as those used originally, with many obtained from the original suppliers. The chrysotile used historically in these products was primarily Grade 7RF9 from the Philip Carey mine. Because this mine is closed, a suitable alternate was identified by comparing the sizes and mineral composition of asbestos structures in a sample of what has been represented to be historical joint compound (all of which were chrysotile) to those in samples of three currently commercially available Grade 7 chrysotile products. The re-created materials generally conformed to original product specifications (e.g. viscosity, workability, crack resistance), indicating that these materials are sufficiently representative of the original products to support research activities.


Leveraging Technology to Improve Health Disparity Research: Trilingual Data Collection Using Tablets.
Survey research is an essential component of epidemiological research to understand the health of older adults. However, there are several limitations to conventional data collection methods that may serve as barriers for recruitment and retention of research participants, especially from minority populations. With recent technological advancements, our research team developed an innovative data collection and management system to address linguistic and cultural barriers, data quality, data security, and data preparation issues. This platform has been utilized in the Population Study of Chinese Elderly in Chicago since 2011. Future use and improvement of this system will facilitate research among minority older adults and increase research participation and representativeness to ultimately understand and improve the health and well-being of diverse populations. J Am Geriatr Soc 67:S479-S485, 2019.


CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice.
Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene (DMD), is characterized by fatal degeneration of striated muscles. Dilated cardiomyopathy is one of the most common lethal features of the disease. We deployed Cpf1, a unique class 2 CRISPR (clustered regularly interspaced short palindromic repeats) effector, to correct DMD mutations in patient-derived induced pluripotent stem cells (iPSCs) and mdx mice, an animal model of DMD. Cpf1-mediated genomic editing of human iPSCs, either by skipping of an out-of-frame DMD exon or by correcting a nonsense mutation, restored dystrophin expression after differentiation to cardiomyocytes and enhanced contractile function. Similarly, pathophysiological hallmarks of muscular dystrophy were corrected in mdx mice following Cpf1-mediated germline editing. These findings are the first to show the efficiency of Cpf1-mediated correction of genetic mutations in human cells and an animal disease model and represent a significant step toward therapeutic translation of gene editing for correction of DMD.


Olaratumab for advanced soft tissue sarcoma.
Olaratumab is a humanized IgG1 monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα). Its antagonistic behavior inhibits the receptor's tyrosine kinase activity, thereby, turning off the downstream signaling cascades responsible for soft tissue sarcoma tumorigenesis. In October 2016, olaratumab received Food and Drug Administration (FDA) approval for its use in combination with doxorubicin for treatment of advanced soft tissue sarcoma. Areas covered: This drug profile takes a comprehensive look at the clinical studies leading to FDA approval of olaratumab as well as its safety and efficacy as a front-line treatment option for sarcoma patients. The literature search was primarily conducted using PubMed. Expert commentary: The combination of olaratumab plus doxorubicin has provided a new front-line therapeutic option for soft tissue sarcoma patients. An open-label phase Ib and randomized phase II trial in patients with advanced soft tissue sarcoma demonstrated that the addition of olaratumab to doxorubicin prolonged progression-free survival by 2.5 months and overall survival by 11.8 months when compared to doxorubicin alone. Of importance, this clinically meaningful increase in overall survival did not come at the expense of a significantly greater number of toxicities. A phase III confirmatory trial (ClinicalTrials.gov Identifier NCT02451943) will be completed in 2020.


Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells.
Activation of T cells requires co-stimulation, in addition to signals through the antigen-receptor complex. Antigen encounter without adequate co-stimulation results in T-cell desensitization or anergy, a mechanism of peripheral tolerance and an apparent obstacle to cancer immunotherapy. One important co-stimulatory pathway involves CD28 engagement by CD80 or CD86. However, other ligand-receptor pairs can also provide co-stimulation and may have important functions modulating the immune response. Previous reports indicated that co-stimulation using 4-1BB ligand (4-1BBL) or agonistic anti-4-1BB antibodies could prolong T-cell responses, avoid activation-induced cell death and promote anti-tumour responses in mice. To further investigate the potential for cancer immunotherapy, we studied the effects of CD80/CD86 and 4-1BBL in repeated stimulation of human T cells and asked whether 4-1BBL might be capable of reversing anergy. We expressed CD80, CD86 and 4-1BBL in A549 lung carcinoma cells using adenovirus vectors and co-cultured these with human T cells stimulated with anti-CD3 antibody. Proliferation co-stimulated by CD80 or CD86 was transient; however, 4-1BBL-co-stimulated cultures continued to proliferate for up to 5 weeks, with repeated stimulation. Combined co-stimulation with CD80/CD86 and 4-1BBL also allowed continuous proliferation at a faster rate than either signal alone. Co-stimulation with 4-1BBL did not suppress expression of the inducible, inhibitory CD80/CD86R, CTLA-4. Significantly, we show that T cells that had become non-responsive to anti-CD3, either alone or together with CD80/CD86 co-stimulation, and thus were anergic, could be reactivated to proliferate when costimulated with 4-1BBL, either alone or combined with CD80/CD86.


Percutaneous fetal endoscopic third ventriculostomy for severe isolated cerebral ventriculomegaly.
To demonstrate the feasibility and preliminary results of percutaneous fetal endoscopic third ventriculostomy (ETV) in human fetuses (pfETV) with isolated progressive and/or severe bilateral cerebral ventriculomegaly (IPSBV). The initial results of pfETV for IPSBV were described. Perioperative, perinatal and postnatal variables were described. The Ages and Stages Questionnaire (ASQ-3), 3rd edition (ASQ-3) was used for follow-up of all infants. Successful pfETV was performed in 10/11 (91%) fetuses, at a median gestational age (GA) of 28.7 weeks (25.3-30.7). There were no perioperative complications. After pfETV, 70% (7/10) of the fetuses had a decreased or stabilized lateral ventricle atria|lateral ventricle's atria. The median GA at delivery was 38.2 weeks (35.9-39.3). There were no perinatal complications. The postnatal ventriculoperitoneal shunt rate was 80% (8/10). Among neonates/infants who had prenatal stabilization or a decrease in the LVAs, 4 (4/7: 57.1%) had abnormal scores on the ASQ-3. Among neonates/infants that experienced prenatal increases in the LVAs, all of them (3/3: 100%) had abnormal scores on the ASQ-3. Percutaneous ETV is feasible in human fetuses with progressive and/or severe cerebral ventriculomegaly and seems to be a safe procedure for both the mother and the fetus.


[Results of treatment of primary bone neoplasms of the sacrococcygeal region].
In the clinic 53 patients with primary bone tumors of the sacrococcygeal region and sacroiliac junctions were observed. Surgical methods of treatment were used in 33, combined--in 7, radiation therapy--in 10, drug therapy--in 3. Recurrences developed in 7 cases, metastases were revealed in 14. The results of treatment in patients with neoplasms in this region were studied. Twenty five patients died from generalization of the process, metastases, intestinal obstruction and uremia. The remaining 28 patients have been followed up within the terms from 1 to 5 years and longer.


Parallel independent evolution of pathogenicity within the genus Yersinia.
The genus Yersinia has been used as a model system to study pathogen evolution. Using whole-genome sequencing of all Yersinia species, we delineate the gene complement of the whole genus and define patterns of virulence evolution. Multiple distinct ecological specializations appear to have split pathogenic strains from environmental, nonpathogenic lineages. This split demonstrates that contrary to hypotheses that all pathogenic Yersinia species share a recent common pathogenic ancestor, they have evolved independently but followed parallel evolutionary paths in acquiring the same virulence determinants as well as becoming progressively more limited metabolically. Shared virulence determinants are limited to the virulence plasmid pYV and the attachment invasion locus ail. These acquisitions, together with genomic variations in metabolic pathways, have resulted in the parallel emergence of related pathogens displaying an increasingly specialized lifestyle with a spectrum of virulence potential, an emerging theme in the evolution of other important human pathogens.


The influence of serum cytokines and growth factors on osteoclast formation in Paget's disease.
Osteoclasts are multinucleated cells (MNCs) that form from circulating mononuclear precursors in the presence of the receptor activator of nuclear factor kappa B-ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). To determine whether cytokines and growth factors influence RANKL/M-CSF induced osteoclastogenesis and bone resorption in Paget's disease. Prospective case-control study. Serum levels of M-CSF, interleukin (IL)-1 beta, IL-6 and tumour necrosis factor-alpha (TNFalpha) were measured in 13 Paget's disease patients and 8 normal controls. The effect of serum from Paget's patients on osteoclast formation was also assessed. Serum levels of IL-1 beta, IL-6 and TNFalpha were low or undetectable in Paget's disease patients and normal controls. Levels of M-CSF were significantly increased in Paget's patients who were not currently under treatment. In Paget's patients under treatment, serum M-CSF levels were not significantly different from normal controls. The addition of serum from untreated Paget's patients dose-dependently increased RANKL-induced osteoclast formation and lacunar resorption in normal monocyte cultures; elevated IL-6 levels were found in the supernatant and the addition of a specific antibody to human IL-6 blocked the increase in osteoclast formation and resorption. Serum from untreated Paget's patients also induced osteoclast formation in the absence of exogenous M-CSF; an antibody specific to human M-CSF abolished this effect. Both M-CSF and IL-6 play a major role in osteoclast formation and bone resorption in Paget's disease and measurement of serum M-CSF may provide a useful indicator of disease activity.


Protein import into plant mitochondria: precursor proteins differ in ATP and membrane potential requirements.
The import pathways of the alternative oxidase and the F(A)d subunit of the ATP synthase from soybean were characterised. The F(A)d precursor does not require extramitochondrial ATP for import and this was shown to be a characteristic of the mature protein. The alternative oxidase and F(A)d precursors were shown to differ in their requirement for a membrane potential. The membrane potential was modified using malonate, a competitive inhibitor to complex II. The alternative oxidase could be imported at higher malonate concentrations compared to the F(A)d. This difference could not be ascribed to the number of positive charges in each presequence as would be predicted from similar studies in fungi.


Salt and water: not so simple.
It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water consumption to balance the salt load. Two studies in this issue of the JCI challenge this notion and demonstrate that osmotic balance in response to high salt intake involves a complex regulatory process that is influenced by hormone fluctuation, metabolism, food consumption, water intake, and renal salt and water excretion. Rakova et al. report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. Kitada et al. extend upon these findings in mouse models and determined that increased urea and a corresponding increase in urea transporters in the renal medulla as the result of increased protein intake promote the water retention that is needed to achieve osmotic homeostasis. Together, the results of these two studies lay the groundwork for future studies to determine how, in the face of chronic changes in salt intake, humans maintain volume and osmotic homeostasis.


Regulation of neutrophil-mediated killing of Staphylococcus aureus and chemotaxis by c-jun NH2 terminal kinase.
The role of JNK in neutrophil chemotaxis and killing of microbial pathogens remains unclear. Using a recently described cell-permeable peptide inhibitor of the JNK pathway, based on the JBD of JIP-1, coupled to the protein transduction domain of HIV-TAT (TAT-JIP), in association with control peptides, we demonstrate that the JNK pathway plays a major role in regulating human neutrophil chemotaxis and killing of microbial pathogens. Serum-opsonized Staphylococcus aureus elicited JNK activation and c-jun phosphorylation. The activation of the JNK pathway and bactericidal activity were inhibited by the TAT-JIP peptide. The stimulation of oxygen radical generation by S. aureus was dependent on the JNK signaling pathway, as was the phagocytosis of serum-opsonized bacteria. Chemotaxis to activated serum complement but not random migration was inhibited by the TAT-JIP peptide. The findings demonstrate a major role for the JNK signaling pathway in neutrophil-mediated defense against microbial pathogens.


Modifying Thermal Switchability of Liquid Crystalline Nanoparticles by Alkyl Ligands Variation.
By coating plasmonic nanoparticles (NPs) with thermally responsive liquid crystals (LCs) it is possible to prepare reversibly reconfigurable plasmonic nanomaterials with prospective applications in optoelectronic devices. However, simple and versatile methods to precisely tailor properties of liquid-crystalline nanoparticles (LC NPs) are still required. Here, we report a new method for tuning structural properties of assemblies of nanoparticles grafted with a mixture of promesogenic and alkyl thiols, by varying design of the latter. As a model system, we used Ag and Au nanoparticles that were coated with three-ring promesogenic molecules and dodecanethiol ligand. These LC NPs self-assemble into switchable lamellar (Ag NPs) or tetragonal (Au NPs) aggregates, as determined with small angle X-ray diffraction and transmission electron microscopy. Reconfigurable assemblies of Au NPs with different unit cell symmetry (orthorombic) are formed if hexadecanethiol and 1H,1H,2H,2H-perfluorodecanethiol were used in the place of dodecanethiol; in the case of Ag NPs the use of 11-hydroxyundecanethiol promotes formation of a lamellar structure as in the reference system, although with substantially broader range of thermal stability (140 vs. 90 °C). Our results underline the importance of alkyl ligand functionalities in determining structural properties of liquid-crystalline nanoparticles, and, more generally, broaden the scope of synthetic tools available for tailoring properties of reversibly reconfigurable plasmonic nanomaterials.


Basal cell adhesion molecule/lutheran protein. The receptor critical for sickle cell adhesion to laminin.
Sickle red cells bind significant amounts of soluble laminin, whereas normal red cells do not. Solid phase assays demonstrate that B-CAM/LU binds laminin on intact sickle red cells and that red cell B-CAM/LU binds immobilized laminin, whereas another putative laminin binding protein, CD44, does not. Ligand blots also identify B-CAM/LU as the only erythrocyte membrane protein(s) that binds laminin. Finally, transfection of murine erythroleukemia cells with human B-CAM cDNA induces binding of both soluble and immobilized laminin. Thus, B-CAM/LU appears to be the major laminin-binding protein of sickle red cells. Previously reported overexpression of B-CAM/LU by epithelial cancer cells suggests that this protein may also serve as a laminin receptor in malignant tumors.


Environmental implications of anaerobic digestion for manure management in dairy farms in Mexico: a life cycle perspective.
The environmental profile of milk production in Mexico was analysed for three manure management scenarios: fertilization (F), anaerobic digestion (AD) and enhanced anaerobic digestion (EAD). The study used the life cycle assessment (LCA) technique, considering a 'cradle-to-gate' approach. The assessment model was constructed using SimaPro LCA software, and the life cycle impact assessment was performed according to the ReCiPe method. Dairy farms with AD and EAD scenarios were found to exhibit, respectively, 12% and 27% less greenhouse gas emissions, 58% and 31% less terrestrial acidification, and 3% and 18% less freshwater eutrophication than the F scenario. A different trend was observed in the damage to resource availability indicator, as the F scenario presented 6% and 22% less damage than the EAD and AD scenarios, respectively. The magnitude of environmental damage from milk production in the three dairy manure management scenarios, using a general single score indicator, was 0.118, 0.107 and 0.081 Pt/L of milk for the F, AD and EAD scenarios, respectively. These results indicate that manure management systems with anaerobic digestion can improve the environmental profile of each litre of milk produced.


Thrombin Time is a Diagnostic Biomarker of Sudden Sensorineural Hearing Loss and Predicts the Prognosis.
The aim of this study is to determine whether thrombin time (TT) could be used as diagnostic biomarkers and predict the prognosis for sudden sensorineural hearing loss (SSNHL). Sixty-one patients diagnosed with SSNHL and 65 people who underwent physical examination were recruited. Data on the patient's background, clinical course, and laboratory findings were collected. SSNHL patients were divided into the effective and ineffective groups according to the hearing recovery from the treatment and were assessed by binary logistic regression. Receiver-operating characteristic (ROC) analysis was carried out for the best discriminating cutoff value of the biomarker with the corresponding sensitivity and specificity was calculated. The SSNHL group exhibited prolonged TT (19.11 ± 1.12 seconds) compared to the control group (17.58 ± 2.18 seconds, P < .001). Binary logistic regression analysis found a significant positive association between TT and SSNHL and was observed with an odds ratio (OR) 1.769 [95% confidence interval (CI) 1.344-2.330, P < .001] in the unadjusted model. Even after adjustment using the variables included in the multivariate models, TT was significantly predictive of SSNHL. A TT cutoff value of 17.65 seconds provides optimal separation between patients with SSNHL and controls in the ROC analysis [Area Under the Curve (AUC) 0.773, 95% CI 0.689-0.856; sensitivity, 0.918; and specificity, 0.569]. TT in the effective group of SSNHL patients was shorter (18.76 ± 1.06 seconds) than that in the ineffective group (19.43 ± 1.09 seconds, P = .018). The cutoff value of TT as progress predictors was 19.85 seconds. The TT < 19.85 seconds showed an effective rate 59.09% (26/44) higher than 17.65% (3/17) of TT ≥ 19.85 seconds. TT is a potential biomarker of SSNHL and is independently associated with the prognosis of patients with SSNHL.


Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis.
Traditionally, the transcriptomic and proteomic characterisation of CD4+ T cells at the single-cell level has been performed by two largely exclusive types of technologies: single-cell RNA sequencing (scRNA-seq) and antibody-based cytometry. Here, we present a multi-omics approach allowing the simultaneous targeted quantification of mRNA and protein expression in single cells and investigate its performance to dissect the heterogeneity of human immune cell populations. We have quantified the single-cell expression of 397 genes at the mRNA level and up to 68 proteins using oligo-conjugated antibodies (AbSeq) in 43,656 primary CD4+ T cells isolated from the blood and 31,907 CD45+ cells isolated from the blood and matched duodenal biopsies. We explored the sensitivity of this targeted scRNA-seq approach to dissect the heterogeneity of human immune cell populations and identify trajectories of functional T cell differentiation. We provide a high-resolution map of human primary CD4+ T cells and identify precise trajectories of Th1, Th17 and regulatory T cell (Treg) differentiation in the blood and tissue. The sensitivity provided by this multi-omics approach identified the expression of the B7 molecules CD80 and CD86 on the surface of CD4+ Tregs, and we further demonstrated that B7 expression has the potential to identify recently activated T cells in circulation. Moreover, we identified a rare subset of CCR9+ T cells in the blood with tissue-homing properties and expression of several immune checkpoint molecules, suggestive of a regulatory function. The transcriptomic and proteomic hybrid technology described in this study provides a cost-effective solution to dissect the heterogeneity of immune cell populations at extremely high resolution. Unexpectedly, CD80 and CD86, normally expressed on antigen-presenting cells, were detected on a subset of activated Tregs, indicating a role for these co-stimulatory molecules in regulating the dynamics of CD4+ T cell responses.


Effect of preparatory information prior to elective total hip replacement on post-operative physical coping outcomes.
The aim of the study was to evaluate the effect of preparatory information on a patient's post-operative physical coping outcomes following a Total Hip Replacement (THR). The research design was quasi-experimental. Eighty-two healthy individuals, scheduled for an elective THR were used and selected using non-random techniques, and placed into one of two groups on an alternating basis. The subjects in the experimental group were given procedural, sensory and coping information relating to the whole surgical procedure of a THR. In addition, written information was provided for each experimental subject to support the verbal information. Subjects in the control group only received the advice and support that would routinely be given to THR patients by ward, medical and nursing staff. The study measured a number of physical outcomes using a "Physical Indicators of Coping Questionnaire" developed to measure physiological and physical outcomes post-operatively. In addition, a Linear Analogue Coping Scale was developed to assess a patient's personal perception of their overall coping ability with the THR. The study demonstrated that preparatory information, given pre-operatively, post-operatively and pre-discharge had positive effects on the physical recovery and coping outcomes measured. Subjects in the experimental group had significantly less post-operative intramuscular analgesia, mobilized sooner with a Zimmer frame and walking sticks and lastly, their length of stay was on average, 2 days less than the control group. The Linear Analogue Coping Scale demonstrated that patients in the experimental group did perceive they were coping more effectively post-operatively. Preparatory information of various types and in different forms appear to have positive effects on the ability of patients to cope with and recover physically from a THR in the immediate post-operative period.


Developing mHealth Remote Monitoring Technology for Attention Deficit Hyperactivity Disorder: A Qualitative Study Eliciting User Priorities and Needs.
Guidelines in the United Kingdom recommend that medication titration for attention deficit hyperactivity disorder (ADHD) should be completed within 4-6 weeks and include regular reviews. However, most clinicians think that weekly clinic contact is infeasible, and audits have shown that this timeline is rarely achieved. Thus, a more effective monitoring and review system is needed; remote monitoring technology (RMT) may be one way to improve current practice. However, little is known about whether patients with ADHD, their families, and clinicians would be interested in using RMT. To explore patients', parents', and health care professionals' views and attitudes toward using digital technology for remote monitoring during titration for ADHD. This was a qualitative study, and data were collected through 11 focus groups with adults and young people with ADHD, parents of children with ADHD, and health care professionals (N=59). All participant groups were positive about using RMT in the treatment of ADHD, but they were also aware of barriers to its use, especially around access to technology and integrating RMT into clinical care. They identified that RMT had the most potential for use in the ongoing management and support of ADHD, rather than during the distinct titration period. Participants identified features of RMT that could improve the quality of consultations and support greater self-management. RMT has the potential to augment support and care for ADHD, but it needs to go beyond the titration period and offer more to patients and families than monitoring through outcome measures. Developing and evaluating an mHealth app that incorporates the key features identified by end users is required.


Water oxidation catalyzed by mononuclear ruthenium complexes with a 2,2'-bipyridine-6,6'-dicarboxylate (bda) ligand: how ligand environment influences the catalytic behavior.
A new water oxidation catalyst [Ru(III)(bda)(mmi)(OH2)](CF3SO3) (2, H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; mmi = 1,3-dimethylimidazolium-2-ylidene) containing an axial N-heterocyclic carbene ligand and one aqua ligand was synthesized and fully characterized. The kinetics of catalytic water oxidation by 2 were measured using stopped-flow technique, and key intermediates in the catalytic cycle were probed by density functional theory calculations. While analogous Ru-bda water oxidation catalysts [Ru(bda)L2] (L = pyridyl ligands) are supposed to catalyze water oxidation through a bimolecular coupling pathway, our study points out that 2, surprisingly, undergoes a single-site water nucleophilic attack (acid-base) pathway. The diversion of catalytic mechanisms is mainly ascribed to the different ligand environments, from nonaqua ligands to an aqua ligand. Findings in this work provide some critical proof for our previous hypothesis about how alternation of ancillary ligands of water oxidation catalysts influences their catalytic efficiency.