Application of electroporation in DNA vaccination protocols.
Vaccination is historically one of the most important methods for preventing infectious diseases in humans and animals. Due to recent advances in understanding the biology of the immune system, a more rational design of vaccines and vaccination strategies such as those based on gene transfer have been proposed. In particular, naked DNA vaccination is emerging as a promising approach for introducing foreign antigens into the host, inducing protective immunity against infectious diseases and malignant tumours. Plasmid DNA vaccines offer several advantages in comparison to traditional vaccines such as safety, tolerability and feasibility in manufacture. Nevertheless, because of their poor immunogenicity, plasmid DNA vaccines need further implementation. Recent data suggest electroporation as useful strategy to improve DNA-based vaccination protocols, being able to stimulate both the humoural and cellular immune responses. In pre-clinical trials, electroporation is successfully used in prime-boost combination protocols and its efficacy and tolerability has been demonstrated in Phase I clinical trials. Since these initial results appear promising, in the next future we will assist to further developments of naked DNA vaccination associated to the electroporation technology. This approach not only provides the basis for human studies but also a practical application to veterinary medicine.


Dynamics and spatial organization of plant communities in water-limited systems.
A mathematical model for plant communities in water-limited systems is introduced and applied to a mixed woody-herbaceous community. Two feedbacks between biomass and water are found to be of crucial importance for understanding woody-herbaceous interactions: water uptake by plants' roots and increased water infiltration at vegetation patches. The former acts to increase interspecific competition while the latter favors facilitation. The net interspecific interaction is determined by the relative strength of the two feedbacks. The model is used to highlight new mechanisms of plant-interaction change by studying factors that tilt the balance between the two feedbacks. Factors addressed in this study include environmental stresses and patch dynamics of the woody species. The model is further used to study mechanisms of species-diversity change by taking into consideration tradeoffs in species traits and conditions giving rise to irregular patch patterns.


Electronic State-Resolved Electron-Phonon Coupling in an Organic Charge Transfer Material from Broadband Quantum Beat Spectroscopy.
The coupling of electron and lattice phonon motion plays a fundamental role in the properties of functional organic charge-transfer materials. In this Letter we extend the use of ultrafast vibrational quantum beat spectroscopy to directly elucidate electron-phonon coupling in an organic charge-transfer material. As a case study, we compare the oscillatory components of the transient reflection (TR) of a broadband probe pulse from single crystals of quinhydrone, a 1:1 cocrystal of hydroquinone and p-benzoquinone, after exciting nonresonant impulsive stimulated Raman scattering and resonant electronic transitions using ultrafast pulses. Spontaneous resonance Raman spectra confirm the assignment of these oscillations as coherent lattice phonon excitations. Fourier transforms of the vibrational quantum beats in our broadband TR measurements allow construction of spectra that we show report the ability of these phonons to directly modulate the electronic structure of quinhydrone. These results demonstrate how coherent ultrafast processes can characterize the complex interplay of charge transfer and lattice motion in materials of fundamental relevance to chemistry, materials sciences, and condensed matter physics.


Comparison of a dietary intervention promoting high intakes of fruits and vegetables with a low-fat approach: long-term effects on dietary intakes, eating behaviours and body weight in postmenopausal women.
The aim of the present study was to compare the long-term effects of two dietary approaches on changes in dietary intakes, eating behaviours and body weight: (1) approach using restrictive messages to limit high-fat foods (low-fat intake; LOFAT); (2) approach emphasising non-restrictive messages directed towards the inclusion of fruits and vegetables (high intake of fruits and vegetables; HIFV). A total of sixty-eight overweight or obese postmenopausal women were randomly assigned to one of the two dietary approaches. The 6-month dietary intervention included three group sessions and ten individual sessions with a dietitian. Dietary intakes, eating behaviours and anthropometrics were measured at baseline, at the end of the dietary intervention (T = 6) and 6 months and 12 months after the end of the intervention (T = 12 and T = 18). In the LOFAT group, energy and fat intakes were lower at T = 6 when compared with baseline and remained lower at T = 12 and T = 18. In the HIFV group, fruit and vegetable intakes increased significantly at T = 6 but were no longer significantly different from baseline at T = 12 and T = 18. Dietary restraint increased at T = 6 and remained higher than baseline at T = 18 in the LOFAT group while no significant change was observed in the HIFV group. At T = 6, body weight was significantly lower than baseline in both groups (LOFAT: - 3.7 (SD 2.8) kg; HIFV: - 1.8 (SD 3.0) kg) and no significant difference in body-weight change from baseline was found between groups at T = 18. We concluded that weight loss was similar at 1-year follow-up in both dietary approaches. Despite relatively good improvements in the short term, the adherence to a 6-month dietary intervention promoting high intakes of fruits and vegetables was difficult to maintain.


Calcium binding protein-like immunoreactivity labels the terminal field of nucleus laminaris of the barn owl.
Nucleus laminaris (NL) is the site at which the timing of sounds arriving in the 2 ears is compared in the auditory system of the barn owl. Earlier studies have reported vitamin D-dependent calcium binding protein (CaBP)-like immunoreactivity in the somata of NL. We report here that CaBP-like immunoreactivity stains the terminal field of NL. The specific CaBP immunoreactivity is localized to a dense plexus of fibers that have bouton-like swellings, usually around unstained somata. This type of immunoreactivity is found in a restricted portion of the central nucleus of the inferior colliculus (ICc), in the anterior division of the ventral lateral lemniscal complex (VLVA), and in the superior olivary nucleus (SO), all of which have been shown by anterograde transport of 3H-proline to be innervated by NL. The immunoreactivity is absent from the posterior division of ventral lateral lemniscal complex and from the region that surrounds the portion of ICc innervated by NL. A restricted lesion in NL results in a localized deficit in immunoreactivity in those regions of ICc and VLVA that are known to be innervated by the lesioned area of NL. In adjacent sections processed by the Fink-Heimer method, degenerating axons are present in the region of the deficit in immunoreactivity.


Altered Corticomuscular Coherence (CMCoh) Pattern in the Upper Limb During Finger Movements After Stroke.
Background: Proximal compensation to the distal movements is commonly observed in the affected upper extremity (UE) of patients with chronic stroke. However, the cortical origin of this compensation has not been well-understood. In this study, corticomuscular coherence (CMCoh) and electromyography (EMG) analysis were adopted to investigate the corticomuscular coordinating pattern of proximal UE compensatory activities when conducting distal UE movements in chronic stroke. Method: Fourteen chronic stroke subjects and 10 age-matched unimpaired controls conducted isometric finger extensions and flexions at 20 and 40% of maximal voluntary contractions. Electroencephalogram (EEG) data were recorded from the sensorimotor area and EMG signals were captured from extensor digitorum (ED), flexor digitorum (FD), triceps brachii (TRI), and biceps brachii (BIC) to investigate the CMCoh peak values in the Beta band. EMG parameters, i.e., the EMG activation level and co-contraction index (CI), were analyzed to evaluate the compensatory muscular patterns in the upper limb. Result: The peak CMCoh with statistical significance (P < 0.05) was found shifted from the ipsilesional side to the contralesional side in the proximal UE muscles, while to the central regions in the distal UE muscle in chronic strokes. Significant differences (P < 0.05) were observed in both peak ED and FD CMCohs during finger extensions between the two groups. The unimpaired controls exhibited significant intragroup differences between 20 and 40% levels in extensions for peak ED and FD CMCohs (P < 0.05). The stroke subjects showed significant differences in peak TRI and BIC CMCohs (P < 0.01). No significant inter- or intra-group difference was observed in peak CMCoh during finger flexions. EMG parameters showed higher EMG activation levels in TRI and BIC muscles (P < 0.05), and higher CI values in the muscle pairs involving TRI and BIC during all the extension and flexion tasks in the stroke group than those in the control group (P < 0.05). Conclusion: The post-stroke proximal muscular compensations from the elbow to the finger movements were cortically originated, with the center mainly located in the contralesional hemisphere.


Optimised neural network model for river-nitrogen prediction utilizing a new training approach.
In the past few decades, there has been a rapid growth in the concentration of nitrogenous compounds such as nitrate-nitrogen and ammonia-nitrogen in rivers, primarily due to increasing agricultural and industrial activities. These nitrogenous compounds are mainly responsible for eutrophication when present in river water, and for 'blue baby syndrome' when present in drinking water. High concentrations of these compounds in rivers may eventually lead to the closure of treatment plants. This study presents a training and a selection approach to develop an optimum artificial neural network model for predicting monthly average nitrate-N and monthly average ammonia-N. Several studies have predicted these compounds, but most of the proposed procedures do not involve testing various model architectures in order to achieve the optimum predicting model. Additionally, none of the models have been trained for hydrological conditions such as the case of Malaysia. This study presents models trained on the hydrological data from 1981 to 2017 for the Langat River in Selangor, Malaysia. The model architectures used for training are General Regression Neural Network (GRNN), Multilayer Neural Network and Radial Basis Function Neural Network (RBFNN). These models were trained for various combinations of internal parameters, input variables and model architectures. Post-training, the optimum performing model was selected based on the regression and error values and plot of predicted versus observed values. Optimum models provide promising results with a minimum overall regression value of 0.92.


Demineralized bone matrix as a biological scaffold for bone repair.
Experimental models were created in rat fibula to represent impaired bone healing so that biological deficiencies that cause bone repair to fail or to be delayed may be investigated. These models consist of a 4-mm-long segmental defect, created in rat fibula by osteotomy, and fitted with a 7-mm-long tubular specimen of demineralized bone matrix (DBM) over the cut ends of the fibula. The experiments in this study involved various modifications of the DBM scaffold designed to reduce its osteoinductive activity: steam sterilization (sDBM), ethylene oxide sterilization (eoDBM), trypsin digestion (tDBM), and guanidine hydrochloride extraction (gDBM). Bone healing was evaluated by bending rigidity of the fibula and mineral content of the repair site at 7 weeks post-surgery. The sDBM scaffolds resorbed completely by 7 weeks and hence this model was a nonhealing negative control. Rigidities in the unmodified DBM and tDBM groups were comparable, whereas in the gDBM and eoDBM groups it was significantly reduced. Histologically, in the 4-mm defects repaired with unmodified DBM, direct and endochondral bone formation in the scaffold and the defect resulted in a neocortex consisting of woven and lamellar bone uniting the broken bone by 7 weeks post-surgery. We conclude that the eoDBM and gDBM groups represent failure or delay of the bone repair process when compared with the unmodified DBM group in which the process is analogous to normal bone healing.


The social brain and reward: social information processing in the human striatum.
In the highly social life of humans, rewards that are sought and experienced are intertwined with social relationships and interactions between people. Just as we value nonsocial rewards such as food or money, we also value social outcomes (e.g., praise from a superior). We use social information to evaluate and form expectations of others and to make decisions involving others. Here we review research demonstrating how the neural circuitry of reward, particularly the striatum, is also involved in processing social information and making decisions in social situations. This research provides an understanding of the neural basis for social behavior from the perspective of how we evaluate social experiences and how our social interactions and decisions are motivated. We review research addressing the common neural systems underlying evaluation of social and nonsocial rewards. The human striatum, known to play a key role in reward processing, displays signals related to a broad spectrum of social functioning, including evaluating social rewards, making decisions influenced by social factors, learning about social others, cooperating, competing, and following social norms. WIREs Cogn Sci 2014, 5:61-73. doi: 10.1002/wcs.1266 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.


Megarectum after surgery for anorectal malformations.
Megarectum complicating surgery for anorectal malformation (ARM) has implications for long-term continence. Factors influencing continence and defecation include intact rectal reservoir, innervation/proprioception of the anorectal muscle complex, functioning anorectal inhibitory reflex (AIR), and intact perception at the anal margin. We studied outcomes after surgery for ARM with emphasis on megarectum; particularly as to whether altered rectal proprioception from anatomic sacrococcygeal anomalies affect incidence. We also assessed whether an abnormal AIR could trigger passive rectal dilatation without mechanical obstruction. Eighty six infants (53 male) with ARM over 20 years were included. Demographics, surgical history, pathology, defecation patterns, imaging, manometry, and morbidity were analyzed. Incidence of sacrococcygeal malformations in children with and without megarectum was compared using Fisher exact test. Manometry results were evaluated for integrity of AIR and correlated to megarectum occurrence. There were 23 high/intermediate and 63 low ARMs. Fourteen (16%) developed a megarectum: 6 of 23 in high and 8 of 63 in low anomalies (P = .33). Twelve patients underwent megarectum resection at a median of 2.6 years (7 months to 10 years); 2 received bowel management protocols. Fifty-seven percent (8/14) of children with and 7% (5/72) without megarectum had sacrovertebral anomalies (P = .0001). Patients with preoperative manometry (n = 5) demonstrated an intact AIR. Colonic manometry demonstrated hyperactive colons (n = 2). Constipation was the predominant preoperative symptom; 3 patients suffered from incontinence after resection. All the specimens showed normal innervation and thickened muscularis on pathology. Sacral anomalies, which are more prevalent in children who developed megarectum, may result in abnormal rectal proprioception contributing to this pathology. Innervation anomalies may coexist, although preoperative manometries showed normal AIRs. Rectal dysmotility may lead to stool retention with subsequent dilatation, and patients who underwent colonic manometry had diffuse colonic hypermotility. Further physiologic and cellular studies are needed to elucidate the causes of this significant complication after surgical ARM repair in the absence of obstruction.


[Potentially productive years of life lost among adults in Metropolitan Santiago. Is there an improvement in equality?].
Potentially productive years of life lost (PPYLL) is an impact measure that illustrates the lost that a society suffers as a consequence of deaths of young people or premature deaths. To study the evolution of PPYLL in adults in the periods 1994-1996 and 1999-2001, according to sex, income quintiles and main diagnostic groups in the communities of Metropolitan Santiago. Ecological study analyzing the population of Metropolitan Santiago, that represents 36% of the national population. A total of 87,969 deaths in people aged 20 to 79 years were analyzed. There is a greater amount of PPYLL among the poorest quintiles and men represent the higher number of PPYLL. In the different analyzed periods, all quintiles experienced a reduction in PPYLL. According to diagnosis, endocrine diseases experienced the greater decrease between periods, followed by respiratory disease. Noteworthy was the increase of PPYLL due to infectious diseases. PPYLL due to digestive diseases was 2.3 higher in the poorest quintile, as compared with the wealthiest quintile (20/20 ratio). The ratio for traumatic disease was 1.8. When comparing both periods, there is a net gain of potentially productive years of life in all income quintiles and in both genders.


Curculigoside attenuates osteoporosis through regulating DNMT1 mediated osteoblast activity.
This work aims to study the function of curculigoside in osteoporosis and explore whether DNMT1 is closely involved in osteoblast activity. After OB-6 osteoblasts were treated with hydrogen peroxide (H2O2), a curculigoside treatment group was set up and a series of biological tests including MTT, flow cytometry, western blotting, ROS fluorescence intensity, mitochondrial membrane potential, and ELISA experiments were performed to verify the effect of curculigoside on the activity of osteoblasts. Then, alkaline phosphatase (ALP) activity, alizarin red staining, PCR, and western blotting assays were performed to detect the effects of curculigoside on osteoblast function. By constructing DNMT1 knockdown and overexpression OB-6 cell lines, the effect of DNMT1 on osteoblast function was verified. In addition, the expression level of Nrf2 in each group was detected to speculate the mechanism of DNMT1 in osteoporosis. The cell activity and level of bcl-2 and SOD were significantly increased; the cell apoptosis, ROS fluorescence intensity, mitochondrial membrane potential, MDA and level of caspase-3, Bax, and CAT was reduced in curculigoside treatment group compared with H2O2-induced OB-6 osteoblasts. Meanwhile, the ALP activity, number and area of bone mineralized nodules, and gene and protein expression of OSX and OPG were significantly elevated in curculigoside group. Moreover, DNMT1 knockdown had a similar promotion effect on osteoblast function as curculigoside, and DNMT1 overexpression could reverse the promotion effect of curculigoside on osteoblast function. Further mechanistic studies speculated that DNMT1 might play a role in osteoporosis by affecting Nrf2 methylation. Curculigoside enhances osteoblast activity through DNMT1 controls of Nrf2 methylation.


Predictors of Dyslipidemia Over Time in Youth With Type 1 Diabetes: For the SEARCH for Diabetes in Youth Study.
Understanding the risk factors associated with progression and regression of dyslipidemia in youth with type 1 diabetes may guide treatments. We studied 1,478 youth with type 1 diabetes (age 10.8 ± 3.9 years, 50% male, 77% non-Hispanic white, not on lipid-lowering medications) at baseline and at a mean follow-up of 7.1 ± 1.9 years in the SEARCH for Diabetes in Youth (SEARCH) study. Progression to dyslipidemia was defined as normal lipid concentrations at baseline and abnormal at follow-up (non-HDL-cholesterol [C] >130 mg/dL or HDL-C <35 mg/dL). Regression was defined as abnormal lipids at baseline and normal at follow-up. Multivariable logistic regression was used to evaluate factors associated with progression and regression compared with stable normal and stable abnormal, respectively. An area under the curve (AUC) variable was used for the time-varying covariates A1C and waist-to-height ratio (WHtR). Non-HDL-C progressed, regressed, was stable normal, and stable abnormal in 19%, 5%, 69%, and 7% of youth with type 1 diabetes, respectively. Corresponding percentages for HDL-C were 3%, 3%, 94%, and 1%, respectively. Factors associated with non-HDL-C progression were higher A1C AUC and higher WHtR AUC in males. Non-HDL-C regression was associated with lower WHtR AUC, and HDL-C progression was associated with male sex and higher WHtR AUC. HDL-C regression was not modeled due to small numbers. A1C and WHtR are modifiable risk factors associated with change in dyslipidemia over time in youth with type 1 diabetes.


CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.
Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).


Antibody-catalyzed oxidation of delta(9)-tetrahydrocannabinol.
Marijuana abuse continues to plague society and the lack of effective treatments warrants concern. Catalytic antibodies capable of oxidatively degrading the major psychoactive component of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), are presented. The antibodies generate reactive oxygen species from singlet oxygen (1O2*), using riboflavin (vitamin B2) and visible light as the 1O2* source. Cannabitriol was identified as the major degradation product of this reaction, demonstrating the ability of an antibody to catalyze a complex chemical transformation with therapeutic implications for treating marijuana abuse.


Model for evaluating patterned charge-regulation contributions to electrostatic interactions between low-dielectric spheres.
We study the electrostatic contribution to the effective potential between two spherical low-dielectric particles that carry proton-titratable sites within a linearized setting. To evaluate the needed work of charging for each possible proton occupancy configuration, together with its crucial dependence on sphere separation, we numerically solve a coarse-grained linear Debye-Hückel model that incorporates nonuniform dielectric and ionic solution properties at a series of intersphere separations and for chosen titratable charge locations on each sphere. We combine the resulting work-of-charging matrix with site-specific chemical potentials of proton binding to construct the Boltzmann-weighted probabilities of each possible occupancy pattern of the titratable sites as functions of intersphere separation. With the use of these probabilities we find that a nonmonotonic average electrostatic potential can result that is repulsive at larger sphere separations but attractive at close separations. The nonmonotonic potential corresponds to particular choices of site-specific unoccupied charge values and their corresponding proton affinities, and its occurrence is dependent on pH in relation to the pKa values of the titratable groups. For the chosen titratable groups, we identify the particular change from repulsive to attractive proton occupancy patterns with decreasing intersphere separation that gives rise to the modeled nonmonotonic dependence and derive more general conditions under which such a nonmonotonic dependence can occur. Within the present model we find that stationary points of the charge-regulated average electrostatic potential, considered as a function of intersphere separation, occur when a normalized Boltzmann-averaged intersphere charge number product equals its covariance with an average free energy of charging divided by k(B)T. We derive more general conditions for the location and nature of critical points in the electrostatic intersphere potential, which are not dependent on the validity of the present linear model. Analysis of the present simple prototype model can be a helpful step toward developing a framework for predicting when (i) patterned charge-regulated occupancy patterns, (ii) orientation-dependent attractions due to relatively fixed heterogeneous charging patterns, and (iii) screened net protein charge could separately dominate the electrostatic portion of the interactions between model biological macromolecules and other nanoparticles.


Fluorescent azobenzene-confined coiled-coil mesofibers.
Fluorescent protein biomaterials have important applications such as bioimaging in pharmacological studies. Self-assembly of proteins, especially into fibrils, is known to produce fluorescence in the blue band. Capable of self-assembly into nanofibers, we have shown we can modulate its aggregation into mesofibers by encapsulation of a small hydrophobic molecule. Conversely, azobenzenes are hydrophobic small molecules that are virtually non-fluorescent in solution due to their highly efficient photoisomerization. However, they demonstrate fluorogenic properties upon confinement in nanoscale assemblies by reducing the non-radiative photoisomerization. Here, we report the fluorescence of a hybrid protein-small molecule system in which azobenzene is confined in our protein assembly leading to fiber thickening and increased fluorescence. We show our engineered protein Q encapsulates AzoCholine, bearing a photoswitchable azobenzene moiety, in the hydrophobic pore to produce fluorescent mesofibers. This study further investigates the photocontrol of protein conformation as well as fluorescence of an azobenze-containing biomaterial.


Prevalence of sexually transmitted infections and enteric protozoa among homosexual men in western Sicily (south Italy).
In recent years an increase in the number of sexually transmitted infections (STIs) in men who have sex with men (MSM) has been reported in different industrialised countries. Because few epidemiological data on the STls/MSM population in Sicily are available, a survey was conducted to assess the prevalence of STls/enteric protozoa and risky sexual behaviours among MSM in western Sicily. In 2010, 74 MSM with median age of 30 years old, were recruited via networks. All participants to the study were interviewed by anonymous self-administered questionnaire in order to collect social/demographic information, clinic data and STI-related risky sexual behaviours. After completing the questionnaire, blood samples were collected to determine HIV, HCV, HHV8 and Treponema pallidum antibodies; presence of Giardia duodenalis and Cryptosporidium parvum was also investigated in faecal samples by immunofluorescence assay. HIV, HHV8, T. pallidum and Giardia prevalence were 8.1%, 16.2%, 21.6% and 16.4% respectively; all patients were negative for HCV and Cryptosporidium infections. The median values of sexual anal intercourse and oral sex per week were 2 and 1, respectively. 7% of participants always had unprotected anal sex, 50.7% sometimes used condom during sexual anal intercourse and 42.3% always had protected anal sex. All MSM-HIV+ and 7 (43.7%) syphilis seropositives were unaware of their own infection. MSM in western Sicily are a high risk group for important STIs. It seems necessary that continuous interventions for preventing HIV/AIDS and other STls and for improving the level of knowledge of symptoms are needed.


Correlations in ion channel expression emerge from homeostatic tuning rules.
Experimental observations reveal that the expression levels of different ion channels vary across neurons of a defined type, even when these neurons exhibit stereotyped electrical properties. However, there are robust correlations between different ion channel expression levels, although the mechanisms that determine these correlations are unknown. Using generic model neurons, we show that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of individual conductances to cellular readouts of activity. The correlations depend on the relative rates of expression of different conductances. Thus, variability is consistent with homeostatic regulation and the structure of this variability reveals quantitative relations between regulation dynamics of different conductances. Furthermore, we show that homeostatic regulation is remarkably insensitive to the details that couple the regulation of a given conductance to overall neuronal activity because of degeneracy in the function of multiple conductances and can be robust to "antihomeostatic" regulation of a subset of conductances expressed in a cell.


Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma.
Claudin (CLDN)-1, a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas. To investigate the clinical significance of CLDN1 expression in patients with lung adenocarcinoma and its role in cancer invasion and metastasis. We examined the CLDN1 mRNA expression in tumor specimens from 64 patients with lung adenocarcinoma and protein expression by immunohistochemistry in an independent cohort of 67 patients with lung adenocarcinoma. CLDN1 functions in cancer cell migration, invasion, and metastatic colonization were studied by overexpression and knockdown of CLDN1. Affymetrix microarrays were performed to identify gene expression changes associated with CLDN1 overexpression. We found that low-CLDN1 mRNA expression had shorter overall survival (P = 0.027, log-rank test) in 64 patients with lung adenocarcinoma, and we confirmed by immunohistochemistry that low CLDN1 expression had shorter overall survival (P = 0.024, log-rank test) in an independent cohort of 67 patients with lung adenocarcinoma. Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, and suppressed cancer cell migration, invasion, and metastasis. Knockdown CLDN1 expression increased cancer cell invasive and metastatic abilities. Affymetrix microarrays identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., connective tissue growth factor [CTGF], thrombospondin 1 [THBS1], deleted in liver cancer 1 [DLC1], occludin [OCLN], zona occludens 1 [ZO-1]) and suppressed expressions of invasion/metastasis enhancers (e.g., secreted phosphoprotein 1 [SPP1], cut-like homeobox 1 [CUTL1], transforming growth factor alpha [TGF-alpha], solute carrier family 2 [faciliated glucose transporter] member 3 [SLC2A3], placental growth factor [PGF]), supporting a role for CLDN1 as an invasion and metastasis suppressor. CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma.


Reading skill and structural brain development.
Reading is a learned skill that is likely influenced by both brain maturation and experience. Functional imaging studies have identified brain regions important for skilled reading, but the structural brain changes that co-occur with reading acquisition remain largely unknown. We investigated maturational volume changes in brain reading regions and their association with performance on reading measures. Sixteen typically developing children (5-15 years old, eight boys, mean age of sample=10.06 ± 3.29) received two MRI scans (mean interscan interval=2.19 years), and were administered a battery of cognitive measures. Volume changes between time points in five bilateral cortical regions of interest were measured, and assessed for relationships to three measures of reading. Better baseline performances on measures of word reading, fluency, and rapid naming, independent of age and total cortical gray matter volume change, were associated with volume decrease in the left inferior parietal cortex. Better baseline performance on a rapid naming measure was associated with volume decrease in the left inferior frontal region. These results suggest that children who are better readers, and who perhaps read more than less skilled readers, exhibit different development trajectories in brain reading regions. Understanding relationships between reading performance, reading experience, and brain maturation trajectories may help with the development and evaluation of targeted interventions.


Electronic and magnetic properties of multiferroic ScFeO3 available from diffraction experiments.
Electronic and magnetic properties of ferric ions (3d 5) in multiferroic ScFeO3 are puzzling, in part because they are different from the only other multiferroic known to possess the same polar chemical structure, BiFeO3. Open questions about ScFeO3 can be addressed by confronting observations with results for G-type antiferromagnetism allowed by the lithium niobate (LiNbO3)-like parent R3c structure. Calculated structure factors for resonant x-ray diffraction include all charge-like quadrupoles allowed by symmetry, and if experimental results for ScFeO3 subsequently imply they are different from zero then ferric ions cannot be in the high-spin 6S state. The same type of experiment can reveal the moment direction in the G-type antiferromagnetism, according to our calculations, and thereby contribute to understanding magnetic anisotropy. Furthermore, structure factors for magnetic neutron diffraction by ScFeO3 include Dirac multipoles that are time-odd and parity-odd, e.g. dipoles that are often called anapoles or toroidal moments. Apart from Dirac multipoles, the conventional approach to the interpretation of neutron Bragg diffraction data will be inadequate if ferric ions (Fe3+) are not in the high-spin 6S state, because the scattering amplitude includes more than simple dipole moments in the general case.


Diagnostic investigation into the role of Chlamydiae in cases of increased rates of return to oestrus in pigs.
Cervical swabs and serum samples were taken from Swiss herds of sows with high rates of irregular return to oestrus (group A) and from control herds without reproductive problems (group B. The genital tracts of 21 slaughtered sows of group A were also examined. The swabs and genital tracts were screened for Chlamydiae by a new 16S rRNA PCR and the sera by an ELISA for Chlamydiaceae lipopolysaccharide. Chlamydophila (Cp) abortus was isolated from seven of the 65 swabs taken from group A but from none of the 128 swabs taken from group B. Chlamydia suis was present in swabs from both groups A (1.5 per cent) and B (2.3 per cent). In addition, Cp abortus was detected in 33.3 per cent of the genital tracts. Of the 193 sera tested, 61.7 per cent were positive, with no significant difference between group A (52.3 per cent) and group B (66.4 per cent). Chlamydia-like organisms were detected in 28.2 per cent of the swabs from group A and in 22 per cent of those from group B.


Evidence-based medicine between explicit rationing, medical deontology and rights of patients.
Today a "just" health policy is balanced between the problem of the allocation of scarce resources and the priority setting of services, care and cures. Despite technologies and molecular medicine, with their tendency to reach absolute prediction of disease or absence of disease and to cure with predicted efficacy, a large portion of the public refuse the results of experimental procedures and prefer to place trust in so-called alternative medicine or in drugs which are not in the official guide-lines following the principles of evidence-based medicine according to DL Sackett. Juridical problems arise between the rights of free choice of cure and social dimension of Governmental care programs, which include the maximum of benefits (i.e. effective therapies) for a pre-fixed total budget. An explicit rationing only on budgetary bases without rationalisation of medical procedures reduces the rights to care of citizens-patients. Thus, an explicit rationing-rationalisation seems to be the only procedure compatible with the interest of patients in a social security system allocating "scarce" resources.


So, what's the problem?
Medical care presents complex problems to physician executives--thoughtful problem definition is a crucial management task. Without understanding the context, cultures, bottom line implications, and personal relevance, problem definition is incomplete and problem resolution may be inadequate or inappropriate. If our choices are complex, some of the difficulty may lie in our understanding of the problem. Until we have properly defined the problem, we can't act to resolve it. We need to step back, reframe the issue, ask if it feels right, and understand the whole story, not just the situation at hand. The tests of an organized story are coherence, direction, meaning, and implication. These should be perceptible both as individual attributes and as a whole. The purpose of such a story is not the resolution of the problem, but a coherent understanding of the direction to be taken. When the diagnostic work-up is complete, the next step can begin.


Dupuytren's disease in epilepsy: result of prolonged administration of anticonvulsants.
In a study of chronic epileptics in a residential centre we recorded a 56% incidence of Dupuytren's disease. The lesions were usually bilateral and symmetrical and frequently associated with knuckle pads and plantar nodules. There was no direct relationship between Dupuytren's disease and frozen shoulder. Dupuytren's disease was seen equally in those with idiopathic or symptomatic epilepsy. The incidence increased with the duration of epilepsy and is probably a sequel to long-term administration of phenobarbitone. Reasons are given for presuming that the association between Dupuytren's disease and antiepileptic therapy is mediated through the peripheral stimulation of tissue growth factors and not through the central release of growth hormone or through alterations in liver metabolism.


Scientific priorities and relational dynamics during the COVID-19 pandemic: A qualitative study.
To rapidly respond to the COVID-19 public health crisis, researchers have been called upon to prioritize pandemic research, while simultaneously modifying their existing research to maintain the safety of all stakeholders. This study aims to explore the experiences of health science researchers in their scientific practices, research priorities, and professional relational dynamics due to COVID-19. Specifically, we interviewed 31 researchers from diverse fields at the University of Texas Medical Branch. Participants worked on COVID-19, non-COVID-19 related research, or both. We integrated inductive and deductive coding using a thematic coding method. The following four themes were explored: 1) impact of research, 2) research priorities, 3) professional relationships and 4) contextual influences on science. Participants were drawn to COVID-19 work for a diversity of reasons including social need, scientific interest, professional duty, and increased access to funding opportunities. While collaborations have increased for COVID-19 researchers, interpersonal relationships have been challenging for participants. Additionally, political, familial, and personal stresses due to the pandemic have taken a toll on researchers in very different and often inequitable ways. To ensure team cohesion, there is a need to develop research practices, policies and systems that value empathy, flexibility, and interdependence.


A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies.
Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients. We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans). A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05). Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.


Effects of California Assembly Bill 2109 in Low Vaccination Rate Counties: Are We Looking at the Right Variables?
California Assembly Bill 2109 (AB2109) was passed in 2012 and restricted the obtainment of personal belief exemptions (PBEs) for vaccination requirements for school-aged children. This study examined changes in up-to-date (UTD) vaccination rates, PBEs, and conditionally accepted students (CASs) at 3 time points. The study also examined the association of PBEs and CASs on county and school immunization rates. This study utilized 6 academic years of immunization data from all kindergartens in California from 2010-2011 to 2015-2016. The years were selected to include data 2 years prior to the introduction of the bill, 2 years prior to implementation, and 2 years after the new legislation went into effect in 2014. Data were analyzed for changes in variables over time at the state, county, and school levels. A Pearson correlation was performed to assess the association between CAS, PBE, and not-UTD rates in low- and high-UTD counties. Counties with the highest percentage of unimmunized students have significantly higher mean CAS rates than PBE rates (P < .01 for all years). CASs were found to be more highly correlated with students not-UTD with immunizations than PBEs in all years studied (P < .01 for all years) and with far greater effect size in low-UTD counties (<90% UTD rate). There was a small rise in PBEs and a small reduction in UTD rates after AB2109 was signed but a fall in PBE and CAS rates and a rise in UTD rates postimplementation. Many California counties have high levels of CASs at the time of kindergarten entry. The extent to which schools require CASs to complete required vaccinations is not known, which could contribute to the pool of undervaccinated students in California. Public health officials should be vigilant to ensure that schools follow up and enforce the completion of vaccines for conditionally admitted students. This study has policy implications due to the fact that it has been revealed that there is a large undervaccinated population remaining relatively unaccounted for in California despite recent efforts.


Verbal Lie Detection: Its Past, Present and Future.
This article provides an overview of verbal lie detection research. This type of research began in the 1970s with examining the relationship between deception and specific words. We briefly review this initial research. In the late 1980s, Criteria-Based Content Analysis (CBCA) emerged, a veracity assessment tool containing a list of verbal criteria. This was followed by Reality Monitoring (RM) and Scientific Content Analysis (SCAN), two other veracity assessment tools that contain lists of verbal criteria. We discuss their contents, theoretical rationales, and ability to identify truths and lies. We also discuss similarities and differences between CBCA, RM, and SCAN. In the mid 2000s, 'Interviewing to deception' emerged, with the goal of developing specific interview protocols aimed at enhancing or eliciting verbal veracity cues. We outline the four most widely researched interview protocols to date: the Strategic Use of Evidence (SUE), Verifiability Approach (VA), Cognitive Credibility Assessment (CCA), and Reality Interviewing (RI). We briefly discuss the working of these protocols, their theoretical rationales and empirical support, as well as the similarities and differences between them. We conclude this article with elaborating on how neuroscientists can inform and improve verbal lie detection.


Abuse liability of flunitrazepam.
Flunitrazepam is among the most frequently prescribed hypnotics in many countries. Although it was never marketed in the United States, flunitrazepam, in recent years, has been smuggled into the country, and reports of abuse--including alleged use of the drug to facilitate "date rape"--have attracted a great deal of scrutiny. It has been suggested that flunitrazepam may have greater liability for abuse than other benzodiazepines; such suggestions are supported by surveys of opioid abusers, many of whom report a distinct preference for flunitrazepam over other benzodiazepines. Experimental studies of animals and normal human subjects indicate that, although flunitrazepam has high efficacy and is very potent, it is pharmacologically similar to most other benzodiazepines. Although the studies are limited in number and scope, the data show no apparent differences between flunitrazepam and other benzodiazepines in ability to produce drug-taking or drug-seeking behavior, in capacity to produce physiologic dependence, nor in the characteristics of withdrawal after administration of an antagonist or discontinuation of treatment. Similar to other benzodiazepines, flunitrazepam produces dose-dependent effects on psychomotor performance and recall. Flunitrazepam does not seem to be involved in medical emergencies more often than other benzodiazepines, and there is no indication that flunitrazepam is more toxic than other benzodiazepines when taken in overdose by drug abusers or other individuals. Survey research among typical patient populations suggests that flunitrazepam is characteristic of benzodiazepines in that it is used appropriately and conservatively, with low liability for abuse. Thus the reported preference for flunitrazepam among opioid abusers seems to be the only way in which flunitrazepam is distinguished from other benzodiazepines; it is unclear what characteristics of the drug may be responsible for this reported preference. The evidence considered in this review indicates that abuse of flunitrazepam in this special population is not associated with any distinctive threats to the health of the general public.


Effects of early intervention on EEG power and coherence in previously institutionalized children in Romania.
Two groups of Romanian children were compared on spectral power and coherence in the electroencephalogram (EEG) in early childhood. One group consisted of previously institutionalized children who had been randomly assigned to a foster care intervention at a mean age of 23 months. The second group had been randomized to remain in institutional care. Because of a policy of noninterference, a number of these children also experienced placement into alternative family care environments. There were minimal group differences between the foster care and institutionalized groups in EEG power and coherence across all measured frequency bands at 42 months of age. However, age at foster care placement within the foster care group was correlated with certain measures of EEG power and coherence. Earlier age at foster care placement was associated with increased alpha power and decreased short-distance EEG coherence. Further analyses separating age at placement from duration of intervention suggest that this effect may be more robust for EEG coherence than EEG band power. Supplementary analyses examined whether the EEG measures mediated changes in intellectual abilities within the foster care children, but no clear evidence of mediation was observed.


Purposeful Outdoor Learning Empowers Children to Deal with School Transitions.
UK schoolchildren are vulnerable to transitional stress between primary and secondary school, which may impact negatively upon their psychological health and academic achievement. This is experienced most acutely by children from ethnic minorities and lower socio-economic status (SES) households. Outdoor Adventure (OA) residential programmes are purported to develop behavioural adaptations which enable positive educational transitions of children. Personal, social and academic skills (self-reliance, getting along with others, curriculum alignment) may be best acquired through bespoke nature-based residential OA programmes. A mixed methods study evaluated the efficacy of a bespoke OA programme for developing school children's psychological well-being and self-determination during their transition into secondary school. Participants were representantives of ethnic minorities and lower SES groups. A bespoke OA residential programme achieved the strongest scale of change in children's psychological well-being (F (30,69) = 1.97 < 0.05) and self-determination (effect size 0.25) compared to a generic OA residential and a non-OA school-based induction programme. Qualitative testimonies illuminated personal experiences and processes underpinning the perceived changes in the self-determination domains of Autonomy (the capacity to self-direct learning), Competence (the ability to complete tasks) and Relatedness (developing connections with others). Providing early opportunities for children to take control for their own learning through nature-based tailored OA programming improves their psychological well-being and adaptability to combat transitional stress.


Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.
We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation.


Natural products as new antimitotic compounds for anticancer drug development.
Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.


QSAR studies on antimalarial 2,4-diamino-6-quinazoline sulfonamides.
The present paper discusses QSAR studies on antimalarial 2,4-diamino-6-quinazoline sulfonamide derivatives using electronic parameters, namely energy of highest occupied molecular orbitals (EH), energy of lowest unoccupied molecular orbitals (EL) and charge density (CD). The results have shown that better results are obtained by introducing dummy parameters (indicator parameter), Ip. Excellent results are obtained when all the four parameters (EH, EL, CD and Ip) are used in correlation analysis.


[Analysis of the academic advantage of Huangdi Neijing based on future medical trends].
Combined with the transformation of modern medicine, the author analyzed the instructional value of the academic theories proposed in the Huangdi Neijing. These theories include medical modes varying from medicine focusing on disease to medicine focusing on health, from biomedicine to ecological medicine, from the treatment of conditions to the treatment of the patient, from group therapy to individual therapy, and from disease treatment to holistic treatment. Through analysis of these treatment modalities the implications of their possible use in future medicine can be assessed.


Transjugular Intrahepatic Portosystemic Shunts in Patients with Cirrhosis with Refractory Ascites: Comparison of Clinical Outcomes by Using 8- and 10-mm PTFE-covered Stents.
Purpose To compare the efficacy and complications of transjugular intrahepatic portosystemic shunt (TIPS) creation performed by using a 10-mm or an 8-mm-diameter polytetrafluoroethylene (PTFE)-covered stent in a consecutive series of patients with cirrhosis with refractory ascites (RA). Materials and Methods The institutional review board approved this retrospective study and informed consent was waived. One hundred seventy-one patients with RA (mean age, 58.7 years ± 10.3; 95% confidence interval [CI]: 57.2 years, 60.3 years) had undergone TIPS placement by using 10-mm (60 patients) or 8-mm (111 patients) covered stent between January 2004 and December 2012. Median follow-up time was 16.8 months (range, 3.4-84.8 months). Hemodynamic changes, incidence of hepatic encephalopathy, and long-term (>3 months) need for paracentesis after TIPS placement were evaluated and calculated by using the Kaplan-Meier method and were compared by using the log-rank test. Results Pre-TIPS demographics and clinical characteristics of the two groups were comparable. The portosystemic gradient before TIPS was 17.0 mm Hg ± 4.2 (95% CI: 15.9 mm Hg, 18.1 mm Hg) in the 10-mm group versus 16.1 mm Hg ± 3.7 (95% CI: 15.4 mm Hg, 16.8 mm Hg) in the 8-mm group (P = .164). After TIPS, the portosystemic gradient was 6.5 mm Hg ± 3.4 (95% CI: 5.7 mm Hg, 7.4 mm Hg) in the 10-mm group versus 7.5 mm Hg ± 2.6 (95% CI: 6.9 mm Hg, 7.9 mm Hg) in the 8-mm group (P = .039). The long-term need for paracentesis was greater in the 8-mm group (64 of 111 patients [58%] vs 18 of 60 patients [31%], P = .003). Overall, hepatic encephalopathy was similar in both groups (45 of 111 patients [41%] vs 26 of 60 patients [44%], P = .728). Conclusion A10-mm PTFE-covered stent leads to better control of RA secondary to portal hypertension in patients with cirrhosis, compared with an 8-mm stent, without increasing the incidence of hepatic encephalopathy. © RSNA, 2017.


Propagation of CJD Prions in Primary Murine Glia Cells Expressing Human PrPc.
There are various existing cell models for the propagation of animal prions. However, in vitro propagation of human prions has been a long-standing challenge. This study presents the establishment of a long-term primary murine glia culture expressing the human prion protein homozygous for methionine at codon 129, which allows in vitro propagation of Creutzfeldt-Jakob disease (CJD) prions (variant CJD (vCJD) and sporadic CJD (sCJD) type MM2). Prion propagation could be detected by Western blotting of pathological proteinase K-resistant prion protein (PrPSc) from 120 days post exposure. The accumulation of PrPSc could be intensified by adding a cationic lipid mixture to the infectious brain homogenate at the time of infection. Stable propagation of human prions in a long-term murine glia cell culture represents a new tool for future drug development and for mechanistic studies in the field of human prion biology. In addition, our cell model can reduce the need for bioassays with human prions and thereby contributes to further implementation of the 3R principles aiming at replacement, reduction and refinement of animal experiments.


Employment of dental hygienists and registered dental assistants: highlights of the 1996 survey.
The purpose of this study was to determine various employment characteristics of Minnesota's allied dental health workforce, specifically dental hygienists and registered dental assistants. In 1995 and 1996, two questionnaires one-year period apart were mailed to all licensed dentists in the state, accompanied with a request that only one survey form per practice be returned. An estimated 73 percent and 65 percent of all practices reported in the two years respectively. Results suggest few changes over the two-year period. Information is reported on a wide variety of conditions, including practice configurations, workload distributions, turnover, salaries, and relative demand for hygienists and registered assistants. These studies provide a good baseline for future reports and suggest that, at present, patient demand is stable or strong, and that while an adequate supply of allied dental health workers is available statewide, some local supply problems exist.


An investigation into the lability of the bioactivity of human growth hormone using the ESTA bioassay.
We compared the bioactivity attributable to human growth hormone (hGH) in serum samples, determined at the time of their collection, with that after storage for 2-18 months at -20 degrees C. The samples were obtained from volunteers and patients who underwent provocative tests of hGH secretion, and the bioactivity was determined in the ESTA bioassay, which is based upon the use of Nb2 cells. We report that, in some subjects, the bioactivity of samples collected at the response peaks deteriorated on storage for as little as 2 months. The decrease in hGH bioactivity was systematic in that it consistently declined so as to approach the values initially determined by an immunoassay (Hybritech IRMA). This differential lability was a characteristic of the peak samples, and was not observed for either samples collected before and after the peaks of hGH secretion or for purified preparations of hGH which were subjected to a range of freeze/thaw and storage regimens. We suggest that this unusual lability is indicative of transient shifts in the spectrum of the variants of hGH which are present in the circulation following stimulation by provocative agents. This study emphasises the need to minimise the risk of introducing storage artefacts in investigations into the responses of hGH to provocation.


Ethical issues in using Twitter for population-level depression monitoring: a qualitative study.
Recently, significant research effort has focused on using Twitter (and other social media) to investigate mental health at the population-level. While there has been influential work in developing ethical guidelines for Internet discussion forum-based research in public health, there is currently limited work focused on addressing ethical problems in Twitter-based public health research, and less still that considers these issues from users' own perspectives. In this work, we aim to investigate public attitudes towards utilizing public domain Twitter data for population-level mental health monitoring using a qualitative methodology. The study explores user perspectives in a series of five, 2-h focus group interviews. Following a semi-structured protocol, 26 Twitter users with and without a diagnosed history of depression discussed general Twitter use, along with privacy expectations, and ethical issues in using social media for health monitoring, with a particular focus on mental health monitoring. Transcripts were then transcribed, redacted, and coded using a constant comparative approach. While participants expressed a wide range of opinions, there was an overall trend towards a relatively positive view of using public domain Twitter data as a resource for population level mental health monitoring, provided that results are appropriately aggregated. Results are divided into five sections: (1) a profile of respondents' Twitter use patterns and use variability; (2) users' privacy expectations, including expectations regarding data reach and permanence; (3) attitudes towards social media based population-level health monitoring in general, and attitudes towards mental health monitoring in particular; (4) attitudes towards individual versus population-level health monitoring; and (5) users' own recommendations for the appropriate regulation of population-level mental health monitoring. Focus group data reveal a wide range of attitudes towards the use of public-domain social media "big data" in population health research, from enthusiasm, through acceptance, to opposition. Study results highlight new perspectives in the discussion of ethical use of public data, particularly with respect to consent, privacy, and oversight.


Rifampicin prophylaxis for throat carriage of Haemophilus influenzae type b in patients with invasive disease and their contacts.
To determine rates of colonisation with Haemophilus influenzae type b among household contacts of children with invasive H influenzae type b disease; compliance among medical staff with recommendations for use of rifampicin prophylaxis; and effects of rifampicin treatment in H influenzae type b colonisation of patients and contacts. Prospective study of patients and their household contacts. Royal Children's Hospital (the major paediatric hospital) in Victoria, Australia, with catchment population of 4.2 million, including 300,000 children aged under 5 years. 234 patients (age range 6 weeks to 8 years) with 235 episodes of all types of invasive H influenzae type b disease admitted during 1988-9 and their contacts. Positive cultures of H influenzae type b from throat swabs taken at admission and six weeks subsequently; recording of rifampicin prophylaxis. The percentage of patients with positive throat cultures fell from 69% (33/48) on day 1 of admission to 9% (4/47) after three days' treatment; at six weeks' follow up 32% (32/99) of patients who had not received rifampicin and 8% (5/61) who had, had positive throat cultures. Among household contacts, 33% (62/190) of children and 7% (25/359) of adults were colonised, and the colonisation rates were similar in contacts of patients with all types of H influenzae type b disease. Rifampicin prophylaxis was indicated in 85 families; in 34% it was not prescribed at all for contacts and in 41% not as recommended. The colonisation rates at follow up were significantly less in siblings given rifampicin (12%, 9/78), particularly in families in which all members were treated (3%), than in those in which they were not (36%) (odds ratio 21.5; 95% confidence interval 3.0 to 103.4). The rate of throat colonisation with H influenzae type b was similar among siblings of children with all types of invasive H influenzae type b disease. Colonisation in contacts can be reduced by rifampicin prophylaxis, but some contacts remained colonised or were recolonised by the time of follow up. Medical staff complied poorly with current recommendations for rifampicin prophylaxis, which reduces its intrinsically limited value in preventing H influenzae type b disease.


Synergistic efficacy of ultrasound, sonosensitizers and chemotherapy: a review.
Chemotherapeutic agents, either in the form of systemically injected free drug or encapsulated in nanoparticles transport vehicles, must overcome three main obstacles prior to reaching and interacting with their intended target inside tumor cells. Drugs must leave the circulation, overcome the tissue-tumor barrier and penetrate the cell's plasma membrane. Since, many agents enter the cell by endocytosis, they must avoid entrapment and degradation by the intracellular endolysosome complex. Ultrasound has demonstrated potential to enhance the efficacy of chemotherapy by reducing these barriers. The purpose of this review is to highlight the potential of ultrasound in combination with sonosensitizers to enhance the efficacy of chemotherapy by optimizing the anticancer agent's intracellular ability to engage and interact with its target.


[Expression of somatostatin gene in E. coli D29A1].
Somatostatin gene fragment extracted and purified from plasmid pSom5 bacterium was ligated with the plasmid pBD2 DNA. Transformation of E. coli D29A1 with the chimeric plasmid DNA led to the synthesis of a polypeptide including the sequence of amino acids corresponding to somatostatin. The chimeric protein (50000 dalton) was purified and characterized by the beta-galactosidase affinity chromatography and the expression of the somatostatin gene in E. coli D29A1 is certain after the radioimmunoassay of the chimeric protein and its mixture by treatment with cyanogen bromide.


Oncological genetic counseling (OGC) for high-risk hereditary cancer: what can hospital anxiety and depression scale (HADs) tell us?
This study aimed to verify whether and how anxiety and depression symptoms are associated both to socio-demographic and clinical variables (age, civil status, type of cancer diagnosed, time elapsed between cancer diagnosis and Oncologic Genetic Counseling/OGC, number of relatives affected by cancer) and to psychological features (presence/absence of previous psychological suffering), subjective cancer risk perception, psychological attitude approaching/OGC) in a sample of Caucasian patients accessing OGC. 201 participants (193 female and 8 male) accessing OGC in the Istituto di Ricovero e Cura Carattere Scientifico (IRCCS) Giovanni Paolo II in Bari completed the Hospital Depression and Anxiety Scale (HADs) that was analyzed as global scoring, anxiety (HAD-A) and depression subscale (HAD-D). In our sample, higher HADs, HAD-A and HAD-D scorings were associated in different ways to both socio-demographic information (age: p value 0.019), clinical and medical features (personal history of cancer: HAD-D p value 0.02; months elapsed between diagnosis and OGC, HAD-A p value 0.004 and HADs p value 0.008) and psychological dimensions (approaching genetic counseling: anxiety p value 0.06; fear p value 0.02; duty p value 0.04). This study showed that during the process of oncological genetic counseling the importance of taking into consideration not only medical variables but also cognitive and emotional aspects from both the individual and family spheres, in order to assure adequate care of the patient.


In vitro studies of alpha-carboxyl-3-thienylmethyl penicillin, a new semisynthetic penicillin.
The activity of a new semisynthetic penicillin, alpha-carboxyl-3-thienylmethyl penicillin (BRL-2288) was determined against 535 clinical isolates of gram-negative bacilli, by using the tube dilution technique. Nearly 80% of isolates of Proteus spp. were inhibited by 3.12 mug or less of this antibiotic per ml. BRL-2288 was as active as ampicillin against Escherichia coli. It was slightly more active than carbenicillin or 6-(d-alpha-sulfoaminophenylacetamido)-penicillanic acid against Pseudomonas sp., with over half of the isolates being inhibited by 50 mug or less of BRL-2288 per ml. Isolates of Klebsiella sp. were routinely resistant to this antibiotic. The drug was bactericidal against most sensitive organisms. BRL-2288 was less active against large inocula. A strain of Pseudomonas sp. which developed resistance to carbenicillin also developed resistance to BRL-2288 simultaneously.


Gene Augmentation and Editing to Improve TCR Engineered T Cell Therapy against Solid Tumors.
Recent developments in gene engineering technologies have drastically improved the therapeutic treatment options for cancer patients. The use of effective chimeric antigen receptor T (CAR-T) cells and recombinant T cell receptor engineered T (rTCR-T) cells has entered the clinic for treatment of hematological malignancies with promising results. However, further fine-tuning, to improve functionality and safety, is necessary to apply these strategies for the treatment of solid tumors. The immunosuppressive microenvironment, the surrounding stroma, and the tumor heterogeneity often results in poor T cell reactivity, functionality, and a diminished infiltration rates, hampering the efficacy of the treatment. The focus of this review is on recent advances in rTCR-T cell therapy, to improve both functionality and safety, for potential treatment of solid tumors and provides an overview of ongoing clinical trials. Besides selection of the appropriate tumor associated antigen, efficient delivery of an optimized recombinant TCR transgene into the T cells, in combination with gene editing techniques eliminating the endogenous TCR expression and disrupting specific inhibitory pathways could improve adoptively transferred T cells. Armoring the rTCR-T cells with specific cytokines and/or chemokines and their receptors, or targeting the tumor stroma, can increase the infiltration rate of the immune cells within the solid tumors. On the other hand, clinical "off-tumor/on-target" toxicities are still a major potential risk and can lead to severe adverse events. Incorporation of safety switches in rTCR-T cells can guarantee additional safety. Recent clinical trials provide encouraging data and emphasize the relevance of gene therapy and gene editing tools for potential treatment of solid tumors.


Breaking the Chain of Infection: Dental Unit Water Quality Control.
The air-water syringes, ultrasonic scalers, high speed air turbine handpieces are connected to dental units by a network of small-bore plastic tubes through which water and air travel to activate or cool the instruments and it had been shown that this system is extensively contaminated with microbial biofilms and pose a potential risk of infection for patients as well as dental professionals. To evaluate and compare the efficacy of various disinfectants in reducing the microbial colony count in water derived from Dental Unit Waterlines. Five random dental units were selected and samples were collected before and after intervention with 5 disinfectants (0.02% H2O2 continuously, 0.02% H2O2 continuously with shock treatment with 0.25% H2O2 weekly, 0.12% Chlorohexidine and 12% Ethanol overnight, 1:50 Original Listerine overnight, 2% Sodium Perborate and 2% EDTA 5 minutes in morning) using different disinfection methods for 4 weeks. Samples were cultured on Reasoner's 2A (R2A) agar for microbial counting. Results were recorded as Colony forming units/ml (cfu/ml) and were evaluated statistically. Results showed that all the dental unit waterlines were heavily contaminated with microbes before any intervention. After 1 day of disinfection regime the counts reduced significantly and showed progressive reduction in consecutive weeks. Goals set by ADA & CDC were ultimately achieved at the end of 4 weeks. All the disinfectants were equally effective in reducing the microbial colony count of DUWLs, irrespective of their concentration and method of disinfection.


Life insurance for living kidney donors: a Canadian undercover investigation.
Some living kidney donors encounter difficulties obtaining life insurance, despite previous surveys of insurance companies reporting otherwise. To better understand the effect of donation on insurability, we contacted offices of life insurance companies in five major cities in Canada to obtain $100 000 of life insurance (20-year term) for 40 fictitious living kidney donors and 40 paired controls. These profiles were matched on age, gender, family history of kidney disease and presence of hypertension. The companies were blinded to data collection. The study protocol was reviewed by the Office of Research Ethics. The main study outcomes were the annual premium quoted and total time spent on the phone with the insurance agent. All donor and control profiles received a quote, with no significant difference in the premium quoted (medians $190 vs. $209, p = 0.89). More time was spent on the phone for donor compared to control profiles, but the absolute difference was small (medians 9.5 vs. 7.0 min, p = 0.046). Age, gender, family history of kidney disease and new-onset hypertension had no further effect on donor insurability in regression analysis. We found no evidence that kidney donors were disadvantaged in the first step of applying for life insurance. The effect donation has on subsequent phases of insurance underwriting remains to be studied.


[The quality of life after stem cell transplantation: problems with fatigue, sexuality, finances and employment].
To determine the quality of life in patients after high dose chemo/radiotherapy followed by bone marrow stem cell transplantation for the treatment of a malignancy. Structured questionnaire and in-depth interview. Academic Hospital Maastricht, the Netherlands. All patients who had undergone stem cell transplantation (SCT) at least 6 months previously (n = 54) were asked to participate in an analysis of their quality of life using the 'Quality of life questionnaire' (QLQ-C30) developed by the European Organization for Research and Treatment of Cancer (EORTC) and an in-depth interview. The EORTC QLQ-C30 was answered by 52 (96%) of the patients and 46 (85%) participated in the interview. The patients were divided in cohorts of 6-24 (n = 16), 25-48 (n = 22) and more than 48 months (n = 14) after SCT. Quality of life was 73.9 on a 100 per cent scale. There were no significant differences between various cohorts after SCT. However, patients transplanted more than 4 years before had significantly more complaints of nausea and vomiting. The structured interview revealed significant problems with fatigue, sexuality, finances and return to work. No clear relation with time elapsed after transplantation was found. SCT has a significant impact on several quality of life issues, which should be considered in the application of this modality in palliative situations. The EORTC QLQ-C30 may be helpful to analyse overall quality of life after transplantation, but provides no information on individual effects on quality of life.


Catch-bond behavior of bacteria binding by slip bonds.
It is shown that multipili-adhering bacteria expressing helix-like pili binding by slip bonds can show catch-bond behavior. When exposed to an external force, such bacteria can mediate adhesion to their hosts by either of two limiting means: sequential or simultaneous pili force exposure (referring to when the pili mediate force in a sequential or simultaneous manner, respectively). As the force is increased, the pili can transition from sequential to simultaneous pili force exposure. Since the latter mode of adhesion gives rise to a significantly longer bacterial adhesion lifetime than the former, this results in a prolongation of the lifetime, which shows up as a catch-bond behavior. The properties and conditions of this effect were theoretically investigated and assessed in some detail for dual-pili-adhering bacteria, by both analytical means and simulations. The results indicate that the adhesion lifetime of such bacteria can be prolonged by more than an order of magnitude. This implies that the adhesion properties of multibinding systems cannot be directly conveyed to the individual adhesion-receptor bonds.


Assessment of salivary Lactobacillus and Streptococcus mutans counts following sodium fluoride mouthrinsing in Egyptian children.
The salivary Lactobacillus and Streptococcus mutans counts were assessed in 100 Egyptian children, initially before mouthrinsing with 0.05% sodium fluoride solution, 24 hours and 48 hours following rinsing. A statistically significant reduction in Lactobacillus and Streptococcus mutans counts of 49% and 44% respectively was obtained 24 hours following rinsing. This percentage decrease in both bacterial counts was reduced to 27% and 31% respectively, 48 hours following rinsing.


Differential impact of APOBEC3-driven mutagenesis on HIV evolution in diverse anatomical compartments.
Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure. To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day. APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells. APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.


Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation.
Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3-derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3-derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications.


A series of simple oligomer-like small molecules based on oligothiophenes for solution-processed solar cells with high efficiency.
A series of acceptor-donor-acceptor simple oligomer-like small molecules based on oligothiophenes, namely, DRCN4T-DRCN9T, were designed and synthesized. Their optical, electrical, and thermal properties and photovoltaic performances were systematically investigated. Except for DRCN4T, excellent performances were obtained for DRCN5T-DRCN9T. The devices based on DRCN5T, DRCN7T, and DRCN9T with axisymmetric chemical structures exhibit much higher short-circuit current densities than those based on DRCN6T and DRCN8T with centrosymmetric chemical structures, which is attributed to their well-developed fibrillar network with a feature size less than 20 nm. The devices based on DRCN5T/PC71BM showed a notable certified power conversion efficiency (PCE) of 10.10% under AM 1.5G irradiation (100 mW cm(-2)) using a simple solution spin-coating fabrication process. This is the highest PCE for single-junction small-molecule-based organic photovoltaics (OPVs) reported to date. DRCN5T is a rather simpler molecule compared with all of the other high-performance molecules in OPVs to date, and this might highlight its advantage in the future possible commercialization of OPVs. These results demonstrate that a fine and balanced modification/design of chemical structure can make significant performance differences and that the performance of solution-processed small-molecule-based solar cells can be comparable to or even surpass that of their polymer counterparts.


Gastric Antral Vascular Ectasia: A Case Report and Literature Review.
Gastric antral vascular ectasia (GAVE) is a rare but an important cause of upper gastrointestinal bleeding (UGIB) and commonly presents as occult bleeding that manifests as iron deficiency anemia (IDA). GAVE is commonly associated with chronic illnesses, most frequently liver cirrhosis and connective tissue diseases. The pathogenesis of GAVE is still obscure, and many hypotheses such as mechanical stress, hormonal factors, and autoimmune factors, have been proposed. Upper gastrointestinal endoscopy has a major role in the diagnosis and treatment of GAVE.


Adherence of Yersinia enterocolitica to mammalian epithelial cell lines.
Yersinia enterocolitica RIMD 2501003 grown at 25 C avidly adhered to various kinds of cultured epithelial cell lines (HeLa, FL, Y-1 adrenal, human intestine, human conjunctiva) but the bacteria grown at 37 C did not adhere. This phenomenon paralleled the temperature-dependent motility of the bacteria. To clarify the adherence mechanism, we obtained two kinds of mutants, an immobile mutant and a nonadherent mutant, by treatment with N-methyl-N'-nitro-N-nitrosoguanidine. The immobile mutant did not move on soft agar but retained the capacity to adhere to cultured epithelial cells when grown at 25 C. The nonadherent mutant did not adhere to cultured epithelial cells but retained the ability to move on soft agar when grown at 25 C. When the bacteria were killed by heat, ultraviolet light irradiation or formaldehyde they lost their capacity to adhere to the cultured epithelial cells. Antiserum against Y. enterocolitica RIMD 2501003 grown at 25 C was absorbed with the bacteria grown at 37 C, with the bacteria grown at 25 C, with the nonadherent mutant grown at 25 C and with the bacteria killed by various means. Only the antiserum absorbed with bacteria grown at 37 C inhibited the adherence of bacteria. These data indicate that motility does not correlate with adherence of Y. enterocolitica. It appears that the adherence factor involves both a temperature-dependent surface factor and a factor synthesized de novo during the interaction of susceptible cells with the bacteria.


Influence of the X-ray beam quality on the dose increment in CT with iodinated contrast medium.
In computed tomography (CT), the image contrast is given by the difference in X-ray attenuation in the various tissues of the patient and contrast media are used to enhance image contrast in anatomic regions characterized by similar attenuation coefficients. Aim of the present work is to enlarge the range of applicability of the method previously introduced for organ dosimetry in contrast-enhanced CT, by studying the effects of X-ray beam quality on the parameters of the model. Furthermore, an experimental method for the evaluation of the attenuation properties of iodinated solutions is proposed. Monte Carlo simulations of anthropomorphic phantoms were carried out to determine a bi-parametrical (a and b) analytical relationship between iodine concentration and dose increase in organs of interest as a function of the tube kilo-voltage peak potential (kVp) and filtration. Experimental measurements of increments in Hounsfield Units (HU) were conducted in several CT scanners, at all the kVp available, in order to determine the parameter γ which relates the HU increment with the iodine mass fraction. A cylindrical phantom that can be filled with iodine solutions provided with an axial housing for a pencil ionization chamber was designed and assembled in order to measure the attenuation properties of iodine solutions under irradiation of a CT scanner and to obtain a further validation of Monte Carlo simulations. The simulation-derived parameters of the model, a and b, are only slightly dependent upon the tube kilo-voltage peak potential and filtration, while such scanner-dependent features influence mainly the experimentally-derived γ parameter. Relative dose variations registered by the ionization chamber inside the iodine-filled cylindrical phantom decrease when the X-ray mean energy increases, and reaches about 50% for 10 mg/ml of iodine. The dosimetric method for contrast-enhanced CT can be applied to all CT scanners by adopting average simulative parameters and by carrying out a simple measurement with a series of iodine contrast solutions. The novel experimental methodology introduced can provide a direct measurement of iodine attenuation properties.


Management of dyspnea in advanced pulmonary arterial hypertension.
Pulmonary hypertension leads to progressive increase in pulmonary vascular resistance, heart failure, and death. Pulmonary arterial hypertension (PAH) is a subset of pulmonary hypertension affecting small pulmonary arteries and not associated with underlying heart or lung disease. Dyspnea and exercise intolerance are hallmarks of PAH and are used to monitor disease progression. This review focuses on recent advances in the pathophysiology and treatment of dyspnea in PAH. The etiological classification of pulmonary hypertension and World Health Organization functional class clinical classification, as used to guide management, have recently been revised. Dyspnea and PAH disease progression are best assessed by cardiopulmonary exercise testing and the six-minute walk test. Understanding of the molecular pathogenesis of PAH has led to new classes of treatments, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Prostanoids have the longest track record in treatment of PAH but a short half-life and cumbersome delivery systems limit their utility. More convenient endothelin receptor antagonists are becoming mainstream in PAH management. Phosphodiesterase-5 inhibitors improve exercise capacity and quality of life, although long-term outcome data are pending. Combination therapy with different medication classes appears promising for progressive disease. Establishing the cause and clinical severity of pulmonary hypertension is critical for management. The pathophysiology of dyspnea in PAH is complex and related to pulmonary vascular resistance. Although disease-specific treatments are now available, a cure for PAH remains elusive and trials of combination treatments to improve symptoms and outcomes are ongoing.


The Association of Standardized Patient Educators (ASPE) Standards of Best Practice (SOBP).
In this paper, we define the Association of Standardized Patient Educators (ASPE) Standards of Best Practice (SOBP) for those working with human role players who interact with learners in a wide range of experiential learning and assessment contexts. These human role players are variously described by such terms as standardized/simulated patients or simulated participants (SP or SPs). ASPE is a global organization whose mission is to share advances in SP-based pedagogy, assessment, research, and scholarship as well as support the professional development of its members. The SOBP are intended to be used in conjunction with the International Nursing Association for Clinical Simulation and Learning (INACSL) Standards of Best Practice: SimulationSM, which address broader simulation practices. We begin by providing a rationale for the creation of the ASPE SOBP, noting that with the increasing use of simulation in healthcare training, it is incumbent on ASPE to establish SOBP that ensure the growth, integrity, and safe application of SP-based educational endeavors. We then describe the three and a half year process through which these standards were developed by a consensus of international experts in the field. Key terms used throughout the document are defined. Five underlying values inform the SOBP: safety, quality, professionalism, accountability, and collaboration. Finally, we describe five domains of best practice: safe work environment; case development; SP training for role portrayal, feedback, and completion of assessment instruments; program management; and professional development. Each domain is divided into principles with accompanying key practices that provide clear and practical guidelines for achieving desired outcomes and creating simulations that are safe for all stakeholders. Failure to follow the ASPE SOBP could compromise the safety of participants and the effectiveness of a simulation session. Care has been taken to make these guidelines precise yet flexible enough to address the diversity of varying contexts of SP practice. As a living document, these SOBP will be reviewed and modified periodically under the direction of the ASPE Standards of Practice Committee as SP methodology grows and adapts to evolving simulation practices.


Dignity in situations of ethical difficulty in intensive care.
In intensive care, situations of ethical difficulty are common. For the purpose of illuminating the meaning of being in ethically difficult situations, 20 registered nurses (RNs) employed in six intensive care units in Sweden narrated episodes of ethical difficulty. From a phenomenological hermeneutic perspective, the core theme of 'dignity' was identified in 85 stories. Stories with the concept of dignity reveal a threefold meaning; transforming disrespect into respect for the inviolable value of the human being; transforming ugly situations into beautiful ones; transforming discord of death into togetherness. Stories without the concept of dignity were oriented toward skills and physical care without reflection on actions and a 'taken-for-granted attitude' that good will prevail. Comparing and contrasting stories with and without dignity revealed the demands of dignity: attentiveness, awareness, personal responsibility, engagement, fraternity and active defence of dignity. In light of the philosophies of Weil, Marcel and Ricoeur, the demands of dignity correspond to qualities generated when struggling for respecting the dignity of human beings. This study reveals that dignity begets dignity, which opens the RNs to the ethical dimension. This, in turn, counteracts the risk of dehumanizing care in technocratic environments.


Independent studies using deep sequencing resolve the same set of core bacterial species dominating gut communities of honey bees.
Starting in 2003, numerous studies using culture-independent methodologies to characterize the gut microbiota of honey bees have retrieved a consistent and distinctive set of eight bacterial species, based on near identity of the 16S rRNA gene sequences. A recent study [Mattila HR, Rios D, Walker-Sperling VE, Roeselers G, Newton ILG (2012) Characterization of the active microbiotas associated with honey bees reveals healthier and broader communities when colonies are genetically diverse. PLoS ONE 7(3): e32962], using pyrosequencing of the V1-V2 hypervariable region of the 16S rRNA gene, reported finding entirely novel bacterial species in honey bee guts, and used taxonomic assignments from these reads to predict metabolic activities based on known metabolisms of cultivable species. To better understand this discrepancy, we analyzed the Mattila et al. pyrotag dataset. In contrast to the conclusions of Mattila et al., we found that the large majority of pyrotag sequences belonged to clusters for which representative sequences were identical to sequences from previously identified core species of the bee microbiota. On average, they represent 95% of the bacteria in each worker bee in the Mattila et al. dataset, a slightly lower value than that found in other studies. Some colonies contain small proportions of other bacteria, mostly species of Enterobacteriaceae. Reanalysis of the Mattila et al. dataset also did not support a relationship between abundances of Bifidobacterium and of putative pathogens or a significant difference in gut communities between colonies from queens that were singly or multiply mated. Additionally, consistent with previous studies, the dataset supports the occurrence of considerable strain variation within core species, even within single colonies. The roles of these bacteria within bees, or the implications of the strain variation, are not yet clear.


Integrated drought monitoring framework for Eswatini applying standardised precipitation index and normalised difference vegetation index.
In the last decade, Eswatini has been affected by moderate to severe droughts, leading to huge impacts on the economic, environmental and societal sectors. The frequency and magnitude of drought have also increased, emphasising on the importance of drought monitoring. In view of the impacts of drought, it is of critical importance to monitor drought in near real-time and provide early warning information to stakeholders. The challenge however is the fragmentation of climatic data collection, the lack of agreed indicators and the poor coordination amongst institutions resulting in drought management being reactive, or 'crisis management' approach. A paradigm shift to a more risk reduction approach is therefore required to enable cost-effective and timely response to drought disasters. The capacity to monitor and predict the drought attributes (onset, frequency, duration and severity) is fundamental for spatiotemporal (drought) monitoring. Based on a review of country and regional networks, this research developed an integrated drought monitoring and early warning framework for Eswatini. The framework incorporated an early warning response trigger threshold derived from an integration of the standardised precipitation index and normalised difference vegetation index. The adoption of the framework allows for early warning and early action to mitigate the consequences of drought disasters. Drought preparedness and risk mitigation will help lower the eventual drought relief costs, protect food security and reduce the humanitarian impact on the population.