Transcriptome profiling of the whitefly Bemisia tabaci reveals stage-specific gene expression signatures for thiamethoxam resistance.
Bemisia tabaci has developed high levels of resistance to many insecticides including the neonicotinoids and there is strong evidence that for some compounds resistance is stage-specific. To investigate the molecular basis of B. tabaci resistance to the neonicotinoid thiamethoxam we used a custom whitefly microarray to compare gene expression in the egg, nymph and adult stages of a thiamethoxam-resistant strain (TH-R) with a susceptible strain (TH-S). Gene ontology and bioinformatic analyses revealed that in all life stages many of the differentially expressed transcripts encoded enzymes involved in metabolic processes and/or metabolism of xenobiotics. Several of these are candidate resistance genes and include the cytochrome P450 CYP6CM1, which has been shown to confer resistance to several neonicotinoids previously, a P450 belonging to the Cytochrome P450s 4 family and a glutathione S-transferase (GST) belonging to the sigma class. Finally several ATP-binding cassette transporters of the ABCG subfamily were highly over-expressed in the adult stage of the TH-R strain and may play a role in resistance by active efflux. Here, we evaluated both common and stage-specific gene expression signatures and identified several candidate resistance genes that may underlie B. tabaci resistance to thiamethoxam.


α4α6β2* nicotinic acetylcholine receptor activation on ventral tegmental area dopamine neurons is sufficient to stimulate a depolarizing conductance and enhance surface AMPA receptor function.
Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine's action in humans. However, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing α6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9'S mice). In voltage-clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via α6β2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through α6β2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, α6β2* activation did not enhance N-methyl-D-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from α6L9'S mice lacking α4 nAChR subunits, suggesting that α4α6β2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of α4α6β2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. α4α6β2* nAChRs may be a promising target for future smoking cessation pharmacotherapy.


Thermal properties and physicochemical behavior in aqueous solution of pyrene-labeled poly(ethylene glycol)-polylactide conjugate.
A fluorescence-labeled bioresorbable polymer was prepared by a coupling reaction of poly(ethylene glycol)-polylactide (PEG-PLA) with carboxyl pyrene, using N,N'-diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole (DIC/HOAt) as a coupling agent and 4-dimethylaminopyridine (DMAP) as a catalyst. The obtained copolymer, termed PEG-PLA-pyrene, was characterized using various analytical techniques, such as gel permeation chromatography (GPC), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), proton nuclear magnetic resonance ((1)H-NMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), to identify the molecular structure and to monitor the thermal property changes before and after the reaction. The presence of a pyrene moiety at the end of polylactide (PLA) did not alter the crystallization ability of the poly(ethylene glycol) (PEG) blocks, indicating that the conjugate preserved the inherent thermal properties of PEG-PLA. However, the presence of PEG-PLA blocks strongly reduced the melting of pyrene, indicating that the thermal characteristics were sensitive to PEG-PLA incorporation. Regarding the physicochemical behavior in aqueous solution, a higher concentration of PEG-PLA-pyrene resulted in a higher ultraviolet-visible (UV-vis) absorbance and fluorescence emission intensity. This is of great interest for the use of this conjugate as a fluorescence probe to study the in vivo distribution as well as the internalization and intracellular localization of polymeric micelles.


[Contribution of I. V. Davydovskiy in the development of gerontology].
This article represents a historical review concerning a period of work of prominent Russian pathologist Prof. I. Davydovski on a field of gerontology. At the end of his professional activity I. Davydovski has organized a gerontological laboratory. His research works have been summarized in the popular monograph "Gerontology", which appeared in 1966. This book served as a guidance in general and systemic gerontology for many years.


Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women.
We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between -1.0 and -2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints. © 2019 American Society for Bone and Mineral Research.


A physiologically based toxicokinetic model for dietary uptake of hydrophobic organic compounds by fish: II. simulation of chronic exposure scenarios.
A physiologically based toxicokinetic (PBTK) model for dietary uptake of hydrophobic organic compounds by fish was used to simulate dosing scenarios commonly encountered in experimental and field studies. Simulations were initially generated for the model compound [UL-(14)C] 2,2',5,5'-tetrachlorobiphenyl ([(14)C] PCB 52). Steady-state exposures were simulated by calculating chemical concentrations in tissues of the predator corresponding to an equilibrium distribution between the fish and water (termed the bioconcentration or BCF residue data set). This residue data set was then varied in a proportional manner until whole-body chemical concentrations exhibited no net change for each set of exposure conditions. For [(14)C] PCB 52, the proportional increase in BCF residues (termed the biomagnification factor or BMF) required to achieve steady state in a food-only exposure was 2.24, while in a combined food and water exposure the BMF was 3.11. Additional simulations for the food and water exposure scenario were obtained for a set of hypothetical organic compounds with increasing log K(OW) values. Using gut permeability coefficients determined for [(14)C] PCB 52, predicted BMFs increased with chemical log K(OW), achieving levels much higher than those reported in field sampling efforts. BMFs comparable to measured values were obtained by reducing permeability coefficients within each gut segment in a log K(OW)-dependent manner. This predicted decrease in chemical permeability is consistent with earlier work, suggesting that dietary absorption of hydrophobic compounds by fish is controlled in part by factors that vary with chemical log K(OW). Relatively low rates of metabolism or growth were shown to have a substantial impact on steady-state biomagnification of chemical residues.


Psychometric Properties of the Chinese version of UPPS-P Impulsive Behavior Scale.
The present study aimed to assess the psychometric properties of a Chinese version of the UPPS-P Impulsive Behavior Scale. The associations between the UPPS-P scale and impulsivity choice, gender, smoking, and drinking status were also assessed. A total of 127 adults ranging from 21 to 65 years old participated in the study. Participants were administered with the Chinese version of the UPPS-P Impulsive Behavior Scale, Beck Depression Inventory II (BDI-II), and State-Trait Anxiety Inventory (STAI). Impulsivity choice tasks were also tested including the Delay Discounting Task (DDT), Balloon Analogue Risk Task (BART), and Beads Task (Beads). A new version of the UPPS-P Impulsive Behavior Scale was formed that includes 40 items. The scores of the UPPS-P Impulsive Behavior Scale demonstrated adequate internal consistency on five subscales but less sufficient structure validity in the present sample. In addition, positive urgency was negatively related to the Beads task; negative urgency and positive urgency were positively related to the DDT and BART. Moreover, positive and negative urgency were positively correlated with depression; all five subscales were positively correlated with anxiety; sensation seeking was higher in males than females and in alcohol drinkers than non-drinkers; and lack of premeditation and lack of perseverance were higher in nonsmokers than smokers. The present study supports the reliability but not the structure validity of the UPPS-P Impulsive Behavior Scale. The impulsivity personality trait assessed by the UPPS-P scale was associated with impulsivity choice, depression, anxiety, gender, and drinking and smoking status. Further studies should be conducted to explore the structure of impulsivity in the Chinese population.


[T-lymphocyte subsets and serum carcinoembryonic antigen in patients with lung cancer and its dynamic changes after therapy].
Using the indirect immunofluorescent assay, we observed the variation of T-lymphocyte subsets of peripheral blood in 100 patients of primary bronchogenic carcinoma and 31 cases with active pulmonary tuberculosis. Serum CEA were measured simultaneously. The decrease of OKT3+, OKT4+, OKT8+ lymphocytes were significant in patients with lung cancer than that in healthy controls (P less than 0.01). The ratio of OKT4+/OKT8+ increased. It suggested that both cellular immunoincompetence and immunoregulatory abnormality were present in patients with lung cancer. After the resection of tumors 65 cases, the percentage of OKT4+ cells increased at the first week. Fourty seven cases were observed continuously for six months, it was found that OKT8+ cells increased (P less than 0.01). After anticancer chemotherapy, the patients with small cell carcinoma revealed a similar changes too. After operation and chemotherapy, serum CEA level decreased significantly too.


Longitudinal dynamics of gut microbiota in the pathogenesis of acute graft-versus-host disease.
The gut microbiota has been reported to be associated with acute graft-versus-host disease (aGvHD) in hematopoietic stem cell transplantation (HSCT). Dynamic surveillance of the microbiota is required to understand the detailed pathogenesis involved in the process of aGvHD. Fecal samples were collected prospectively at four timepoints, including pre-HSCT (T1), graft infusion (T2), neutrophil engraftment (T3), and 30 days after transplantation (T4). Fecal samples were profiled by 16S ribosomal RNA gene sequencing to assess the microbiota composition. From the T1 to T4 timepoint, the diversity of the gut microbiota decreased, and the dominant species also changed, with a decrease in the obligate anaerobic bacteria and a shift toward a "pathogenic community". Compared with non-aGvHD patients, aGvHD patients had a lower abundance of Roseburia at T1 and a higher abundance of Acinetobacter johnsonii at T2. Furthermore, Acinetobacter johnsonii was negatively correlated with the secretion of IL-4 and TNF-α. At T3, Rothia mucilaginos was demonstrated to be linked with a decreased risk of aGvHD, which was accompanied by decreased secretion of IL-8. At T4, higher abundances of Lactobacillus paracasei and Acinetobacter johnsonii were identified to be related with aGvHD. Lactobacillus paracasei was associated with the downregulation of IL-10, and Acinetobacter johnsonii was associated with the downregulation of IL-2 and TNF-α. Dynamic changes in gut microbiota composition and related cytokines were found to be related to aGvHD, including pathogenic or protective changes. These findings suggested that manipulation of gut microbiota at different timepoints might be a promising avenue for preventing or treating this common complication.


Dirac cone move and bandgap on/off switching of graphene superlattice.
Using the density functional theory with generalized gradient approximation, we have studied in detail the cooperative effects of degenerate perturbation and uniaxial strain on bandgap opening in graphene. The uniaxial strain could split π bands into πa and πz bands with an energy interval Es to move the Dirac cone. The inversion symmetry preserved antidot would then further split the πa (πz) bands into πa1 (πz1) and πa2 (πz2) bands with an energy interval Ed, which accounts for the bandgap opening in a kind of superlattices with Dirac cone being folded to Γ point. However, such antidot would not affect the semimetal nature of the other superlattices, showing a novel mechanism for bandstructure engineering as compared to the sublattice-equivalence breaking. For a superlattice with bandgap of ~Ed opened at Γ point, the Es could be increased by strengthening strain to close the bandgap, suggesting a reversible switch between the high velocity properties of massless Fermions attributed to the linear dispersion relation around Dirac cone and the high on/off ratio properties associated with the sizable bandgap. Moreover, the gap width actually could be continuously tuned by controlling the strain, showing attractive application potentials.


Prediction of the cause, effects, and prevention of drug-nutrient interactions using attributes and attribute values.
Drug-nutrient interactions and their adverse outcomes have previously been identified by observation, investigation, and literature reports. Knowing the attributes of the drugs, availability of knowledge base management systems for microcomputer use can facilitate prediction of the mechanism and the effects of drug-nutrient interactions. Examples used to illustrate this approach are prediction of lactose intolerance in drug-induced malabsorption, and prediction of the mechanism responsible for drug-induced flush reactions. In the future we see that there may be many opportunities to use this system further in the investigation of complex drug-nutrient interactions.


Cytomegalovirus pneumonitis after cardiac transplantation.
To evaluate the incidence and clinical features of cytomegalovirus (CMV) pneumonitis after cardiac transplantation, we identified 27 (16%) of 171 consecutive recipients in whom CMV pneumonitis was confirmed by strict diagnostic criteria. Cytomegalovirus pneumonitis occurred in 6 (30%) of 20 patients treated with azathioprine and prednisone, and 8 (25%) of 32 patients treated with azathioprine, cyclosporine, and prednisone, but only 13 (11%) of 119 patients treated with cyclosporine and prednisone. The incidence of CMV pneumonitis was not related to recipient preoperative CMV titers or to postoperative cardiac rejection, but there was a trend toward increased CMV pneumonitis in patients who received organs from CMV-positive donors. Mean onset of CMV pneumonitis was 2.9 +/- 1.6 (SD) months after transplantation. In the azathioprine-prednisone group, CMV was always associated with at least one other respiratory pathogen (Aspergillus, n = 5; Pneumocystis carinii, n = 2). In the two cyclosporine groups, CMV was either the sole respiratory pathogen (n = 9), or associated with P carinii (n = 11). Roentgenographically, diffuse bilateral hazy pulmonary opacities were present in 19 (70%) of 27 patients, but focal subsegmental opacity (26%), small pleural effusion (26%), and lobar consolidation (7%) were also observed. When bronchoscopy was performed, bronchoalveolar lavage was the most sensitive technique for detecting CMV (72%), whereas transbronchial biopsy (39%) and combined washings and brushings (33%) were relatively insensitive techniques. Respiratory failure and death occurred in 52% and 44%, respectively, of patients with CMV pneumonitis. In this population of immunocompromised hosts: (1) CMV pneumonitis, alone or with other respiratory pathogens, was a major cause of morbidity and mortality; (2) localized roentgenographic opacity did not exclude CMV pneumonitis; (3) bronchoalveolar lavage was the most sensitive bronchoscopic technique for detecting CMV pneumonitis.


Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons.
Extracellular single-cell recording techniques were employed to study the mechanism of action of repeated oral clozapine administration on the in vivo spontaneous activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA)-containing neurons in the rat. Clozapine was observed to affect DA neurons differentially within these two regions when compared to haloperidol. Acute treatment (1 hr) with both drugs increased the number of spontaneously firing neurons in both A9 and A10. Chronic (21 day) treatment with haloperidol decreased the number of cells encountered in both regions, whereas repeated treatment with clozapine reduced the number of DA cells per track only in A10. In all cases, the silent DA neurons were inferred to be in a state of depolarization inactivation since they could be induced to discharge normally by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid. These effects were not due to an effect of chloral hydrate anesthesia since they were also observed in gallamine-paralyzed, artificially respired animals. Chronic co-administration with haloperidol of either an anticholinergic (trihexyphenidyl) or the alpha 1-norepinephrine (NE) receptor antagonist, prazosin, but not an alpha 2-NE antagonist, RX781094, resulted in a differential effect on A9 and A10 DA neurons identical to that observed with repeated clozapine administration alone. Thus, chronic treatment with these combinations of drugs resulted in the depolarization inactivation of only A10 cells. These data suggest that anticholinergic and/or alpha 1-NE-blocking properties of clozapine may, in part, mediate its differential effects on A9 and A10 midbrain DA neurons.


Reconstruction of Female Urethra with Tubularized Anterior Vaginal Flap.
Female urethral injury is a rare disease. Causes of urethral injuries are prolonged obstructed labour, gynaecological surgeries like vaginoplasty and post traumatic urethral injuries. The present study was conducted to evaluate outcome of female urethral reconstruction using tubularized anterior vaginal wall flap covered with fibroadipose martius flap and autologous fascia sling in patients with urethral loss. Aim of study was to evaluate outcome of reconstruction of female urethra with tubularized anterior vaginal flap. Retrospective analysis of all the patients with complete urethral loss was done from August 2008 to July 2015. Total seven patients were included in study. All patients presenting with total urethral loss were included. These patients were treated with tubularized anterior vaginal flap. Neourethra was covered with Martius labial flap and autologous fascia lata or rectus abdominis fascia sling. Most common cause of urethral loss was obstructed labour (57.1%). Postoperatively patients were assessed for continence, urine flow rate, ultrasound for upper urinary tract and post void residue. Mean operative time was 180 minutes (160-200 minutes) and Intraoperative blood loss was 220ml (170-260 ml). Mean postoperative hospital stay was eight days (seven to nine days) Mean post surgery maximum urine flow rate was more than 15ml/sec (6.7-18.2ml/sec) and mean post void residual urine was 22.5ml (10-50ml). Median follow-up time was 35 months. All patients were catheter free and continent post three weeks of surgery except one patient who developed mild stress urinary incontinence. One patient developed urethral stenosis which was managed by intermittent serial urethral dilatation. Female neourethral reconstruction with tabularized anterior vaginal flap and autologous pubovaginal sling is feasible in patients of total urethral loss with success rate of approximately 86%. It should be considered in patients of complete urethral loss with adequate healthy vaginal tissue.


Sodium arsenite toxicity on hematology indices and reproductive parameters in Teddy goat bucks and their amelioration with vitamin C.
Arsenic is a major environmental toxicant of concern, affecting both female and male reproductive systems. The present study was conducted to investigate the toxic effects of arsenic on semen quality and reproductive hormones of Teddy bucks, an important domestic species in regions of Pakistan. In addition to arsenic, vitamin C was fed to a subset of animals to determine if there were ameliorative effects on reproductive parameters. Sixteen adult Teddy bucks were randomly divided into four experimental groups: A (control), B (arsenic 5 mg/kg BW/day orally), and C (arsenic 5 mg/kg BW/day plus vitamin C of an oral dose of 200 mg/kg BW/day). The animals in experimental group D were given only vitamin C (oral dose of 200 mg/kg BW/day). Animals were fed treated food once a day for 12 weeks. Semen quality parameters (volume, motility, count, sperm morphology, live dead ratio, sperm membrane integrity, and sperm DNA integrity) of bucks from each experimental group were evaluated on a weekly basis. Hematology and the level of arsenic in the blood were assessed every 2 weeks. Serum was collected fortnightly to measure reproductive and stress hormones (testosterone, luteinizing hormone, follicle-stimulating hormones, and cortisol). At the end of the study, all the animals were slaughtered, and the testes of all the animals were collected and evaluated for histopathology. Semen parameters in arsenic-treated bucks were significantly reduced (p < 0.05) compared with controls. Moreover, the levels of male hormones (testosterone, luteinizing hormone, and follicle-stimulating hormone) were significantly decreased in arsenic-treated animals, while cortisol was significantly increased with arsenic exposure. The histopathological lesions in the testes were present in the form of the loss of germinal epithelium and atrophy of Leydig cells. Supplementation of vitamin C however ameliorated the adverse effects of arsenic on semen quality and hormones. The histopathological lesions were also ameliorated due to vitamin C treatment. This study demonstrates that arsenic can adversely affect reproductive endpoints in Teddy goat bucks and supports the hypothesis that vitamin C is an effective treatment in arsenic-induced toxicosis. This study has high significance for Pakistan, as water contaminated with arsenic is a top health concern and is a recurring issue for both domestic animals and humans.


Risk factors for coronary artery disease in old persons in an academic hospital-based geriatrics practice.
Risk factors for coronary artery disease (CAD) in old men and women include age, cigarette smoking, hypertension, diabetes mellitus, dyslipidemia, and obesity. To investigate the association of risk factors with prevalence of CAD. We performed a retrospective analysis of charts for all old persons seen during the period from 1 January 1998 through 15 June 1999 at an academic hospital-based geriatric practice to investigate associations of risk factors with prevalence of CAD among old persons. We studied 467 men, mean age 80 +/- 8 years, and 1444 women, mean age 81 +/- 8 years. CAD was present in 201 of 467 men (43%) and in 473 of 1444 women (33%; P < 0.0001). Risk factors for CAD according to univariate analysis were age (P < 0.0001 for women), cigarette smoking (P < 0.0001 for men and women), hypertension (P < 0.0001 for men and women), diabetes mellitus (P < 0.0001 for men and women), obesity (P < 0.0001 for men and women), and serum levels of total cholesterol (P < 0.0001 for men and P = 0.0001 for women), low-density lipoprotein (LDL) cholesterol (P < 0.0001 for men and P = 0.001 for women), and high-density lipoprotein (HDL) cholesterol (inverse association; P = 0.0001 for men and women). Stepwise logistic regression analysis showed that significant independent risk factors for CAD were cigarette smoking (odds ratio 6.7 for men), hypertension (odds ratios 3.3 for men and 2.7 for women), and serum levels of HDL cholesterol (odds ratio 0.83 for men and women) and LDL cholesterol (odds ratios 1.10 for men and 1.09 for women). Significant independent risk associations with prevalence of CAD among old persons were found for cigarette smoking by men, hypertension in men and women, and serum levels of HDL cholesterol (inverse association) in men and women, and of LDL cholesterol in men and women.


Neural correlates of social perception on response bias.
Accurate person perception is crucial in social decision-making. One of the central elements in successful social perception is the ability to understand another's response bias; this is because the same behavior can represent different inner states depending on whether other people are yea-sayers or naysayers. In the present study, we have tried to investigate how the internal biases of others are perceived. Using a multi-trial learning paradigm, perceivers made predictions about a target's responses to various suggested activities and then received feedback for each prediction trial-by-trial. Our hypotheses were that (1) the internal decision criterion of the targets would be realized through repeated experiences, and (2) due to positive-negative asymmetry, yea-sayers would be recognized more gradually than naysayers through the probabilistic integration of repeated experiences. To find neural evidence that tracks probabilistic integration when forming person knowledge on response biases, we employed a model-based fMRI with a State-Space Model. We discovered that person knowledge about yea-sayers modulated several brain regions, including caudate nucleus, DLPFC, hippocampus, etc. Moreover, when person knowledge was updated with incorrect performance feedback, brain regions including the caudate nucleus, DLPFC, dmPFC, and TPJ were also involved. There were overlapping regions for both processes, caudate nucleus and DLPFC, suggesting that these regions take crucial roles in forming person knowledge with repeated feedback, while reflecting acquired information up to the current prediction.


Using predictions from a joint model for longitudinal and survival data to inform the optimal time of intervention in an abdominal aortic aneurysm screening programme.
Joint models of longitudinal and survival data can be used to predict the risk of a future event occurring based on the evolution of an endogenous biomarker measured repeatedly over time. This has led naturally to the use of dynamic predictions that update each time a new longitudinal measurement is provided. In this paper, we show how such predictions can be utilised within a fuller decision modelling framework, in particular to allow planning of future interventions for patients under a 'watchful waiting' care pathway. Through the objective of maximising expected life-years, the predicted risks associated with not intervening (e.g. the occurrence of severe sequelae) are balanced against risks associated with the intervention (e.g. operative risks). Our example involves patients under surveillance in an abdominal aortic aneurysm screening programme where a joint longitudinal and survival model is used to associate longitudinal measurements of aortic diameter with the risk of aneurysm rupture. We illustrate how the decision to intervene, which is currently based on a diameter measurement greater than a certain threshold, could be made more personalised and dynamic through the application of a decision modelling approach.


Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.


Evaluating the Effectiveness of NORTH STAR: a Community-Based Framework to Reduce Adult Substance Misuse, Intimate Partner Violence, Child Abuse, Suicidality, and Cumulative Risk.
We evaluated the effectiveness of NORTH STAR, a community assessment, planning, and action framework to reduce the prevalence of several secretive adult problems (hazardous drinking, controlled prescription drug misuse, suicidality, and clinically significant intimate partner violence and child abuse [both emotional and physical]) as well as cumulative risk. One-third of US Air Force (AF) bases worldwide were randomly assigned to NORTH STAR (n = 12) or an assessment-and-feedback-only condition (n = 12). Two AF-wide, cross-sectional, anonymous, web-based surveys were conducted of randomly selected samples assessing risk/protective factors and outcomes. Process data regarding attitudes, context, and implementation factors were also collected from Community Action Team members. Analyzed at the level of individuals, NORTH STAR significantly reduced intimate partner emotional abuse, child physical abuse, and suicidality, at sites with supportive conditions for community prevention (i.e., moderation effects). Given its relatively low cost, use of empirically supported light-touch interventions, and emphasis on sustainability with existing resources, NORTH STAR may be a useful framework for the prevention of a range of adult behavioral health problems that are difficult to impact.


Augmentation of elastase-induced emphysema by cigarette smoke. Description of a model and a review of possible mechanisms.
Rats were treated with a single endotracheal dose of purified porcine pancreatic elastase (400 IU/kg), exposed to undiluted cigarette smoke from Kentucky 2RI reference cigarettes (one 35-ml puff/min for 10 min daily, 5 days per week, for 12 wk) or with a combination of elastase followed by smoke exposure. A number of significant functional abnormalities were observed in the lungs of rats receiving elastase; these included reduced spontaneous ventilation, enlarged subdivisions of lung volume, loss of elastic recoil, and diminished gas exchange capacity. Rats receiving both elastase and cigarette smoke had significantly more severe pulmonary dysfunction than did rats treated with elastase alone. Morphometric measurements of mean linear intercept demonstrated a loss of alveolar fine structure, with enlargement of distal air spaces in elastase-treated rats. These changes were significantly more severe in rats treated with both elastase and cigarette smoke. Pulmonary function tests and morphometric measurements in sham-treated rats and in rats exposed to cigarette smoke only were not significantly different from those in untreated control animals. It is concluded that elastase-induced emphysema in rats is enhanced by exposure to whole cigarette smoke.


Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment.
Lung cancer screening with low-dose computed tomography (LDCT) has been recommended, based primarily on the results of the NLST (National Lung Screening Trial). The American College of Radiology recently released Lung-RADS, a classification system for LDCT lung cancer screening. To retrospectively apply the Lung-RADS criteria to the NLST. Secondary analysis of a group from a randomized trial. 33 U.S. screening centers. Participants were randomly assigned to the LDCT group of the NLST, were aged 55 to 74 years, had at least a 30-pack-year history of smoking, and were current smokers or had quit within the past 15 years. 3 annual LDCT lung cancer screenings. Lung-RADS classifications for LDCT screenings. Lung-RADS categories 1 to 2 constitute negative screening results, and categories 3 to 4 constitute positive results. Of 26 722 LDCT group participants, 26 455 received a baseline screening; 48 671 screenings were done after baseline. At baseline, the false-positive result rate (1 minus the specificity rate) for Lung-RADS was 12.8% (95% CI, 12.4% to 13.2%) versus 26.6% (CI, 26.1% to 27.1%) for the NLST; after baseline, the false-positive result rate was 5.3% (CI, 5.1% to 5.5%) for Lung-RADS versus 21.8% (CI, 21.4% to 22.2%) for the NLST. Baseline sensitivity was 84.9% (CI, 80.8% to 89.0%) for Lung-RADS versus 93.5% (CI, 90.7% to 96.3%) for the NLST, and sensitivity after baseline was 78.6% (CI, 74.6% to 82.6%) for Lung-RADS versus 93.8% (CI, 91.4% to 96.1%) for the NLST. Lung-RADS criteria were applied retrospectively. Lung-RADS may substantially reduce the false-positive result rate; however, sensitivity is also decreased. The effect of using Lung-RADS criteria in clinical practice must be carefully studied. National Institutes of Health.


High-frequency electrical stimulation can be a complementary therapy to promote nerve regeneration in diabetic rats.
The purpose of this study was to evaluate whether 1 mA of percutaneous electrical stimulation (ES) at 0, 2, 20, or 200 Hz augments regeneration between the proximal and distal nerve stumps in streptozotocin diabetic rats. A10-mm gap was made in the diabetic rat sciatic nerve by suturing the stumps into silicone rubber tubes. Normal animals were used as the controls. Starting 1 week after transection, ES was applied between the cathode placed at the distal stump and the anode at the proximal stump every other day for 3 weeks. At 4 weeks after surgery, the normal controls and the groups receiving ES at 20, and 200 Hz had a higher success percentage of regeneration compared to the ES groups at 0 and 2 Hz. In addition, quantitative histology of the successfully regenerated nerves revealed that the groups receiving ES at a higher frequency, especially at 200 Hz, had a more mature structure with more myelinated fibers compared to those in the lower-frequency ES groups. Similarly, electrophysiology in the ES group at 200 Hz showed significantly shorter latency, larger amplitude, larger area of evoked muscle action potentials and faster conduction velocity compared to other groups. Immunohistochemical staining showed that ES at a higher frequency could significantly promote calcitonin gene-related peptide expression in lamina I-II regions in the dorsal horn and recruit a higher number of macrophages in the diabetic distal sciatic nerve. The macrophages were found that they could stimulate the secretion of nerve growth factor, platelet-derived growth factor, and transforming growth factor-β in dissected sciatic nerve segments. The ES at a higher frequency could also increase cutaneous blood flow in the ipsilateral hindpaw to the injury. These results indicated that a high-frequency ES could be necessary to heal severed diabetic peripheral nerve with a long gap to be repaired.


Effect of drugs on the pulmonary changes in experimental acute pancreatitis in the rat.
Respiratory complications of acute pancreatitis are well recognised and are closely related to a poor prognosis. Using an experimental model in the rat, a decrease in lung compliance and an increase in lung weight were produced in acute pancreatitis. The effects of dexamethasone, heparin, and aspirin on these changes were studied. The mean specific lung compliance was reduced by 16% in the pancreatitis group compared with the control group (p less than 0.05) and this change was abolished by dexamethasone (p less than 0.02), heparin (p less than 0.01), and aspirin (p less than 0.001). Percentage lung weight (as percentage of total body weight) was raised by 22% in the pancreatitis group compared with the sham operation group (p less than 0.01) and this change was abolished by heparin (p less than 0.01) and aspirin (p less than 0.05), but not affected by dexamethasone (p less than 0.5). The results indicate that 'stiff' and heavy lungs occur in experimental acute pancreatitis. The fact that these changes are abolished by heparin and improved by aspirin suggests that intrapulmonary fibrin deposition is a factor in the pathogenesis of the important respiratory complications of this condition.


Splicing regulator SRSF1-3 that controls somatic hypermutation of IgV genes interacts with topoisomerase 1 and AID.
Somatic hypermutation (SHM) of Ig genes is initiated by activation-induced cytidine deaminase (AID) and requires target gene transcription. A splice isoform of SRSF1, SRSF1-3, is necessary for AID-dependent SHM of IgV genes. Nevertheless, its exact molecular mechanism of action in SHM remains unknown. Our in silico studies show that, unlike SRSF1, SRSF1-3 lacks a strong nuclear localization domain. We show that the absence of RS domain in SRSF1-3 affects its nuclear localization, as compared to SRSF1. Consequently, SRSF1-3 is predominantly present in the cytoplasm. Remarkably, co-immunoprecipitation studies showed that SRSF1-3 interacts with Topoisomerase 1 (TOP1), a crucial regulator of SHM that assists in generating ssDNA for AID activity. Moreover, the immunofluorescence studies confirmed that SRSF1-3 and TOP1 are co-localized in the nucleus. Furthermore, Proximity Ligation Assay corroborated the direct interaction between SRSF1-3 and TOP1. An interaction between SRSF1-3 and TOP1 suggests that SRSF1-3 likely influences the TOP1 activity and consequently can aid in SHM. Accordingly, SRSF1-3 probably acts as a link between TOP1 and SHM, by spatially regulating TOP1 activity at the Ig locus. We also confirmed the interaction between SRSF1-3 and AID in chicken B-cells. Thus, SRSF1-3 shows dual-regulation of SHM, via interacting with AID as well as TOP1.


Impacts of onsite greywater reuse on wastewater systems.
Together with significant water savings that onsite greywater reuse (GWR) may provide, it may also affect the performance of urban sewer systems and wastewater treatment plants (WWTPs). In order to examine these effects, an integrated stochastic simulation system for GWR in urban areas was developed. The model includes stochastic generators of domestic wastewater streams and gross solids (GSs), a sewer network model which includes hydrodynamic simulation and a GS transport module, and a dynamic process model of the WWTP. The developed model was applied to a case study site in Israel. For the validation of the sewer simulator, field experiments in a real sewer segment were conducted. The paper presents the integration and implementation of these modules and depicts the results of the effects of various GWR scenarios on GS movement in sewers and on the performance of the WWTP.


Treatment Deintensification Is Uncommon in Adults With Type 2 Diabetes Mellitus: A Retrospective Cohort Study.
Whether treatment deintensification in Americans with diabetes mellitus varies by glycemic control, health status, and calendar year (before/after February 2008 when safety concerns about intensive glucose control were reported in the ACCORD trial [Action to Control Cardiovascular Risk in Diabetes]) is unclear. We defined deintensification as discontinuation or dosage decrease of at least 1 glycemic medication without addition of, or uptitration of, another agent in the 120 days after the index glycosylated hemoglobin (HbA1C) measurement. Of 99 694 individuals (mean age 54 years) in this retrospective cohort study being actively treated for new diabetes mellitus (50% 1 drug, 33% 2 drugs, and 17% ≥3 drugs), 12 921 (13.0%) had HbA1C <6% after 1 year, 19 670 (19.7%) had HbA1C 6.0% to 6.4%, 35 012 (35.1%) had HbA1C 6.5% to 7.5%, and 32 091 (32.2%) had HbA1C >7.5%. Glycemic therapy was deintensified in 18.3% of patients (21.2% of frail patients, 19.4% of those with multiple comorbidities, and 17.7% of otherwise healthy patients) with no gradient across glycemia levels (20.6% of those with HbA1C<6%, 17.3% of those with HbA1C 6.0%-6.4%, 17.7% of those with HbA1C 6.5%-7.5%, and 18.6% of those with HbA1C>7.5%). Similar proportions were seen even after exclusion of 26 985 patients being treated with metformin monotherapy: 23.3%, 20.4%, 20.3%, and 20% across the HbA1C strata. Therapy was deintensified in 22.5% of patients with index HbA1C <6.0% before February 2008 compared with 19.5% after (P<0.001). Among frail patients or those with multiple comorbidities, over three quarters with low HbA1C did not have their glycemic therapy deintensified, even after safety concerns were raised in the ACCORD trial.


Advancements in engineered mesenchymal stem cell exosomes for chronic lung disease treatment.
Chronic lung diseases include an array of conditions that impact airways and lung structures, leading to considerable societal burdens. Mesenchymal stem cells (MSCs) and their exosomes (MSC-exos) can be used for cell therapy and exhibit a diverse spectrum of anti-inflammatory, antifibrotic, and immunomodulatory properties. Engineered MSC-exos possesses enhanced capabilities for targeted drug delivery, resulting in more potent targeting effects. Through various engineering modifications, these exosomes can exert many biological effects, resulting in specific therapeutic outcomes for many diseases. Moreover, engineered stem cell exosomes may exhibit an increased capacity to traverse physiological barriers and infiltrate protected lesions, thereby exerting their therapeutic effects. These characteristics render them a promising therapeutic agent for chronic pulmonary diseases. This article discusses and reviews the strategies and mechanisms of engineered MSC-exos in the treatment of chronic respiratory diseases based on many studies to provide new solutions for these diseases.


Comparison of efficacy and toxicity between nedaplatin and cisplatin in treating malignant pleural effusion.
To evaluate the efficacy and safety of nedaplatin versus cisplatin in treating malignant pleural effusion (MPE) caused by cancers. The clinical data of 219 MPE patients treated from January 2013 to December 2016 were retrospectively reviewed. Intrapleural infusion with nedaplatin 80 mg/m2 (n=110) or with cisplatin 40 mg/m2 (n=109) were used as the treatment. There was no significant difference in the overall response rate between the nedaplatin group (62.73%) and the cisplatin group (54.13%) (P=0.154). The nedaplatin group had significantly lower rates of gastrointestinal side effects and significantly less incidence of increased serum creatinine levels in comparison with the cisplatin group. The overall rate of toxicity in the nedaplatin group (40.00%) was significantly lower than in the cisplatin group (78.90%) (P⩽0.001). The efficacy of pleural perfusion with nedaplatin is noninferior to cisplatin in treating malignancy-induced MPE. Nedaplatin is associated with less toxicity in comparison with cisplatin.


EXPRESSION OF CHEMOKINE (C-C MOTIF) RECEPTOR 7 IN PROSTATE CANCER TISSUE OF YOUNG PATIENTS AND IN METASTATIC CANCER CELLS.
Chemokine (C-C motif) receptor 7 (CCR7) is a chemokine receptor involved in the carcinogenesis of several types of tumors due to its promoting action in epithelial-mesenchymal transition events, invasion, angiogenesis and metastasis. However, its role in prostate cancer (PCa) remains unclear. To evaluate CCR7 expression by immunohistochemistry in prostate tumors from young patients and to determine the possible relationship with the clinicopathological characteristics. We analyzed retrospectively paraffin-embedded tissue sections from 23 young PCa (≤ 55 years old) patients and evaluated the transcriptomic expression in the TCGA database. Expression of CCR7 was observed in 15 cases (65%). The tissue samples from younger patients (≤ 50 years) were mostly positive in 72.7% (8/11) of cases. High grade GS (≥ 3) tumors were CCR7-positive in 71% cases. The malignant cells present in lymph nodes were CCR7 positive in 100% cases. The bioinformatic analysis showed a high CCR7 expression associated with the presence of metastasis (FC = 2.6, p = 0.03) in the Cancer Genome Atlas (TCGA) PCa cohort (PRAD). We showed that CCR7 expression in tumors from young patients is associated with the early onset of the disease and could also be related to lymph node metastasis.


Neuropilin 1: function and therapeutic potential in cancer.
Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.


A serum-free culture model for studying the differentiation of human dendritic cells from adult CD34+ progenitor cells.
The antigen-presenting capacity of dendritic cells (DCs) makes them attractive potential cellular adjuvants for vaccination strategies. Currently, most in vitro culture systems for the production of these DCs include serum. However, this is undesirable because serum contains growth factors that vary between individuals and could affect DC development. Unless the patient's own serum is used, foreign antigens and the risk of infection will detract from the usefulness of these cells in clinical strategies. In this study we investigated the production of DCs from CD34+ progenitor cells of cancer patients or normal donors under serum-free conditions. We have established a model system for the investigation of DC development and maturation. Dendritic cells that developed from myeloid precursors accumulated after 2 weeks in an intermediate CD1a , CD80-, CD83-, CD86- stage. Intermediate DCs adhered to plastic surfaces, expressed Birbeck granules, and were negative for CD2 and CD14. In the presence of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha, interleukin-4 promoted the development of these stages. Spontaneous maturation of intermediate DCs into fully activated DCs expressing CD83 and costimulatory molecules occurred asynchronously over the ensuing 2 to 3 weeks. This maturation involved increased expression of CD80, CD83, CD86, CMRF-44, HLA-A, -B, -C, and -DR as well as downregulation of CD1a and CD11b. Activated DCs are characterized by the lack of adherence to plastic surfaces and the absence of Birbeck granules. By day 28, these cells were nonphagocytic, potent antigen-presenting cells with an irreversible phenotype. This serum-free system offers advantages in that the process of differentiation and maturation of committed DCs is extended over a period of more than 28 days, allowing investigators to study the effects of individual cytokines or other supplements during distinct phases of DC development in a defined environment.


Prophylaxis of venous thromboembolism in medical patients.
Venous thromboembolism is a multifactorial silent disease and tends not to be suspected by physicians, especially in medical patients. Pulmonary embolism is the most preventable cause of death among hospitalized patients. It is of major importance to assess the risk for venous thromboembolism and to adapt the prophylactic strategy with the aim of improving the risk-benefit ratio of the prophylaxis. Prophylaxis of venous thromboembolism can be done by either mechanical means or pharmacologic agents or both. The Medenox trial, the Prime study, the Prince study, the Prevent study, and the Artemis trial demonstrated that acutely ill medical patients are at increased risk of venous thromboembolism and that low molecular weight heparins (enoxaparin 40 mg or dalteparin 5000 IU subcutaneously once daily for 10 days) as well as fondaparinux 2,5 mg subcutaneously once daily for 10 days have a favorable risk-benefit ratio in the prevention of venous thromboembolism in acutely ill medical patients. The publication of the results of the Exclaim study is expected to clarify the optimal duration of prophylaxis in this group of patients. Patients hospitalized in medical intensive care units as well as patients with active cancer or central venous catheters are at increased risk of venous thromboembolism, and the studies published so far demonstrate the favorable risk-benefit ratio of thromboprophylaxis with either low molecular weight heparins or low-dose warfarin. Acutely ill medical patients are at increased risk of venous thromboembolism. Prophylaxis with low molecular weight heparins and fondaparinux is effective and safe. Initiatives to improve venous thromboembolism prophylaxis should be based on the education of physicians regarding the individualized risk assessment.


Bibliometric Analysis to Global Research Status Quo on Photobiomodulation.
Background: Photobiomodulation (PBM) becomes a remedial technology with growing popularity. The primary goal of this article is to conduct a PBM literature review, providing an overall systematic understanding of current and future trends. Methods: A dataset was made with topic retrieval, concerning PBM research retrieved from the Web of Science Core Collection. We analyzed to forecast research frontiers in this field using the softwares: VOSviewer, CiteSpace, and Biblioshiny. Results: Four thousand five hundred thirty pieces of literature were retrieved from our database. Current trends were characterized by keywords of "light," "spinal cord injury," "skeletal muscle," and so on. Future trends were characterized probably by six cutting-edge terms: "wound healing," "pain," "oral mucositis," "Alzheimer's disease," "Parkinson's disease," and "orthodontics." Conclusions: This study finds that the inadequacy of in-depth reliable interpretation of current clinical data calls for molecular biological mechanisms together with well-designed, large-sample, multicenter clinical trials. The study of oral, wound, and neural-related mechanisms and the exploration of therapeutic effects may be the popular trend at present and in the next few years.


Temperamental exuberance and executive function predict propensity for risk taking in childhood.
The present study utilized a multilevel approach to examine developmental trajectories in risk-taking propensity. We examined the moderating role of specific executive function components, attention shifting and inhibitory control, on the link between exuberant temperament in infancy and propensity for risk taking in childhood. Risk taking was assessed using a task previously associated with sensation seeking and antisocial behaviors. Two hundred ninety-one infants were brought into the lab and behaviors reflecting exuberance were observed at 4, 9, 24, and 36 months of age. Executive function was assessed at 48 months of age. Risk-taking propensity was measured when children were 60 months of age. The results indicated that exuberance and attention shifting, but not inhibitory control, significantly interacted to predict propensity for risk taking. Exuberance was positively associated with risk-taking propensity among children who were relatively low in attention shifting but unrelated for children high in attention shifting. These findings illustrated the multifinality of developmental outcomes for temperamentally exuberant young children and pointed to the distinct regulatory influences of different executive functions for children of differing temperaments. Attention shifting likely affords a child the ability to consider both positive and negative consequences and moderates the relation between early exuberance and risk-taking propensity.


(99m)Tc and (111)In-labeling of small biomolecules: bifunctional chelators and related coordination chemistry.
Radiolabeled small biomolecules provide a unique tool for target-specific delivery of radionuclides to the diseased tissues and have emerged as promising candidates in molecular imaging and radiotherapy of cancers. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a "carrier" for specific delivery of the radionuclide. PKM linkers are used to modify the radiotracer's pharmacokinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on biological properties of the target-specific radiopharmaceutical, its in vivo pharmacokinetics can be altered by modifying the coordination environment with various chelators or coligand. Among various SPECT radionuclides, (99m)Tc remains to be the most prominent radionuclide for the development of diagnostic radiopharmaceuticals because of its ideal nuclear properties and easy availability at low cost. (111)In is also widely used in gamma scintigraphy (only second to (99m)Tc). In addition, (111)In-labeld radiotracers are often used as the imaging surrogates for biodistribution and dosimetry determination of their corresponding (90)Y analogs due to their similar coordination chemistry. This chapter will focus on the on the use of different BFCs for (99m)Tc and (111)In-labeling of small biomolecules and the related coordination chemistry.


A study of the environmental survival of Mycobacterium bovis on a farm in New Zealand.
Mycobacterium bovis organisms absorbed on cotton ribbons were placed in different natural habitats on a farm in New Zealand. Mycobacterium bovis was not re-isolated from ribbons placed on pasture after 4 days. Survival on ribbons was longest in brushtail possum dens, where the maximum period of survival in dens was less than 7 days in summer and greater than 14 days but less than 28 days in winter and spring. The maximum period of survival on a forest floor was intermediate between pasture and dens less than 4 days in summer and greater than 14 days but less than 28 days in winter. The overall probability of survival was influenced by season and was shortest in summer and longest in spring and winter. Survival time increased as minimum daily temperatures decreased. These studies showed there was a relatively short period of survival of M. bovis outside hosts and support a conclusion that environmental contamination of pasture, particularly in summer months, may be relatively unimportant in the epidemiology of tuberculosis in cattle, deer and possums.


Locomotion induces changes in Trk B receptors in small diameter cells of the spinal cord.
Locomotor training leads to improvement of stepping ability in animals after spinal cord transection (1). Recent data point to neurotrophins as possible factors involved in this improvement. Motoneurones synthesising BDNF, NT-4 and NT-3 are a potent source of neurotrophins for the spinal network (2, 3). Physical exercise increases BDNF neurotrophin gene expression in the rat hippocampus (4). If exercise enhances BDNF expression also in the spinal cord, upregulation of its receptor Trk B may occur. To verify this hypothesis we tested whether exercise influences TrkB receptor system in the spinal cord. Six adult, male Wistar rats walked on the treadmill five days a week, 1,000 m daily with the speed of 20 to 25 cm/s. After 4 weeks of training animals were anaesthetised with pentobarbital sodium (80 mg/kg b.w.) and perfused with 0.01 M PBS followed by 2% paraformaldehyde and 0.2% parabenzoquinone in 0.1 M PB. Three non-trained animals were used as controls. Cryostat 40 microns sections were processed free-floating with TrkB polyclonal antibody (1:1,000, Santa Cruz) and ABC Vectastain detection system. Sections were examined under Nikon light microscope and analysed with Image-Pro Plus 4 software. TrkB immunoreactivity (IR) was detected in number of spinal cells at the lumbar level in non-trained animals (Fig. 1A). The strongest IR appeared in the perikarya and processes of small diameter cells rarely scattered in the grey and white matter. The average area of these cells was 50 micron 2 (+/- 10). Exercise increased by over 50% the number of TrkB immunostained small cells (Fig. 1B). An enhancement of perikaryonal immunostaining of these cells was also observed (Fig. 1B, inset). Testing the identity of Trk B IR small diameter cells did not prove their astroglial (GFAP IR) and gabaergic (GAD IR) phenotype in the grey matter. Some of TrkB IR cells in the white matter were astrocytes. Our data point to physical exercise as a potent method to make spinal cells more receptive to neurotrophic stimuli.


Management of patients with persistent or recurrent Cushing's disease after initial pituitary surgery.
Treatment options for persistent and recurrent Cushing's disease (CD) include an individualized approach for repeat surgery, medical treatment, radiation therapy (RT), and bilateral adrenalectomy (BLA). In this expert opinion perspective, the authors review the latest treatment(s) for persistent/recurrent CD. A PubMed search was undertaken (English articles through May 2020) and relevant articles discussed. Repeat pituitary surgery should be considered in most patients with proven hypercortisolism; there is potential for cure with low risk of major complications. Medical therapy is valuable either alone, while awaiting the effects of RT, or in preparation for BLA. Medical therapy includes steroidogenesis inhibitors, agents that act at the pituitary or glucocorticoid receptor level, and novel agents in development. Radiation therapy has been used successfully to treat CD, but hypopituitarism risk and delayed efficacy (improved with radiosurgery) are major drawbacks. Laparoscopic BLA is safe and effective in patients with severe, difficult-to-manage hypercortisolism, but long-term follow-up is required as corticotroph tumor progression can develop. Treatment of persistent/recurrent CD is challenging. Most patients require >1 therapy to achieve long-lasting remission. There is currently no ideal single treatment option that provides high and rapid efficacy, low adverse effects, and preserves normal pituitary-adrenal axis function.


The fibrinogen-binding MSCRAMM (clumping factor) of Staphylococcus aureus has a Ca2+-dependent inhibitory site.
The clumping factor (ClfA) is a cell surface-associated protein of Staphylococcus aureus that promotes binding of fibrinogen or fibrin to the bacterial cell. Previous studies have shown that ClfA and the platelet integrin alphaIIbbeta3 recognize the same domain at the extreme C terminus of the fibrinogen gamma-chain. alphaIIbbeta3 interaction with this domain is known to occur in close proximity to a Ca2+-binding EF-hand structure in the alpha-subunit. Analysis of the primary structure of ClfA indicated the presence of a potential Ca2+-binding EF-hand-like motif at residues 310-321 within the fibrinogen-binding domain. Deletion mutagenesis and site-directed mutagenesis of this EF-hand in recombinant truncated ClfA proteins (Clf40, residues 40-559; and Clf41, residues 221-559) resulted in a significant reduction of affinity for native fibrinogen and a fibrinogen gamma-chain peptide. Furthermore, Ca2+ (or Mn2+) could inhibit the binding of the fibrinogen gamma-chain peptide to Clf40-(40-559) and the adhesion of S. aureus cells to immobilized fibrinogen with an IC50 of 2-3 mM. In contrast, Mg2+ (or Na+) at similar concentrations had no effect on the ClfA-fibrinogen interaction. Far-UV CD analysis of Clf40-(40-559) and Clf41-(221-559) in the presence of metal ions indicated Ca2+- and Mn2+-induced differences in secondary structure. These data suggest that Ca2+ binds to an inhibitory site(s) within ClfA and induces a conformational change that is incompatible with binding to the C terminus of the gamma-chain of fibrinogen. Mutagenesis studies indicate that the Ca2+-dependent inhibitory site is located within the EF-hand motif at residues 310-321.


Implantation of cultured thymic fragments in patients with acquired immunodeficiency syndrome.
Cultured thymic fragments were implanted in one patient with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) and in eight AIDS patients with opportunistic infections (OIs, four patients), Kaposi's sarcoma (KS, two patients), or both (two patients). Thereafter, objective clinical improvement was noted in one patient with OI, and a stable symptom-free condition was observed in the ARC patient and in two other patients with OIs. However, the ARC patient and two of the three patients with OIs developed infections three to six months after implantation. A fourth case of OI and the patients with KS showed progression of the disease. Peripheral blood investigations for counts of total leukocytes, lymphocytes, and T-lymphocyte subsets as well as for lymphocyte stimulation with mitogens showed no changes interpretable as an improvement of the cellular immune deficiency status. We conclude that cultured thymic fragments have no distinct in vivo effect on the course of AIDS, except for a temporary clinical improvement or a period of stable condition in some patients with OIs.


Beyond the rhetoric of participatory research in indigenous communities: advances in Australia over the last decade.
Evidence-based approaches to health care have been difficult to achieve in Indigenous populations across the world, a situation which has contributed to the significant health disparities found in this group. One reason for the inadequacy of evidence-based health interventions is that empirical knowledge tends to be organized around professional disciplines that are grounded in Western ways of knowing. In this article we describe events that have led to more appropriate research methods in Australia, and the resulting changes in the research community. The principles that have guided Australian research policy development might not yet be fully matured, but the improvements we have experienced over the last several decades have gone a long way toward acknowledging the significant disparities that affect Indigenous people and the role of researchers in addressing this issue.


Sources of Differences in On-Orbital Total Solar Irradiance Measurements and Description of a Proposed Laboratory Intercomparison.
There is a 5 W/m(2) (about 0.35 %) difference between current on-orbit Total Solar Irradiance (TSI) measurements. On 18-20 July 2005, a workshop was held at the National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland that focused on understanding possible reasons for this difference, through an examination of the instrument designs, calibration approaches, and appropriate measurement equations. The instruments studied in that workshop included the Active Cavity Radiometer Irradiance Monitor III (ACRIM III) on the Active Cavity Radiometer Irradiance Monitor SATellite (ACRIMSAT), the Total Irradiance Monitor (TIM) on the Solar Radiation and Climate Experiment (SORCE), the Variability of solar IRradiance and Gravity Oscillations (VIRGO) on the Solar and Heliospheric Observatory (SOHO), and the Earth Radiation Budget Experiment (ERBE) on the Earth Radiation Budget Satellite (ERBS). Presentations for each instrument included descriptions of its design, its measurement equation and uncertainty budget, and the methods used to assess on-orbit degradation. The workshop also included a session on satellite- and ground-based instrument comparisons and a session on laboratory-based comparisons and the application of new laboratory comparison techniques. The workshop has led to investigations of the effects of diffraction and of aperture area measurements on the differences between instruments. In addition, a laboratory-based instrument comparison is proposed that uses optical power measurements (with lasers that underfill the apertures of the TSI instruments), irradiance measurements (with lasers that overfill the apertures of the TSI instrument), and a cryogenic electrical substitution radiometer as a standard for comparing the instruments. A summary of the workshop and an overview of the proposed research efforts are presented here.


Testing Differential Item Functioning in Small Samples.
Differential item functioning (DIF) is a pernicious statistical issue that can mask true group differences on a target latent construct. A considerable amount of research has focused on evaluating methods for testing DIF, such as using likelihood ratio tests in item response theory (IRT). Most of this research has focused on the asymptotic properties of DIF testing, in part because many latent variable methods require large samples to obtain stable parameter estimates. Much less research has evaluated these methods in small sample sizes despite the fact that many social and behavioral scientists frequently encounter small samples in practice. In this article, we examine the extent to which model complexity-the number of model parameters estimated simultaneously-affects the recovery of DIF in small samples. We compare three models that vary in complexity: logistic regression with sum scores, the 1-parameter logistic IRT model, and the 2-parameter logistic IRT model. We expected that logistic regression with sum scores and the 1-parameter logistic IRT model would more accurately estimate DIF because these models yielded more stable estimates despite being misspecified. Indeed, a simulation study and empirical example of adolescent substance use show that, even when data are generated from / assumed to be a 2-parameter logistic IRT, using parsimonious models in small samples leads to more powerful tests of DIF while adequately controlling for Type I error. We also provide evidence for minimum sample sizes needed to detect DIF, and we evaluate whether applying corrections for multiple testing is advisable. Finally, we provide recommendations for applied researchers who conduct DIF analyses in small samples.


Transformation of the matrix structure of shrimp shells during bacterial deproteination and demineralization.
After cellulose and starch, chitin is the third-most abundant biopolymer on earth. Chitin or its deacetylated derivative chitosan is a valuable product with a number of applications. It is one of the main components of shrimp shells, a waste product of the fish industry. To obtain chitin from Penaeus monodon, wet and dried shrimp shells were deproteinated with two specifically enriched proteolytic cultures M1 and M2 and decalcified by in-situ lactic acid forming microorganisms. The viscosity of biologically processed chitin was compared with chemically processed chitin. The former was further investigated for purity, structure and elemental composition by several microscopic techniques and (13)C solid state NMR spectroscopy. About 95% of the protein of wet shrimp shells was removed by proteolytic enrichment culture M2 in 68 h. Subsequent decalcification by lactic acid bacteria (LAB) took 48 h. Deproteination of the same amount of dried shrimps that contained a 3 × higher solid content by the same culture was a little bit faster and was finished after 140 h. The viscosity of chitin was in the order of chemically processed chitin > bioprocessed chitin > commercially available chitin. Results revealed changes in fine structure and chemical composition of the epi-, exo- and endocuticle of chitin from shrimp shells during microbial deproteination and demineralization. From transmission electron microscopy (TEM) overlays and electron energy loss spectroscopy (EELS) analysis, it was found that most protein was present in the exocuticle, whereas most chitin was present in the endocuticle. The calcium content was higher in the endocuticle than in the exocuticle.13C solid state NMR spectra of different chitin confirmed < 3% impurities in the final product. Bioprocessing of shrimp shell waste resulted in a chitin with high purity. Its viscosity was higher than that of commercially available chitin but lower than that of chemically prepared chitin in our lab. Nevertheless, the biologically processed chitin is a promising alternative for less viscous commercially available chitin. Highly viscous chitin could be generated by our chemical method. Comprehensive structural analyses revealed the distribution of the protein and Ca matrix within the shrimp shell cuticle which might be helpful in developing shrimp waste processing techniques.


Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.
Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.


Nociceptin receptor impairs recognition memory via interaction with NMDA receptor-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in the hippocampus.
Strong evidence suggests a role for nociceptin/orphanin FQ (N/OFQ) neuropeptide and its receptor (NOP) in cognition. However, the signaling mechanisms underlying N/OFQ modulation of memory are less understood. Here, we show that intracerebroventricular or intrahippocampal infusions of N/OFQ impair long-term memory formation in the mouse object recognition task. The synthetic NOP receptor agonist, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (Ro64-6198), administered systemically, also produced amnesic effects that were blocked by coinfusion of the NOP receptor antagonist, [Nphe1,Arg14,Lys15]nociceptin-NH2 (UFP-101), into the dorsal hippocampus. In contrast, Ro64-6198 had no effect on short-term memory or recall performances. Immunoblotting analysis revealed a strong suppressive action of Ro64-6198 on learning-induced upregulation of hippocampal extracellular signal-regulated kinase (ERK) phosphorylation, which is crucial for long-term information storage. Accordingly, pharmacological inhibition of ERK activation after systemic injection of SL327 [alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzene acetonitrile], a selective inhibitor of the upstream kinase MEK (mitogen-activated protein kinase kinase), abolished long-term recognition memory formation. The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801), given systemically, also suppressed ERK activation and disrupted recognition memory. In contrast, no effect of MK-801 was observed on recall, as for Ro64-6198. When administered concurrently at subthreshold doses, Ro64-6198 and MK-801 synergistically suppressed hippocampal ERK activation and impaired long-term memory formation. Under resting conditions, neither Ro64-6198 nor MK-801 affected spontaneous ERK activity in the hippocampus at the amnesic doses whereas at higher doses, only MK-801 had a suppressive effect. We conclude that N/OFQ-NOP receptor system negatively regulates long-term recognition memory formation through hippocampal ERK signaling mechanisms. This modulation may in part take place by inhibiting glutamatergic function at the NMDA receptor.


Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.
The strategy of initiating hypertension treatment with combination versus single-drug therapy was formally tested in a prospective, double-blind, parallel-group trial in blacks with stage 2 hypertension (mean sitting systolic BP (MSSBP) >or=160 and <200 mm Hg). Participants were randomized equally to amlodipine/valsartan (A/V) (n=286) or amlodipine (A) monotherapy (n=286). After 2 weeks, there was forced titration of A/V 5/160 mg to A/V 10/160 mg and of A 5 to A 10 mg followed by 10 additional weeks of treatment. If SBP was >or=130 mm Hg at week 4, the protocol allowed optional titration of A/V to the 10/320 mg dose and, at week 8, hydrochlorothiazide 12.5 mg was optionally added to both A/V and A if SBP >or=130 mm Hg. Amlodipine/valsartan at week 8 lowered MSSBP last observation carried forward significantly>A (33.3 vs 26.6 mm Hg, P<0.0001). Lowering of MSSBP with A/V significantly exceeded that of A in several specified subgroups-the elderly (>or=65 years), isolated systolic hypertension, and those with body mass index (BMI) >or=30 kg/m(2). More patients treated with A/V than A achieved BP control (<140/90 mm Hg) both at weeks 8 (49.8 vs 30.2%; P<0.0001) and 12 (57.2 vs 35.9%; P<0.0001). Both treatment regimens were well tolerated. In conclusion, the strategy of initiating combination antihypertensive drug therapy in blacks with stage 2 hypertension with amlodipine /valsartan achieves greater and quicker reductions in BP as well as significantly higher BP control rates than starting treatment with amlodipine monotherapy.


Two candidate downstream target genes for E2A-HLF.
The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) chromosomal translocation, is thought to drive the leukemic transformation of early B-cell precursors by repressing an evolutionarily conserved apoptotic pathway. To test this hypothesis, we sought to identify downstream targets of E2A-HLF in t(17;19)+ pro-B leukemia cells (UOC-B1) that had been transfected with a zinc-inducible vector encoding a dominant-negative suppressor (E2A-HLF[dn]) of the oncoprotein. Representational difference analysis of mRNAs from E2A-HLF(dn)+ UOC-B1 cells grown with (E2A-HLF inactive) or without (E2A-HLF active) the addition of zinc yielded several differentially expressed cDNA fragments that were individually subcloned. Two of the clones, designated F-5 and G-4, hybridized with mRNAs that were upregulated by E2A-HLF. Levels of both transcripts declined sharply within 8 to 12 hours after suppression of E2A-HLF DNA-binding activity, becoming undetectable after 96 hours. The F-5 cDNA was identified as a portion of ANNEXIN VIII, whose product was expressed in promyelocytic leukemia cells and UOC-B1 cells, but not in other leukemic cell lines. A novel full-length cDNA cloned with the G-4 fragment encoded a protein that we have named SRPUL (sushi-repeat protein upregulated in leukemia). It is normally expressed in heart, ovary, and placenta, but could not be detected in leukemic cell lines other than UOC-B1. Neither protein prevented apoptosis in interleukin-3-dependent murine pro-B cells, suggesting that they have paraneoplastic roles in leukemias that express E2A-HLF, perhaps in the disseminated intravascular coagulopathy and hypercalcemia that characterize these cases.


The biosynthesis of C 55 polyprenols by a cell-free preparation of Lactobacillus plantarum.
A cell-free supernatant of lysates of Lactobacillus plantarum catalyses the synthesis of lipids from [2-(14)C]mevalonate. Of the added mevalonate, 7.5% is incorporated into lipids, which were fractionated into five components. About 4% of the radioactivity in these lipids co-chromatographs with compounds shown by mass spectrometry, n.m.r. and i.r. spectroscopy to be C(55) polyprenols, and about 2% co-chromatographs with a hexamer. The rest of the radioactivity is in more complex fractions. Analysis by mass spectrometry, n.m.r. and i.r. spectroscopy shows that the major C(55) polyprenol is undecaprenol, accompanied by an isomer containing one reduced isoprene unit. A Kuhn-Roth degradation of [(14)C]polyprenols indicates that the supernatant catalyses synthesis of these compounds de novo.


Spontaneous intracranial hypotension due to thoracic disc herniation. Case report.
Spontaneous intracranial hypotension is frequently idiopathic. The authors report on a patient presenting with symptomatic intracranial hypotension caused by a transdural calcified thoracic disc herniation. Cranial magnetic resonance (MR) imaging revealed classic signs of intracranial hypotension, and a combination of spinal MR and computerized tomography myelography confirmed a mid-thoracic transdural calcified herniated disc as the cause. The patient was treated with an epidural blood patch and burr hole drainage of the subdural effusion on two occasions. Postoperatively the headache resolved and there was no neurological deficit. Thoracic disc herniation may be a cause of spontaneous intracranial hypotension.


Arsenic-trioxide-induced apoptosis of chronic lymphocytic leukemia cells.
Chronic lymphocytic leukemia (CLL) cells are characterized by defective apoptosis which leads to their extended survival. Arsenic trioxide (As(2)O(3)) was reported to induce cell death in many malignant cells, but the specific pathway of As(2)O(3)-induced apoptosis/necrosis remains controversial. Our aim was to determine if As(2)O(3) kills CLL cells through apoptosis and whether this is accompanied by reduction in Bcl-2 levels. Cells from nine patients with CLL were incubated with increasing concentrations of As(2)O(3) (0.5-2 microM) for 2, 7, or 14 days. Cells viability was measured using Alamar Blue assay and apoptosis using human Annexin V-FITC and propidium iodine (PI) kit (BMS306FI; Bender MedSystems, Vienna, Austria). Intracellular Bcl-2, Bax, and caspase-3 levels were measured by flow cytometry. As(2)O(3) significantly reduced CLL cell viability (P < 0.01) and induced apoptotic cell death in a time- and dose-dependent manner. After 7 days, CLL cells showed a significant decrease in mean fluorescence intensity (MFI) of Bcl-2 on flow cytometry study. Bax and caspase-3 levels showed significant decrease in MFI only after prolonged incubations (7 and 14 days) and mostly at higher concentrations of As(2)O(3). The mechanism underlying the reduction in viability of CLL cells incubated with As(2)O(3) is mediated by induction of apoptosis maybe through the down-regulation of Bcl-2. Further studies are needed to elucidate the potential therapeutic role of As(2)O(3) in CLL.


A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun.
We have used phospho-specific antibodies to re-examine the multisite phosphorylation of c-Jun in murine RAW macrophages and embryonic fibroblasts. Our results indicate that JNK isoforms are required and sufficient for the phosphorylation of Thr91 and Thr93, as well as the phosphorylation of Ser63 and Ser73, in response to LPS or anisomycin in macrophages and TNFalpha or anisomycin in fibroblasts. However, the phorbol ester (TPA) and EGF-induced phosphorylation of Ser63 and Ser73 is mediated by ERK1/ERK2, as well as JNK1/JNK2, in fibroblasts from wild-type mice and by ERK1/ERK2 alone in fibroblasts from JNK-deficient mice. The phosphorylation of Thr239 is catalysed by GSK3 and the phosphorylation of Ser243 by an as yet unidentified protein kinase. The inhibition of GSK3 is not required for the dephosphorylation of Thr239 in response to LPS, and nor is the phosphorylation of Thr91 and Thr93 required for the TPA- or EGF-induced dephosphorylation of Thr239 in fibroblasts. The agonist-induced dephosphorylation of Thr239 may involve a conformational change that exposes Thr239 to dephosphorylation and/or the activation of a Thr239 phosphatase.


Magnetic modeling of actively shielded rotating MRI magnets in the presence of environmental steel.
Rotating MRI systems could enable novel integrated medical devices such as MRI-Linacs, MRI-xray-angiography systems, and MRI-proton therapy systems. This work aimed to investigate the feasibility of rotating actively shielded superconducting MRI magnets in the presence of environmental steel-in particular, construction steel in the floor of the installation site. Two magnets were investigated: a 1.0 T split bore magnet, and a 1.5 T closed bore magnet. Each magnet was scaled to emulate field strengths of 0.5, 1.0, and 1.5 T. Finite Element Modeling was used to simulate these magnets in the presence of a 3 × 4 m steel plate located 1250 mm or 1400 mm below the isocenter. There are two possible rotation directions: around the longitudinal (z) axis or around the transverse (x) axis. Each model was solved for rotation angles between 0 and 360° in 30° intervals around each of these axes. For each simulation, a 300 mm DSV was extracted and decomposed into spherical harmonics. For the closed-bore magnet, total induced perturbation for the zero degree rotation angle was 223, 432, and 562 μT peak-to-peak (pk-pk) for the 0.5, 1.0, and 1.5 T models respectively (steel at 1250 mm). For the split-bore magnet, the same numbers were 1477, 16747, and 1766 μT. The substantially higher perturbation for the split-bore magnet can be traced to its larger fringe field. For rotation around the z-axis, total perturbation does not change as a function of angle but is exchanged between different harmonics. For rotation around the x-axis, total perturbation is different at each rotation angle. For the closed bore magnet, maximum perturbations occurred for a 90° rotation around the transverse axis. For the split-bore magnet, the opposite was observed, with the same 90° rotation yielding total perturbation lower than the conventional position. In all cases, at least 95% of the total perturbation was composed of 1st and 2nd order harmonics. The presence of environmental steel poses a major challenge to the realization of an actively shielded rotating superconducting MRI system, requiring some novel form of shimming. Possible shimming strategies are discussed at length.


The clinical efficacy of azathioprine as maintenance treatment for autoimmune pancreatitis: a systematic review and meta-analysis.
The effectiveness of azathioprine (AZA) in preventing relapse and maintaining autoimmune pancreatitis (AIP) remission has been reported; however, most of these studies are case series with no randomized control trials available in the literature. Therefore, this study performed a systematic review and meta-analysis of the existing literature on this subject to determine the clinical efficacy of AZA as maintenance therapy for AIP patients. A systematic search was performed to identify studies on the clinical efficacy of AZA as maintenance therapy in AIP patients. The crude multiple relapse rate was estimated to assess the ability of AZA to control relapses in AIP. Pooled estimates were obtained using a random-effects model with the DerSimonian-Laird method. We identified AIP patients who did not respond to initial steroid treatment, experienced steroid weaning failure, or those who relapsed during remission as refractory cases. After reviewing the studies, ten articles fulfilled the inclusion criteria and were selected for meta-analysis. Of all 4504 patients, 3534 patients were treated with steroids, and 346 patients were treated with AZA for relapsed AIP. In this meta-analysis, 14/73 (19.2%) patients receiving AZA for refractory AIP relapsed. Meanwhile, 14/47 (29.8%) patients without AZA experienced relapse. The integrated odds ratio for relapse risk in patients receiving AZA was estimated to be 0.52 (p = 0.15). This systematic review and meta-analysis demonstrated the efficacy of AZA in preventing relapse of AIP, which supports the use of AZA as a maintenance treatment in patients with AIP who relapse upon withdrawal of steroid therapy.


The renin angiotensin system and hymenoptera venom anaphylaxis.
Components of the renin angiotensin system, namely renin, angiotensinogen, angiotensin I and II and aldosterone were measured in plasma of patients with hymenoptera venom anaphylaxis (n = 50) and healthy non-allergic controls (n = 25). Patients with a history of anaphylactic reactions to hymenoptera venom who did not undergo immunotherapy showed significantly reduced renin, angiotensinogen, angiotensin I and angiotensin II in plasma as compared with controls (P < 0.05). There was no difference in the aldosterone concentration between patients and controls. Angiotensin I, angiotensin II, renin and angiotensinogen levels were the same in male and female patients. There was also no difference in the angiotensin I, II, renin or angiotensinogen levels between young and older patients. A significant inverse correlation between the severity of clinical symptoms and the plasma levels of renin (r = -0.382, P < 0.001), angiotensinogen (r = -0.567, P < 0.0001), angiotensin I (r = -0.656, P < 0.0001) and angiotensin II (r = 0.0762, P < 0.0001) was found: the lower the levels the more severe the clinical symptoms. No correlation was found for aldosterone. Hymenoptera venom allergic patients with repeated anaphylactic reactions during hyposensitization did not tolerate the sting of a living insect (n = 6). In these patients, renin, angiotensinogen, angiotensin I and II remained significantly lower than in healthy non-allergic controls. Patients with successful immunotherapy (n = 27) who tolerated the sting of a living insect had renin, angiotensin I and II significantly higher than patients without immunotherapy. These findings suggest a possible role of the renin angiotensin system in hymenoptera venom anaphylaxis.


Effects of invariant sympathetic activity on cutaneous circulatory responses to heat stress.
This study investigated the role of sympathetic withdrawal on blood flow responses in cutaneous arteriovenous anastomoses (AVAs) and capillaries to direct and indirect heat stress. This was achieved by clamping sympathetic activity (SC) to the tail of anesthetized rats so that constrictor tone remained invariant during exposure of either the animal's tail (direct heating) or body (indirect heating) to a 35 degrees C environment. Flow through the AVAs in the tail was evaluated by laser-Doppler flowmetry (LDF), while capillary flow was investigated by videodensitometry measurements of blood cell velocity (CBV) in single capillaries within the subepidermal vascular plexus. Both direct and indirect heating significantly increased LDF and CBV. In comparison to blood flow responses in sham-operated control rats, the SC procedure resulted in significantly lower LDF responses to both direct and indirect heat stress. By contrast, the response of CBV was not significantly affected by SC during either mode of heating. These results indicate that the withdrawal of sympathetic constrictor tone plays a role in the response of cutaneous AVAs, but not precapillary arterioles, to direct as well as indirect heat stress. Additional studies on unanesthetized animals showed that superimposing body heating on a base of local heating elicited a further increase in LDF, suggesting that local heating does not deplete neural mediated dilatory reserve.


Proliferative effect of cannabidiol in human gingival fibroblasts via the mitogen-activated extracellular signal-regulated kinase (MEK) 1/2.
Cannabidiol exerts its anti-inflammatory and anti-oxidant activities in various human cells. However, its proliferative effect has not been extrapolated to human gingival fibroblasts (HGFs). This study aimed to determine the proliferative and promigratory effects of cannabidiol in HGFs and to elucidate the signaling mechanism(s). HGFs, characterized by their CD73, CD90, and CD105 expressions by flow cytometry, were treated with cannabidiol at 0.01-30 μM. The cytotoxicity was determined by the MTT assay, while the proliferative effect was examined by the BrdU assay, immunoblot and immunofluorescence for cyclin D1 and Ki-67 expressions, respectively, and cell cycle analysis. The promigratory effect of cannabidiol was investigated by a wound healing assay. Phosphorylation of the p38 MAPK, JNK, and ERK upon treatment with cannabidiol was explored, and their involvement in cell proliferation and cyclin D1 and Ki-67 expressions was studied using pharmacological inhibitors. No toxicity was found in HGFs treated with any doses of cannabidiol up to 30 μM. The mean percentage of cell proliferation was significantly enhanced by treatment with cannabidiol at 3 or 10 μM (p < .001), consistent with upregulated expressions of cyclin D1 and Ki-67 and increased percentages of HGFs in the S and G2/M phases. Moreover, treatment with cannabidiol significantly induced cell migration (p < .05). The p38 MAPK and ERK1/2 were significantly activated by cannabidiol (p < .05), but only pretreatment with UO126, a MEK1/2 inhibitor, significantly inhibited cell proliferation and cyclin D1 and Ki-67 expressions (p < .05). Treatment with cannabidiol at non-toxic doses promotes HGFs' proliferation and migration.


Compliance of camps in the United States with guidelines for health and safety practices.
To determine the compliance of US camps with guidelines for health and safety practices as set forth by the American Academy of Pediatrics and the US Department of Homeland Security. An electronic questionnaire was distributed to US camps during the summer of 2012 as identified by 3 online summer camp directories. Analysis was performed on 433 completed questionnaires. Fourteen percent of camps were considered medically related. Ninety-three percent of camps have established relationships with community emergency medical services, 34% with local orthodontists, and 37% with local mental health professionals. Camps reported the immediate availability of the following: automated external defibrillators (75%), respiratory rescue inhalers (44%), epinephrine autoinjectors (64%), cervical spine collars (62%), and backboard with restraints (76%). Camps reported the presence of the following written health policies: dehydration (91%), asthma and anaphylaxis (88%), head injuries (90%), seizures (78%), cardiac arrest (76%), and drowning (73%). Although 93% of camps have a disaster response plan, 15% never practice the plan. Sixty-eight percent of camps are familiar with community evacuation plans, and 67% have access to vehicles for transport. Camps reported the presence of the following written disaster policies: fire (96%), tornadoes (68%), arrival of suspicious individuals (84%), hostage situations (18%). Areas for improvement in the compliance of US camps with specific recommendations for health and safety practices were identified, such as medically preparing campers before their attendance, developing relationships with community health providers, increasing the immediate availability of several emergency medications and equipment, and developing policies and protocols for medical and disaster emergencies.


Blue sheep in the Annapurna Conservation Area, Nepal: habitat use, population biomass and their contribution to the carrying capacity of snow leopards.
The Himalaya region of Nepal provides a habitat for the endangered snow leopard (Panthera uncia) and its principal prey species, the blue sheep (Pseudois nayaur). The aim of this study was to describe the habitat, the distribution and the population structure of blue sheep, and to estimate their contribution to the carrying capacity of snow leopard in the upper Mustang region of Nepal. Blue sheep were recorded at altitudes from 3209-5498 m on slopes with gradients of 16-60° and aspects of 40°NE to 140°SE. A total of 939 blue sheep were counted in the upper Mustang region, and 98 were counted in the Yak Kharka region of Manang district; however, upper Mustang had the lowest population density of blue sheep recorded within their distribution range in Nepal (0.86 blue sheep/km(2)). The results of the study show that a higher density of blue sheep is associated with greater plant species diversity. The most important species present in the blue sheep habitat were Kobresia pygmaea, Artemesia spp., Lonicera spp., Lancea tibetica, Poa spp., Astragalus spp. and Ephedra gerardiana. It is estimated that the existing blue sheep population biomass of approximately 38 925 kg in the upper Mustang region could support approximately 19 snow leopards (1.6 snow leopards/100 km(2)).