Scientific solidarity in the face of the COVID-19 pandemic: researchers, publishers, and medical associations.
In the face of COVID-19, the scientific community has rapidly come together to address this outbreak in an open and collaborative manner to support the global response to this outbreak by rapidly sharing and highlighting research data and relevant findings. COVID-19 research is being published at a furious pace. Over 6,000 articles have been published as of 20 April 2020, and at least 15 online resource centers/websites for COVID-19 have been created by publishers to enable fast and free access to the latest research, evidence, and data available. Moreover, many evidence-based guidelines for COVID-19 have been issued based on academic articles and summaries of the experiences of frontline medical personnel. Various academic medical associations are also actively sharing information and providing technical support. As an example, 93 guides/proposals/responses to COVID-19 have been issued so far by 50 medical associations in Japan. However, few publications and national situation reports have provided information on the number of infected healthcare workers (HCWs). More publications and national situation reports are urgently needed to provide scientific information to devise specific infection prevention and control measures in order to protect HCWs from infection.


Teaching methods in Hawler College of Medicine in Iraq: a qualitative assessment from teachers' perspectives.
Medical education in Iraq is poorly assessed and there is a general lack of documented knowledge about the challenges facing this field and the needs for its development. This study aimed to assess the existing teaching methods in the Hawler College of Medicine, Iraq from teaching staff perspectives and assess the knowledge of the teaching staff about student-centred learning. A qualitative study based on a self-administered questionnaire survey of a purposive sample of 83 teaching staff in Hawler Medical University was conducted. The questionnaire addressed the participants' view on the positive aspects and problems of the current teaching methods and priorities to change it. The qualitative data analysis comprised thematic analysis. The study revealed significant problems facing the existing teaching methods including having large number of students in the lecture hall (45.0 %), having focus on teacher-centred teaching (45.0 %) and lack of infrastructures and facilities suitable for proper teaching (26.7 %). The priorities for improving the quality of teaching methods included adoption of small group teaching strategy in all study years (34.6 %), improving the infrastructure and facilities for teaching in the college (34.6 %) and provision of continuous academic development programs for the teaching staff (24.3 %). The existing medical education system face significant problems and it needs important and comprehensive improvements in different areas. There is a need for further research in this field to explore the identified problems in a more in-depth manner in order to better understand of the problems and needs of this important area of education.


Experimental and numerical investigation of interactions between above and below ground drainage systems.
This paper presents the results of the experimental and numerical investigation of interactions between surface flood flow in urban areas and the flow in below ground drainage systems (sewer pipes and manholes). An experimental rig has been set up at the Water Engineering Laboratory at the University of Sheffield. It consists of a full scale gully structure with inlet grating, which connects the 8 m(2) surface area with the pipe underneath that can function as an outfall and is also further connected to a tank so that it can come under surcharging conditions and cause outflow from the gully. A three-dimensional CFD (Computational Fluid Dynamics) model has been set up to investigate the hydraulic performance of this type of gully inlet during the interactions between surface flood flow and surcharged pipe flow. Preliminary results show that the numerical model can replicate various complex 3D flow features observed in laboratory conditions. This agreement is overall better in the case of water entering the gully than for the outflow conditions. The influence of the surface transverse slope on flow characteristics has been demonstrated. It is shown that re-circulation zones can form downstream from the gully. The number and size of these zones is influenced by the transverse terrain slope.


Self-assembly behaviours of primitive and modern lipid membrane solutions: a coarse-grained molecular simulation study.
Researchers have studied the origin of life and the process of evolution on early Earth for decades. However, we lack a comprehensive understanding of biogenesis, because there are many stages in the formation and growth of the first cell. We investigate the self-replication processes of coacervate protocells using computer simulations of single-chain lipid and phospholipid aqueous mixtures. Based on a morphological phase diagram, we develop a model of prebiotic self-replication driven by only environmental factors (i.e. temperature and lipid concentrations) without any external force. Moreover, we investigate high concentration structures during the process of self-replication. These structures have an advantage in fusion and repair of cell membranes. Therefore, lipid hot spots may have existed in primordial soup.


Self-calibrating lensless inline-holographic microscopy by a sample holder with reference structures.
A self-calibration technique for lensless compact chip-microscopes based on inline holography with pinhole illumination is presented. The pinhole illumination wave acts as reference and is needed for the reconstruction process. This reference wave is assumed to be spherical, so that its phase is already determined by the position of the pinhole in relation to the image sensor. It is shown that the reconstructed spatial resolution is strongly dependent on the estimation for the pinhole to sensor distance. A precision in the range of tens of microns was reached for microscopic imaging with a spatial resolution in the range of one micron. Therefore additional reference crosses are prepared lithographically on the sample holder. The hologram, which contains the optical information about the sample as well as the reference crosses, is used for calibration and image reconstruction at the same time. The presented technique was tested to allow the reconstruction of a spatial resolution corresponding to the limit of detection apertures of about 0.66. The technique was applied to holograms of test beads and blood smear samples.


Intracellular localization and in vivo trafficking of p24A and p23.
Recently, p24A and p23 (also termed Tmp21), two members of the p24 protein family, have been proposed to function as integral receptors for the COPI-vesicle coat. This study describes the intracellular localization and trafficking of p24A in comparison to p23. For immunolocalization of p24A and p23, strong reduction and denaturation conditions were necessary to allow antibody interaction. Both p24A and p23 cycle continuously between intermediate compartment (IC) elements and the cis-Golgi network. In vivo trafficking of p24A and p23 tagged to green fluorescent protein (GFP) revealed that both proteins travel by large (up to 1 micrometer in length) microtubule-dependent pre-Golgi carriers with a maximum speed of up to 1.6 micrometer s-1 from the IC to the Golgi cisternae. Aluminum fluoride, a general activator of heterotrimeric G-proteins, blocked peripheral pre-Golgi movements of GFP-p24A/p23 and inhibited fluorescence recovery after photobleaching in the perinuclear Golgi area. p24A and p23 are predominantly colocalized. Overexpression of GFP-p24A, to an extent which did not destroy the Golgi complex, induced delocalization of part of the proteins into ER elements. This study therefore gives new insights into the localization and trafficking behavior of the two COPI-binding proteins p24A and p23.


The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner.
PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110δ in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110δ has a lipid-kinase-independent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110δ is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110δ carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110δ in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110δ could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.


TNF, LTA, HSPA1L and HLA-DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole.
Sulfamethoxazole in combination with trimethoprim (cotrimoxazole) is used for prophylaxis and treatment of several opportunistic infections in HIV-infected patients. It is associated with a high incidence of hypersensitivity reactions, which is thought to have an immune basis. Genetic polymorphisms in MHC are known to predispose to hypersensitivity reactions to a structurally diverse group of drugs in HIV-positive patients. The aim of the study was to determine whether functional polymorphisms in TNF, LTA, HSPA1L and HLA-DRB1 genes influence the risk of cotrimoxazole hypersensitivity in HIV-infected patients. We genotyped 136 HIV-positive patients with (n = 53) and without (n = 83) cotrimoxazole hypersensitivity using a combination of PCR-based techniques, including PCR-restriction fragment length polymorphisms, PCR-sequence specific oligonucleotides and real-time PCR. Genotypes and the haplotype frequencies were analyzed using the chi(2) test in the Haploview and CLUMP programs. No statistically significant difference in SNP or haplotype frequencies were found in HIV-infected sulfamethoxazole hypersensitive patients compared with controls. Our data show that MHC polymorphisms are not major predisposing factors for cotrimoxazole hypersensitivity, although we cannot exclude a minor contribution. An environmental factor (i.e., HIV infection) seems to predominate over any of the genetic factors so far investigated in increasing the risk of cotrimoxazole hypersensitivity.


Reporting of Intimate Partner Violence among Men Who Have Sex with Men in an Online Survey.
A growing body of literature suggests that intimate partner violence (IPV) occurs within same-sex relationships and that members of the Lesbian Gay Bisexual Transgender (LGBT) community face a number of unique challenges in accessing IPV-related services. This paper examines the use of an online survey, marketed through a popular social networking site, to collect data on the experience and perpetration of IPV among men who have sex with men (MSM) in the United States. Internet-using MSM were recruited through selective placement of banner advertisements on MySpace.com. Participants were eligible for the baseline survey if they were males ≥ 18 years of age, and reported at least one male sex partner in the last 12 months. In total 16,597 men responded to the ad, of which 11,681 were eligible for the study, and 5,602 completed the questionnaire; 543 men completed the follow-up survey, which included questions on the experience and perpetration of IPV. The final analysis sample was 402. THE PREVALENCE OF VIOLENCE AMONG THE SAMPLE WAS RELATIVELY HIGH: 11.8% of men reported physical violence from a current male partner, and about 4% reported experiencing coerced sex. Reporting of perpetration of violence against a partner was generally lower, with approximately 7% reporting perpetrating physical violence and less than 1% reporting perpetration of sexual violence. The results presented here find lower levels of experiencing both physical and sexual IPV than have been shown in previous studies, yet show relatively high levels of reporting of perpetration of IPV. Collecting IPV data through surveys administered through social networking sites is feasible and provides a new opportunity to reach currently overlooked populations in IPV research.


Awareness-related activity in prefrontal and parietal cortices in blindsight reflects more than superior visual performance.
Many imaging studies report activity in the prefrontal and parietal cortices when subjects are aware as opposed to unaware of visual stimuli. One possibility is that this activity simply reflects higher signal strength or the superior task performance that is associated with awareness. To find out, we studied the hemianope GY who has unilateral destruction of almost all primary visual cortices. He exhibits 'blindsight', that is, he claims to have no conscious visual phenomenology (i.e., no visual qualia), for stationary stimuli presented to his right visual field (the blind field), although he can press keys to distinguish between different stimuli presented there. We presented to him a visual discrimination task, and equated performance for stimuli presented to the left or right visual field by presenting low contrast stimuli to his normal (left) field and high contrast stimuli to his blind (right) field. Superior accuracy can be a serious confound, and our paradigm allows us to control for it and avoid this confound. Even when performance was matched, and the signal strength was lower, visual stimulation to the normal (conscious) field led to higher activity in the prefrontal and parietal cortices. These results indicate that the activity in the prefrontal and parietal areas that has been reported in previous studies of awareness is not just due to a (signal strength or performance) confounds. One possibility is that it reflects the superior 'metacognitive' capacity that is associated with awareness, because GY was better able to distinguish between his own correct and incorrect responses for stimuli presented to his normal field than to his blind field.


Model reference adaptive scheme for multi-drug infusion for blood pressure control.
Using multiple interacting drugs to control both the mean arterial pressure (MAP) and cardiac output (CO) of patients with different sensitivity to drugs is a challenging task which this paper attempts to address. A multivariable model reference adaptive control (MRAC) algorithm is developed using a two-input, two-output patient model. The control objective is to maintain the homodynamic variables MAP and CO at the normal values by simultaneously administering two drugs; sodium nitroprusside (SNP) and dopamine (DPM). Computer simulations were carried out to investigate the performance of this controller. The results show that the proposed adaptive scheme is robust with respect to disturbances and variations in model parameters.


Growth cones are actively influenced by substrate-bound adhesion molecules.
As axons advance to appropriate target tissues during development, their growth cones encounter a variety of cell adhesion molecules (CAMs) and extracellular matrix molecules (ECM molecules). Purified CAMs and ECM molecules influence neurite outgrowth in vitro and are thought to have a similar function in vivo. For example, when retinal ganglion cell (RGC) neurons are grown on different CAM and ECM molecule substrates in vitro, their growth cones display distinctive morphologies (Payne et al., 1992). Similarly, RGC growth cones in vivo have distinctive shapes at different points in the pathway from the eye to the tectum, suggesting the presence of localized cues that determine growth cone behaviors such as pathway selection at choice points. In this report, time-lapse video microscopy was utilized to examine dynamic transformations of RGC growth cones as they progressed from L1/8D9, N-cadherin, or laminin onto a different substrate. Contact made by the leading edge of a growth cone with a new substrate resulted in a rapid and dramatic alteration in growth cone morphology. In some cases, the changes encompassed the entire growth cone including those regions not in direct contact with the new substrate. In addition, the growth cones displayed a variety of behavioral responses that were dependent upon the order of substrate contact. These studies demonstrate that growth cones are actively affected by the substrate, and suggest that abrupt changes in the molecular composition of the growth cone environment are influential during axonal pathfinding.


Preventive effect of baicalein on methamphetamine-induced amnesia in the passive avoidance test in mice.
Methamphetamine abuse may produce cognitive impairment. Baicalein, a bioactive flavonoid, has antioxidative, anti-inflammatory and neuroprotective effects. This study examined the effects of baicalein pretreatment on memory performance in the passive avoidance test after either one dose or an acute binge of methamphetamine in Institute of Cancer Research (ICR) mice. Methamphetamine was administered by intraperitoneal (i.p.) injection of either one dose (3 mg/kg) or an acute binge (3 mg/kg, 4 i.p. injections at 2-hour intervals). The effects of baicalein pretreatment (1 mg/kg, i.p.) on methamphetamine-induced changes of locomotor activity and memory performance were compared with those of eticlopride, a selective dopamine D2 receptor antagonist. The effects of baicalein on acute binge methamphetamine-induced oxidative stress (malondialdehyde- and nitrotyrosine-modified protein production) in the mouse hippocampus were also examined. One-dose methamphetamine treatment (i.p., 30 min before or immediately after the training trial) induced hyperlocomotion and amnesia in mice, which were blocked by eticlopride but not by baicalein pretreatment. The memory performance in mice was impaired 5 days after acute binge methamphetamine, which was significantly attenuated by baicalein but not by eticlopride pretreatment. Baicalein pretreatment also attenuated acute binge methamphetamine-induced oxidative stress in the mouse hippocampus. Baicalein exhibits antioxidative and neuroprotective effects in attenuating acute binge methamphetamine-induced memory deficits and oxidative hippocampal damage.


Induction of apoptosis and cell cycle arrest by a chalcone panduratin A isolated from Kaempferia pandurata in androgen-independent human prostate cancer cells PC3 and DU145.
Because of unsatisfactory treatment options for prostate cancer (CaP) there is a need to develop novel preventive approaches for this malignancy. One such strategy is through chemoprevention by the use of non-toxic dietary substances and botanical products. We have shown previously that panduratin A isolated from the extract of Kaempferia pandurata (Zingiberaceae) is a strong inhibitor of cyclooxygenase-2 in RAW264.7 cells and induces apoptosis in HT-29 cells. In the present study, we provide evidence that panduratin A treatment to androgen-independent human CaP cells PC3 and DU145 result in a time and dose-dependent inhibition of cell growth with an IC50 of 13.5-14 microM and no to little effect on normal human prostate epithelial cells. To define the mechanism of these anti-proliferative effects of panduratin A, we determined its effect on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Annexin V/propidium iodide staining provided the evidence for the induction of apoptosis which was further confirmed by the observation of cleavage of poly (ADP-ribose) polymerase and degradation of acinus. Panduratin A treatment to cells was found to result in inhibition of procaspases 9, 8, 6 and 3 with significant increase in the ratio of Bax:Bcl-2, suggesting the involvement of a mitochondrial-dependent apoptotic pathway. Panduratin A-mediated apoptosis was accompanied with upregulation of Fas death receptor and TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, cell cycle analysis using flow cytometry showed that panduratin A treatment of cells resulted in a G2/M arrest in a dose-dependent manner. The immunoblot analysis data revealed that in both cell lines panduratin A treatment resulted in a dose-dependent (i) induction of p21WAF1/Cip1 and p27Kip1, (ii) downregulation of cdks 2, 4 and 6 and (iii) decrease in cyclins D1 and E. These findings suggest that panduratin A may be an effective chemopreventive or therapeutic agent against CaP.


Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium.
Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals. Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment. The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.


The Health Promoting Bioactivities of Lactuca sativa can be Enhanced by Genetic Modulation of Plant Secondary Metabolites.
Plant secondary metabolites are protective dietary constituents and rol genes evidently increase the synthesis of these versatile phytochemicals. This study subjected a globally important vegetable, lettuce (Lactuca sativa) to a combination of untargeted metabolomics (LC-QTof-MS) and in vitro bioactivity assays. Specifically, we examined the differences between untransformed cultured lettuce (UnT), lettuce transformed with either rolABC (RA) or rolC (RC) and commercially grown (COM) lettuce. Of the 5333 metabolite features aligned, deconvoluted and quantified 3637, 1792 and 3737 significantly differed in RA, RC and COM, respectively, compared with UnT. In all cases the number of downregulated metabolites exceeded the number increased. In vitro bioactivity assays showed that RA and RC (but not COM) significantly improved the ability of L. sativa to inhibit α-glucosidase, inhibit dipeptidyl peptidase-4 (DPP-4) and stimulate GLP-1 secretion. We putatively identified 76 lettuce metabolites (sesquiterpene lactones, non-phenolic and phenolic compounds) some of which were altered by several thousand percent in RA and RC. Ferulic acid levels increased 3033-9777%, aminooxononanoic acid increased 1141-1803% and 2,3,5,4'tetrahydroxystilbene-2-O-β-d-glucoside increased 40,272-48,008%. Compound activities were confirmed using commercially obtained standards. In conclusion, rol gene transformation significantly alters the metabolome of L.sativa and enhances its antidiabetic properties. There is considerable potential to exploit rol genes to modulate secondary metabolite production for the development of novel functional foods. This investigation serves as a new paradigm whereby genetic manipulation, metabolomic analysis and bioactivity techniques can be combined to enable the discovery of novel natural bioactives and determine the functional significance of plant metabolites.


Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.
BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.


Attenuation of mild hyperandrogenic activity in postpubertal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,l-norgestrel.
The effect of a low dose triphasic oral contraceptive (OC) was evaluated during a 6-month treatment period in 41 patients (mean age, 25.4 +/- 0.7 yr) who had grade I-IV postpubertal acne and normal menses. The OC contained three dose levels of ethynyl estradiol and dl-norgestrel. Acne lesions were assessed, and serum androgen levels were measured during a control cycle and between days 17-21 of treatment cycles 1, 2, 3, and 6. Four patients dropped out after 3 months of treatment. Acne was significantly improved after the first OC cycle. After six cycles, the number of comedones had decreased by 79.6 +/- 3.2% (range, 50-100%) in 69.4% of the patients. Mean baseline levels of testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate were in the upper third of the normal range, with elevated individual values in 18.9%, 36.5%, and 26.8% of the women, respectively. Mean baseline levels of androstenedione, free testosterone (T), and 3 alpha-androstanediol glucuronide (3 alpha-diol-G) were above the normal range, with elevated individual values in 51.2%, 75.0%, and 85.4% of the patients, respectively. Sex hormone-binding globulin (SHBG) levels were below the normal range in 26.8% of the cases. At the end of the first OC cycle, there was a significant (P less than 0.01) decrease in all androgen precursors and a 2-fold increase in SHBG. Androstenedione and free T decreased into the normal range during OC intake. Serum 3 alpha-diol-G levels remained elevated, but had decreased by 34.5% at cycle 6 (P less than 0.05). These results show that the triphasic OC has significantly improved acne in postpubertal women for whom acne was the main manifestation of mild hyperandrogenic activity. The improvement in acne corresponded to a decrease in adrenal/ovarian androgens and free T, which led to a decreased metabolism to 3 alpha-diol-G, presumably by the sebaceous glands. The increase in SHBG is considered an estrogenic effect, and the triphasic formulation containing low dose dl-norgestrel is not androgenic but, rather, an estrogen-dominant formulation; as such, this product is recommended in women requiring contraception who also have idiopathic acne.


Chronic chlorpheniramine therapy: subsensitivity, drug metabolism, and compliance.
To investigate whether patients develop true subsensitivity to antihistamines during chronic therapy, we studied 14 adult subjects who received chlorpheniramine for 3-day and 3-week trials of therapy. Titrated skin tests to histamine and compound 48/80, chlorpheniramine blood levels (by HPLC), compliance, and side effects were monitored and compared during the two courses of therapy and their respective 72-hour washout periods. We found a significant correlation between chlorpheniramine blood levels and skin test suppression during both the 3-day and 3-week therapies. The 3-day chlorpheniramine therapy was more clinically effective (measured by skin test suppression corrected for serum chlorpheniramine concentration) than the 3-week therapy (P less than .01). Chlorpheniramine serum half-lives and 2-hour chlorpheniramine blood levels were not significantly different after the 3-day and 3-week trials. Compliance was significantly worse (P less than .01) during 3-week therapy. Medication side effects (particularly drowsiness) were frequently reported during both courses of therapy. We conclude that subsensitivity to chlorpheniramine does develop in adult patients receiving 3 weeks of therapy. This subsensitivity is not explained by changes in drug metabolism. In addition to subsensitivity, poor compliance may contribute to sub-therapeutic results during chronic antihistamine therapy. Side effects from antihistamines may also require individualization of therapy for certain patients.


Self-regenerating compliance and lubrication of polyacrylamide hydrogels.
Pristine hydrogel surfaces typically have low friction, which is controlled by composition, slip speeds, and immediate slip history. The stiffness of such samples is typically measured with bulk techniques, and is assumed to be homogeneous at the surface. While the surface properties of homogeneous hydrogel samples are generally controlled by composition, the surface also interfaces with the open bath, which distinguishes it from the bulk. In this work, we disrupt as-molded polyacrylamide surfaces with abrasive wear and connect the effects on the surface stiffness and lubrication to the wear events. At both the nanoscale and the microscale, quasistatic indentations reveal a stiffer surface by up to two times following wear events, even considering roughness. Longitudinal experiments with a series of wear episodes interposed with periods of re-equilibration show that increased stiffness is reversible: more compliant surfaces regenerate within 24 hours. The timescale suggests an osmotic swelling mechanism, and we postulate that abrasive wear removes a swollen surface layer, revealing the stiffer bulk. The newly-revealed bulk becomes the surface, which re-swells over time. We quantify the effects on the self-lubricating ability of these surfaces following abrasive wear using micro-tribometry. The lubrication curve shows that robust low friction is maintained, and that the friction becomes less dependent upon the sliding speed. The unique ability of these materials to regenerate swollen surfaces and maintain robust low friction following abrasive wear is promising for designing their slip behavior into aqueous soft robotics components or biomedicine applications.


Fabrication of resonant patterns using thermal nano-imprint lithography for thin-film photovoltaic applications.
A single-step, low-cost fabrication method to generate resonant nano-grating patterns on poly-methyl-methacrylate (PMMA; plexiglas) substrates using thermal nano-imprint lithography is reported. A guided-mode resonant structure is obtained by subsequent deposition of thin films of transparent conductive oxide and amorphous silicon on the imprinted area. Referenced to equivalent planar structures, around 25% and 45% integrated optical absorbance enhancement is observed over the 450-nm to 900-nm wavelength range in one- and two-dimensional patterned samples, respectively. The fabricated elements provided have 300-nm periods. Thermally imprinted thermoplastic substrates hold potential for low-cost fabrication of nano-patterned thin-film solar cells for efficient light management.


A retrospective analysis of oral cholera vaccine use, disease severity and deaths during an outbreak in South Sudan.
To determine whether pre-emptive oral cholera vaccination reduces disease severity and mortality in people who develop cholera disease during an outbreak. The study involved a retrospective analysis of demographic and clinical data from 41 cholera treatment facilities in South Sudan on patients who developed cholera disease between 23 April and 20 July 2014 during a large outbreak, a few months after a pre-emptive oral vaccination campaign. Patients who developed severe dehydration were regarded as having a severe cholera infection. Vaccinated and unvaccinated patients were compared and multivariate logistic regression analysis was used to identify factors associated with developing severe disease or death. In total, 4115 cholera patients were treated at the 41 facilities: 1946 (47.3%) had severe disease and 62 (1.5%) deaths occurred. Multivariate analysis showed that patients who received two doses of oral cholera vaccine were 4.5-fold less likely to develop severe disease than unvaccinated patients (adjusted odds ratio, aOR: 0.22; 95% confidence interval, CI: 0.11-0.44). Moreover, those with severe cholera were significantly more likely to die than those without (aOR: 4.76; 95% CI: 2.33-9.77). Pre-emptive vaccination with two doses of oral cholera vaccine was associated with a significant reduction in the likelihood of developing severe cholera disease during an outbreak in South Sudan. Moreover, severe disease was the strongest predictor of death. Two doses of oral cholera vaccine should be used in emergencies to reduce the disease burden.


White Paper: Movement System Diagnoses in Neurologic Physical Therapy.
The APTA recently established a vision for physical therapists to transform society by optimizing movement to promote health and wellness, mitigate impairments, and prevent disability. An important element of this vision entails the integration of the movement system into the profession, and necessitates the development of movement system diagnoses by physical therapists. At this point in time, the profession as a whole has not agreed upon diagnostic classifications or guidelines to assist in developing movement system diagnoses that will consistently capture an individual's movement problems. We propose that, going forward, diagnostic classifications of movement system problems need to be developed, tested, and validated. The Academy of Neurologic Physical Therapy's Movement System Task Force was convened to address these issues with respect to management of movement system problems in patients with neurologic conditions. The purpose of this article is to report on the work and recommendations of the Task Force. The Task Force identified 4 essential elements necessary to develop and implement movement system diagnoses for patients with primarily neurologic involvement from existing movement system classifications. The Task Force considered the potential impact of using movement system diagnoses on clinical practice, education and, research. Recommendations were developed and provided recommendations for potential next steps to broaden this discussion and foster the development of movement system diagnostic classifications. The Task Force proposes that diagnostic classifications of movement system problems need to be developed, tested, and validated with the long-range goal to reach consensus on and adoption of a movement system diagnostic framework for clients with neurologic injury or disease states.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A198).


Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.
Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic or pharmacological blockade of Src preserves endothelial cell barrier function, suppressing VP and infarct volume, providing long-term improvement in cardiac function, fibrosis, and survival. To our surprise, an intravascular injection of VEGF into healthy animals, but not those deficient in Src, induced similar endothelial gaps, VP, platelet plugs, and some myocyte damage. Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection. Blockade of Src prevents disassociation of this complex with the same kinetics with which it prevents VEGF-mediated VP/edema. These findings define a molecular mechanism to account for the Src requirement in VEGF-mediated permeability and provide a basis for Src inhibition as a therapeutic option for patients with acute MI.


Incidence and Risk Factors for Gadolinium-Based Contrast Agent Immediate Reactions.
Since their clinical introduction in 1988, gadolinium-based contrast agents (GBCAs) have demonstrated an excellent safety profile with a reported acute adverse reaction rate ranging from 0.01% to 2%. By comparison, the acute adverse reaction rate of low osmolar nonionic computed tomography contrast agents (CTCs) ranges from 0.7% to 3.1%. Many of the risk factors associated with CTC reactions (drug allergies, asthma, atopy, prior contrast reaction) also point toward an increased incidence of acute adverse events to GBCAs. With CTCs, an increased adverse event rate was associated with ionic preparations and high osmolality. In response to concerns for nephrogenic systemic fibrosis, GBCAs are now selected for their augmented chemical stability. These agents possess some combination of macrocyclic chelates or ionic preparations. With their improved chemical stability, these agents also possess higher osmolality and the increased potential to elicit an acute adverse reaction. In light of these concerns, researchers are now focusing greater efforts on reexamining acute adverse reactions to GBCAs and whether there is an increased association with certain agents. In addition to hypersensitivity reactions, this article will also discuss contrast extravasations, safety of GBCAs for pregnant and nursing patients, and the potential nephrotoxic effects of GBCAs.


Nutritional rickets still afflict children in north Texas.
Nutritional rickets is uncommon in North America, particularly in regions where sunlight is plentiful. Recent epidemics in North America occurred in dark-skinned toddlers with poor nutrition who had insufficient exposure to sunlight and whose parents were members of ethnic, social, and socioeconomic groups with predisposing practices. Nine children (8 toddlers and 1 infant) were referred to the Bone Metabolic Clinic at Texas Scottish Rite Hospital for suspected rickets between October 1997 and October 1998. The diagnosis of nutritional rickets was based on clinical, biochemical, and radiological evidence. All children were dark-skinned: 8 were African Americans and 1 was of Hispanic parentage. All children were breast-fed with minimal intake of dairy products; none received vitamin supplementation. All children were followed up by health care professionals. Two patients were children of upper-middle class parents. Birth order was not a contributing factor in the development of nutritional rickets. Radiological and biochemical rachitic changes remitted within 3 months of vitamin D therapy combined with dietary modification. Primary care providers should consider vitamin D supplementation in all infants with increased skin pigmentation and especially in those who are primarily breast-fed. Nutritional rickets can develop in dark-skinned infants of any social or ethnic background. Residing in a geographical area with abundant sunlight is not a guarantee against the development of nutritional rickets in dark-skinned children.


Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.


A communitywide perspective of sex differences and temporal trends in the incidence and survival rates after acute myocardial infarction and out-of-hospital deaths caused by coronary heart disease.
The purpose of the study was to examine overall differences and temporal trends therein between men and women regarding the incidence rates, in-hospital and long-term survival after initial acute myocardial infarction (AMI), and out-of-hospital deaths caused by coronary disease. This nonconcurrent prospective study was carried out in 16 teaching and community hospitals in Worcester, Mass., in six time periods between 1975 and 1988. A total of 3,148 patients hospitalized with validated initial AMI comprised the study sample. The age-adjusted incidence rates of initial AMI increased between 1975 and 1981 in the two sexes, with a marked decrease thereafter; these rates declined by 26% in men and by 22% in women between 1975 and 1988. The overall unadjusted in-hospital case-fatality rates after initial AMI were significantly higher in women (21.7%) than in men (12.7%). Age- and multivariable-adjusted in-hospital case-fatality rates, however, were not significantly different for men compared with women (multivariate-adjusted OR, 0.90; 95% CI, 0.70, 1.16). No clear trends in in-hospital case-fatality rates were observed in men or women over the periods under study. There were no significant sex differences in the age-adjusted long-term survival rates of discharged hospital survivors of AMI. The multivariate-adjusted risk of total mortality among discharged hospital survivors, however, was significantly increased in men (multivariate-adjusted OR, 1.20; 95% CI, 1.03, 1.39); neither of the sexes experienced an improvement over time in long-term prognosis. The incidence rates of out-of-hospital deaths caused by coronary disease declined by 60% in men and 69% in women between 1975 and 1988. The results of this multihospital, community-based study suggest declines in the incidence rates of AMI and out-of-hospital deaths caused by coronary disease in men and women over the period under study (1975-1988). No significant sex differences in in-hospital survival were observed, whereas a poorer long-term survival experience after hospital discharge was observed for men compared with women after controlling for potentially confounding prognostic factors.


Is there a future for clinical ethics services in Australia?
Clinical ethics refers to the consideration of ethical issues arising directly in the context of patient care. Health professionals are generally adept at effectively and sensitively managing ethical issues in clinical care. However, in some settings, multidisciplinary clinical ethics services may enhance clinical practice by assisting clinicians, patients and others to identify, understand and manage ethical issues. Clinical ethics services may be particularly valuable for situations in which moral perspectives diverge or communication has deteriorated. Such services may facilitate discussion and help the parties find mutually satisfactory solutions. Clinical ethics services may take various forms, including clinical ethics committees, ethics consultants, patient advocates or other mechanisms for responding to complaints and grievances. There is considerable disagreement about key aspects of clinical ethics services, including who should conduct them, how they should be run and what role they should play in decision-making.


Clinical, radiological, and pathological features in 43 cases of intracranial subependymoma.
Intracranial subependymomas are rarely reported due to their extremely low incidence. Knowledge about subependymomas is therefore poor. This study aimed to analyze the incidence and clinical, radiological, and pathological features of intracranial subependymomas. Approximately 60,000 intracranial tumors were surgically treated at Beijing Tiantan Hospital between 2003 and 2013. The authors identified all cases in which patients underwent resection of an intracranial tumor that was found to be pathological examination demonstrated to be subependymoma and analyzed the data from these cases. Forty-three cases of pathologically confirmed, surgically treated intracranial subependymoma were identified. Thus in this patient population, subependymomas accounted for approximately 0.07% of intracranial tumors (43 of an estimated 60,000). Radiologically, 79.1% (34/43) of intracranial subependymomas were misdiagnosed as other diseases. Pathologically, 34 were confirmed as pure subependymomas, 8 were mixed with ependymoma, and 1 was mixed with astrocytoma. Thirty-five patients were followed up for 3.0 to 120 months after surgery. Three of these patients experienced tumor recurrence, and one died of tumor recurrence. Univariate analysis revealed that shorter progression-free survival (PFS) was significantly associated with poorly defined borders. The association between shorter PFS and age < 14 years was almost significant (p = 0.51), and this variable was also included in the multivariate analysis. However, multivariate analysis showed showed only poorly defined borders to be an independent prognostic factor for shorter PFS (RR 18.655, 95% CI 1.141-304.884, p = 0.040). In patients 14 years of age or older, the lesions tended to be pure subependymomas located in the unilateral supratentorial area, total removal tended to be easier, and PFS tended to be longer. In comparison, in younger patients subependymomas tended to be mixed tumors involving the bilateral infratentorial area, with a lower total removal rate and shorter PFS. Intracranial subependymoma is a rare benign intracranial tumor with definite radiological features. Long-term survival can be expected, although poorly defined borders are an independent predictor of shorter PFS. All the features that differ between tumors in younger and older patients suggest that they might have different origins, biological behaviors, and prognoses.


XR5944: A potent inhibitor of estrogen receptors.
The anticancer drug XR5944 was originally developed as a topoisomerase inhibitor and was subsequently shown to be a transcription inhibitor. It has shown exceptional anticancer activity both in vitro and in vivo and was significantly more potent than traditional topoisomerase inhibitors. The solution structure of the XR5944/DNA complex recently obtained in our laboratory indicates that XR5944 bis-intercalates at the 5'-(TpG):(CpA) site of duplex DNA, which is found in the consensus DNA-binding site of estrogen receptor (ER). Thus, we tested the ability of XR5944 to inhibit ER activity both in vitro and in cultured cells. In electrophoretic mobility shift assays, it is seen that the DNA binding of recombinant ERalpha protein, as well as ER from nuclear extracts, is inhibited by XR5944 in a dose-dependent manner. In luciferase reporter assays, XR5944 inhibited the reporter gene expression from an estrogen response element-containing promoter but not from a basal promoter sequence that lacks any cis-acting elements. In contrast, the RNA polymerase inhibitor actinomycin D inhibits the transcription from both the above-mentioned promoters. The specificity of XR5944 activity is displayed by a separate reporter assay in which the transactivation of reporter gene expression by Sp1 proteins was not inhibited by XR5944. Collectively, these data suggest that XR5944 is capable of specifically inhibiting the binding of ER to its consensus DNA sequence and its subsequent activity. This represents a novel mechanism of ER inhibition, which may allow the development of agents capable of overcoming resistance to current antiestrogens.


High-Conductance Channel Formation in Yeast Mitochondria is Mediated by F-ATP Synthase e and g Subunits.
The permeability transition pore (PTP) is an unselective, Ca2+-dependent high conductance channel of the inner mitochondrial membrane whose molecular identity has long remained a mystery. The most recent hypothesis is that pore formation involves the F-ATP synthase, which consistently generates Ca2+-activated channels. Available structures do not display obvious features that can accommodate a channel; thus, how the pore can form and whether its activity can be entirely assigned to F-ATP synthase is the matter of debate. In this study, we investigated the role of F-ATP synthase subunits e, g and b in PTP formation. Yeast null mutants for e, g and the first transmembrane (TM) α-helix of subunit b were generated and evaluated for mitochondrial morphology (electron microscopy), membrane potential (Rhodamine123 fluorescence) and respiration (Clark electrode). Homoplasmic C23S mutant of subunit a was generated by in vitro mutagenesis followed by biolistic transformation. F-ATP synthase assembly was evaluated by BN-PAGE analysis. Cu2+ treatment was used to induce the formation of F-ATP synthase dimers in the absence of e and g subunits. The electrophysiological properties of F-ATP synthase were assessed in planar lipid bilayers. Null mutants for the subunits e and g display dimer formation upon Cu2+ treatment and show PTP-dependent mitochondrial Ca2+ release but not swelling. Cu2+ treatment causes formation of disulfide bridges between Cys23 of subunits a that stabilize dimers in absence of e and g subunits and favors the open state of wild-type F-ATP synthase channels. Absence of e and g subunits decreases conductance of the F-ATP synthase channel about tenfold. Ablation of the first TM of subunit b, which creates a distinct lateral domain with e and g, further affected channel activity. F-ATP synthase e, g and b subunits create a domain within the membrane that is critical for the generation of the high-conductance channel, thus is a prime candidate for PTP formation. Subunits e and g are only present in eukaryotes and may have evolved to confer this novel function to F-ATP synthase.


A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice.
The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.


Intermittent dynamics of bubble dissolution due to interfacial growth of fat crystals.
Foams are inherently unstable objects, that age and disappear over time. The main cause of foam aging is Ostwald ripening: smaller air bubbles within the foam empty their gas content into larger ones. One strategy to counter Ostwald ripening consists in creating armored bubbles, where solid particles adsorbed at the air/liquid interface prevent bubbles from shrinking below a given size. Here, we study the efficiency of coating air bubbles with fat crystals to prevent bubble dissolution. A monoglyceride, monostearin, is directly crystallized at the air/oil interface. Experiments on single bubbles in a microfluidic device show that the presence of monostearin fat crystals slows down dissolution, with an efficiency that depends on the crystal size. Bubble ripening in the presence of crystals exhibits intermittent dissolution dynamics, with phases of arrest, when crystals jam at the interface, followed by phases of dissolution, when monostearin crystals are ejected from the interface. In the end, crystals do not confer enough mechanical strength to the bubbles to prevent them from fully dissolving.


Does subclinical pancreatic inflammation occur after parathyroidectomy?
Pancreatitis is accepted as an uncommon complication of parathyroid surgery, but it has been suggested that up to 35% of patients may experience hyperamylasaemia after parathyroidectomy indicating subclinical inflammation of the pancreas. A series of 26 patients undergoing parathyroidectomy were studied by preoperative biochemical analyses repeated 24 and 48 h postoperatively allowing changes in calcium metabolism and serum and urinary amylase levels to be documented. Of the patients, 21 also underwent a CT scan of the pancreas between 24 and 48 h after operation. Despite highly significant changes in serum parathormone, calcium and phosphate levels postoperatively, there was no evidence in any patient of acute pancreatic inflammation or hyperamylasaemia. Twenty-one patients underwent unilateral neck exploration, and we suggest that the absence of any detectable amylase elevation supports the suggestion that such elevation may reflect an increase in salivary isoamylase as a result of extensive neck dissection, rather than reflecting a subclinical pancreatitis. The development of postparathyroidectomy pancreatitis appears to be an all or nothing phenomenon of unknown aetiology.


Spouses' Perspective of their Participation and Role in Childbirth Pain Relief.
Childbirth is a period characterized by severe pain, and most women desire to ameliorate their pain among other things by having their spouses present and involved in the birthing process. In developing countries like Nigeria, spousal involvement is still an emerging concept in childbirth. To investigate and provide an insight into spousal perceptions toward their participation and role in labor pain relief during childbirth in Nigeria. A cross-sectional descriptive study of 142 spouses was conducted in the maternity units of four hospitals in Abuja, Nigeria, from June to December 2014. Data were collected through a pretested interview-administered 24 item questionnaire, the Abuja Instrument for Parturient Spouse. The data were analyzed statistically using Chi-square test for association between the variables and content analysis for open-ended questions. Most (94.4%, 134/142) of the spouses had a positive perception toward labor pain relief. They believed that their presence and activities contributed to labor pain relief and are willing to be present at subsequent births. Findings in this study have revealed a positive trend in spousal perception and involvement during childbirth and pain relief, as contrast to the prevailing assumption that childbirth is an exclusive woman affair. Spousal presence during childbirth can be beneficial not only to the woman but also to the spouse and family.


Selective Trapping of DNA Using Glass Microcapillaries.
We show experimentally that an inexpensive glass microcapillary can accumulate λ-phage DNA at its tip and deliver the DNA into the capillary using a combination of electro-osmotic flow, pressure-driven flow, and electrophoresis. We develop an efficient simulation model based on the electrokinetic equations and the finite-element method to explain this phenomenon. As a proof of concept for the generality of this trapping mechanism we use our numerical model to explore the effect of the salt concentration, the capillary surface charge, the applied voltage, the pressure difference, and the mobility of the analyte molecules. Our results indicate that the simple microcapillary system has the potential to capture a wide range of analyte molecules based on their electrophoretic mobility that extends well beyond our experimental example of λ-phage DNA. Our method for separation and preconcentration of analytes therefore has implications for the development of low-cost lab-on-a-chip devices.


Quantum communication with zero-capacity channels.
Communication over a noisy quantum channel introduces errors in the transmission that must be corrected. A fundamental bound on quantum error correction is the quantum capacity, which quantifies the amount of quantum data that can be protected. We show theoretically that two quantum channels, each with a transmission capacity of zero, can have a nonzero capacity when used together. This unveils a rich structure in the theory of quantum communications, implying that the quantum capacity does not completely specify a channel's ability to transmit quantum information.


Serum itraconazole and hydroxyitraconazole concentrations and interaction with digoxin in a case of chronic hypertrophic pachymenigitis caused by Aspergillus flavus.
A patient treated with itraconazole (ITCZ) under the diagnosis of Aspergillus flavus-induced chronic hypertrophic pachymeningitis is presented. The reason for the successful cure of this patient was investigated by the pharmacokinetic analysis of serum levels of ITCZ. Concurrently administered digoxin was also investigated for its drug-drug interaction. The patient (a 75-year-old male) developed ophthalmopathy, and was diagnosed as having A. flavus hypertrophic pachymeningitis by pachymeninx biopsy. After admission, he was treated with FLCZ, AMPH, 5-FC and MCZ. The infection tended to subside with the AMPH administration. Since renal insufficiency was induced by AMPH and the other antifungal drugs were ineffective, daily administration of 200 mg of ITCZ was initiated, and the inflammatory signs and symptoms gradually subsided. The symptoms did not recur during the 36 months of itraconazole treatment after discharge, and it was concluded that ITCZ was effective for A. flavus hypertrophic pachymeningitis. Pharmacokinetic parameters of ITCZ and OH-ITCZ as follows: ITCZ: Cmax 93.2 ng/ml, T1/2 beta 11 hours, AUC0-24 999 ng.h/ml, OH-ITCZ: Cmax 159.4 ng/ml, T1/2 beta 16. 2 hours, AUC0-24 of 1391 ng.h/ml. Both ITCZ and OH-ITCZ reached steady states seven days after administration began. The ITCZ and OH-ITCZ levels in serum collected 36 months after the initiation of administration were 452.9 ng/ml and 1233.6 ng/ml, respectively. Cmax and AUC0-24 of ITCZ and OH-ITCZ on the second day were markedly lower than those in healthy adults reported by Oguchi et al., and hypoalbuminemia observed at administration on that day was considered the most probable cause. It was assumed that the most plausible reason for a successful cure even at a low dose of ITCZ was the increase of distribution to tissue by the increase of the unbound form. Digoxin was concurrently given to this patient at 0. 125 mg/day, but the blood digoxin level was not elevated. Consideration of the blood level of albumin is believed to be important for evaluating the blood concentration of ITCZ.


Challenging Operations: An Ethical Framework to Assist Humanitarian Aid Workers in their Decision-making Processes.
This paper aims to raise awareness regarding ethical issues in the context of humanitarian action, and to offer a framework for systematically and effectively addressing such issues. Several cases highlight ethical issues that humanitarian aid workers are confronted with at different levels over the course of their deployments. The first case discusses a situation at a macro-level concerning decisions being made at the headquarters of a humanitarian organization. The second case looks at meso-level issues that need to be solved at a country or regional level. The third case proposes an ethical dilemma at the micro-level of the individual patient-provider relationship. These real-life cases have been selected to illustrate the ethical dimension of conflicts within the context of humanitarian action that might remain unrecognized in everyday practice. In addition, we propose an ethical framework to assist humanitarian aid workers in their decision-making process. The framework draws on the principles and values that guide humanitarian action and public health ethics more generally. Beyond identifying substantive core values, the framework also includes a ten-step process modelled on tools used in the clinical setting that promotes a transparent and clear decision-making process and improves the monitoring and evaluation of aid interventions. Finally, we recommend organizational measures to implement the framework effectively. This paper uses a combination of public health/clinical ethics concepts and practices and applies them to the decision-making challenges encountered in relief operations in the humanitarian aid context.


Efficiency Fluctuations in Microscopic Machines.
Nanoscale machines are strongly influenced by thermal fluctuations, contrary to their macroscopic counterparts. As a consequence, even the efficiency of such microscopic machines becomes a fluctuating random variable. Using geometric properties and the fluctuation theorem for the total entropy production, a "universal theory of efficiency fluctuations" at long times, for machines with a finite state space, was developed by Verley et al. [Nat. Commun. 5, 4721 (2014)NCAOBW2041-172310.1038/ncomms5721; Phys. Rev. E 90, 052145 (2014)PRESCM1539-375510.1103/PhysRevE.90.052145]. We extend this theory to machines with an arbitrary state space. Thereby, we work out more detailed prerequisites for the "universal features" and explain under which circumstances deviations can occur. We also illustrate our findings with exact results for two nontrivial models of colloidal engines.


Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans.
Potential toxic effects of prolonged NO2 exposure below the current threshold limit value (TLV) were examined in 14 healthy, nonsmoking adults. The subjects were exposed to 2.3 ppm NO2 and to clean air for 5 h with a 1-wk interval between exposures. Physiologic and biochemical measurements were obtained during the exposures and until 24 h after. A 14% decrease in serum glutathione peroxidase activity (GSH-Px) was observed 24 h after the start of the NO2 exposure, while indications of a 22% decrease in alveolar permeability were found 11 h after the start. There were no indications of mucous membrane irritation or of decreased lung function during or after NO2 exposures. The results support the assumption that a delayed response is a feature of the human reaction to NO2 even below the current TLV of 3 ppm, and they stress the importance of an extended period of observation in future NO2 exposure studies.


Effect of lower sodium intake on health: systematic review and meta-analyses.
To assess the effect of decreased sodium intake on blood pressure, related cardiovascular diseases, and potential adverse effects such as changes in blood lipids, catecholamine levels, and renal function. Systematic review and meta-analysis. Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, the Latin American and Caribbean health science literature database, and the reference lists of previous reviews. Randomised controlled trials and prospective cohort studies in non-acutely ill adults and children assessing the relations between sodium intake and blood pressure, renal function, blood lipids, and catecholamine levels, and in non-acutely ill adults all cause mortality, cardiovascular disease, stroke, and coronary heart disease. Potential studies were screened independently and in duplicate and study characteristics and outcomes extracted. When possible we conducted a meta-analysis to estimate the effect of lower sodium intake using the inverse variance method and a random effects model. We present results as mean differences or risk ratios, with 95% confidence intervals. We included 14 cohort studies and five randomised controlled trials reporting all cause mortality, cardiovascular disease, stroke, or coronary heart disease; and 37 randomised controlled trials measuring blood pressure, renal function, blood lipids, and catecholamine levels in adults. Nine controlled trials and one cohort study in children reporting on blood pressure were also included. In adults a reduction in sodium intake significantly reduced resting systolic blood pressure by 3.39 mm Hg (95% confidence interval 2.46 to 4.31) and resting diastolic blood pressure by 1.54 mm Hg (0.98 to 2.11). When sodium intake was <2 g/day versus ≥ 2 g/day, systolic blood pressure was reduced by 3.47 mm Hg (0.76 to 6.18) and diastolic blood pressure by 1.81 mm Hg (0.54 to 3.08). Decreased sodium intake had no significant adverse effect on blood lipids, catecholamine levels, or renal function in adults (P>0.05). There were insufficient randomised controlled trials to assess the effects of reduced sodium intake on mortality and morbidity. The associations in cohort studies between sodium intake and all cause mortality, incident fatal and non-fatal cardiovascular disease, and coronary heart disease were non-significant (P>0.05). Increased sodium intake was associated with an increased risk of stroke (risk ratio 1.24, 95% confidence interval 1.08 to 1.43), stroke mortality (1.63, 1.27 to 2.10), and coronary heart disease mortality (1.32, 1.13 to 1.53). In children, a reduction in sodium intake significantly reduced systolic blood pressure by 0.84 mm Hg (0.25 to 1.43) and diastolic blood pressure by 0.87 mm Hg (0.14 to 1.60). High quality evidence in non-acutely ill adults shows that reduced sodium intake reduces blood pressure and has no adverse effect on blood lipids, catecholamine levels, or renal function, and moderate quality evidence in children shows that a reduction in sodium intake reduces blood pressure. Lower sodium intake is also associated with a reduced risk of stroke and fatal coronary heart disease in adults. The totality of evidence suggests that most people will likely benefit from reducing sodium intake.


Antioxidant Properties of Artemisia annua Extracts in Model Food Emulsions.
Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin. Although artemisinin is a major bioactive component present in this Chinese herb, leaf flavonoids have shown a variety of biological activities. The polyphenolic profile of extract from leaves of A. annua was assessed as a source of natural antioxidants. Total phenolic content and total flavonoid content were established and three assays were used to measure the antioxidant capacity of the plant extract. The measurement of scavenging capacity against the 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation, the oxygen radical absorbance capacity (ORAC) and the ferric reducing antioxidant power (FRAP) were 314.99 µM Trolox equivalents (TE)/g DW, 736.26 µM TE/g DW and 212.18 µM TE/g DW, respectively. A. annua extracts also showed good antioxidant properties in 10% sunflower oil-in-water emulsions during prolonged storage (45 days) at 32 °C. Artemisia extract at 2 g/L was as effective as butylated hydroxyanisole (BHA) at 0.02 g/L in slowing down the formation of hydroperoxides as measured by peroxide value and thiobarbituric acid reactive substances. The results of this study indicate that extract of A. annua may be suitable for use in the food matrix as substitutes for synthetic antioxidants.


Flagellated ectosymbiotic bacteria propel a eucaryotic cell.
A devescovinid flagellate from termites exhibits rapid gliding movements only when in close contact with other cells or with a substrate. Locomotion is powered not by the cell's own flagella nor by its remarkable rotary axostyle, but by the flagella of thousands of rod bacteria which live on its surface. That the ectosymbiotic bacteria actually propel the protozoan was shown by the following: (a) the bacteria, which lie in specialized pockets of the host membrane, bear typical procaryotic flagella on their exposed surface; (b) gliding continues when the devescovinid's own flagella and rotary axostyle are inactivated; (c) agents which inhibit bacterial flagellar motility, but not the protozoan's motile systems, stop gliding movements; (d) isolated vesicles derived from the surface of the devescovinid rotate at speeds dependent on the number of rod bacteria still attached; (e) individual rod bacteria can move independently over the surface of compressed cells; and (f) wave propagation by the flagellar bundles of the ectosymbiotic bacteria is visualized directly by video-enhanced polarization microscopy. Proximity to solid boundaries may be required to align the flagellar bundles of adjacent bacteria in the same direction, and/or to increase their propulsive efficiency (wall effect). This motility-linked symbiosis resembles the association of locomotory spirochetes with the Australian termite flagellate Mixotricha (Cleveland, L. R., and A. V. Grimstone, 1964, Proc. R. Soc. Lond. B Biol. Sci., 159:668-686), except that in our case propulsion is provided by bacterial flagella themselves. Since bacterial flagella rotate, an additional novelty of this system is that the surface bearing the procaryotic rotary motors is turned by the eucaryotic rotary motor within.


The effects of repeated thermal therapy for two patients with chronic fatigue syndrome.
This paper describes the successful treatment of two patients with chronic fatigue syndrome (CFS) using repeated thermal therapy. Two patients with CFS underwent treatment with prednisolone (PSL), with no satisfactory effect. They were subjected to thermal therapy that consisted of a far-infrared ray dry sauna at 60 degrees C and postsauna warming. The therapy was performed once a day, for a total of 35 sessions. After discharge, these subjects continued the therapy once or twice a week on an outpatient basis for 1 year. Symptoms such as fatigue, pain, sleep disturbance, and low-grade fever were dramatically improved after 15 to 25 sessions of thermal therapy. Although PSL administration was discontinued, the subjects showed no relapse or exacerbation of symptoms during the first year after discharge. The patients became socially rehabilitated 6 months after discharge. These results suggest that repeated thermal therapy might be a promising method for the treatment of CFS.


Experience-dependent long-term facilitation of skew adaptation.
Adaptation to changes in the environment allows the visual system to achieve optimal perception in a continuously changing visual world. One particular example regarding recurrently encountered changes in everyday vision is geometrical distortions of the environment when wearing spectacles for vision correction, e.g., image shear by skew geometric distortions in progressive additional lenses. For optimal visual performance, it would be beneficial if the visual system uses previous history of recurrent distortions and learns to adapt fast when they are reapplied, yet this has not been systematically shown. The present study evaluates experience-dependent long-term facilitation of fast adaptation to image skew, i.e., a shear from the x- and y- axis, using ecological stimuli. Immediate and long-term facilitation of fast adaptation induced by minutes time scales of extended skew exposures was tested. Fast adaptation was quantified via the magnitude of perceptual bias after a brief exposure to image skew in a constant stimulus procedure. Immediate facilitation was tested by comparing the magnitudes of fast adaptation that are measured on the same day before, i.e., baseline, and after extended skew exposure. The retention of the facilitation was evaluated by comparing the fast adaptation measured after, on average, 57 days of the previous extended skew exposure with the baseline. After one hour of skew exposure, the amount of fast adaptation significantly increased from the baseline measurement indicating immediate facilitation of the fast adaptation. This facilitation was retained at, on average, 57 days after the extended exposure. Thus, the results depicted experience dependent long-term facilitation of skew adaptation that potentially explains visual habituation to distortions of spectacles.


Multi-Toxin Resistance Enables Pink Bollworm Survival on Pyramided Bt Cotton.
Transgenic crops producing Bacillus thuringiensis (Bt) proteins kill key insect pests, providing economic and environmental benefits. However, the evolution of pest resistance threatens the continued success of such Bt crops. To delay or counter resistance, transgenic plant "pyramids" producing two or more Bt proteins that kill the same pest have been adopted extensively. Field populations of the pink bollworm (Pectinophora gossypiella) in the United States have remained susceptible to Bt toxins Cry1Ac and Cry2Ab, but field-evolved practical resistance to Bt cotton producing Cry1Ac has occurred widely in India. Here we used two rounds of laboratory selection to achieve 18,000- to 150,000-fold resistance to Cry2Ab in pink bollworm. Inheritance of resistance to Cry2Ab was recessive, autosomal, conferred primarily by one locus, and independent of Cry1Ac resistance. We created a strain with high resistance to both toxins by crossing the Cry2Ab-resistant strain with a Cry1Ac-resistant strain, followed by one selection with Cry2Ab. This multi-toxin resistant strain survived on field-collected Bt cotton bolls producing both toxins. The results here demonstrate the risk of evolution of resistance to pyramided Bt plants, particularly when toxins are deployed sequentially and refuges are scarce, as seen with Bt cotton and pink bollworm in India.


Gas/solid carbon branching ratios in surface-mediated reactions and the incorporation of carbonaceous material into planetesimals.
We report the ratio of the initial carbon available as CO that forms gas-phase compounds compared to the fraction that deposits as a carbonaceous solid (the gas/solid branching ratio) as a function of time and temperature for iron, magnetite, and amorphous iron silicate smoke catalysts during surface-mediated reactions in an excess of hydrogen and in the presence of N2. This fraction varies from more than 99% for an amorphous iron silicate smoke at 673 K to less than 40% for a magnetite catalyst at 873 K. The CO not converted into solids primarily forms methane, ethane, water, and CO2, as well as a very wide range of organic molecules at very low concentration. Carbon deposits do not form continuous coatings on the catalytic surfaces, but instead form extremely high surface area per unit volume "filamentous" structures. While these structures will likely form more slowly but over much longer times in protostellar nebulae than in our experiments due to the much lower partial pressure of CO, such fluffy coatings on the surfaces of chondrules or calcium aluminum inclusions could promote grain-grain sticking during low-velocity collisions.


Large heterogeneities in comet 67P as revealed by active pits from sinkhole collapse.
Pits have been observed on many cometary nuclei mapped by spacecraft. It has been argued that cometary pits are a signature of endogenic activity, rather than impact craters such as those on planetary and asteroid surfaces. Impact experiments and models cannot reproduce the shapes of most of the observed cometary pits, and the predicted collision rates imply that few of the pits are related to impacts. Alternative mechanisms like explosive activity have been suggested, but the driving process remains unknown. Here we report that pits on comet 67P/Churyumov-Gerasimenko are active, and probably created by a sinkhole process, possibly accompanied by outbursts. We argue that after formation, pits expand slowly in diameter, owing to sublimation-driven retreat of the walls. Therefore, pits characterize how eroded the surface is: a fresh cometary surface will have a ragged structure with many pits, while an evolved surface will look smoother. The size and spatial distribution of pits imply that large heterogeneities exist in the physical, structural or compositional properties of the first few hundred metres below the current nucleus surface.


Leucine 41 is a gate for water entry in the reduction of Clostridium pasteurianum rubredoxin.
Biological electron transfer is an efficient process even though the distances between the redox moieties are often quite large. It is therefore of great interest to gain an understanding of the physical basis of the rates and driving forces of these reactions. The structural relaxation of the protein that occurs upon change in redox state gives rise to the reorganizational energy, which is important in the rates and the driving forces of the proteins involved. To determine the structural relaxation in a redox protein, we have developed methods to hold a redox protein in its final oxidation state during crystallization while maintaining the same pH and salt conditions of the crystallization of the protein in its initial oxidation state. Based on 1.5 A resolution crystal structures and molecular dynamics simulations of oxidized and reduced rubredoxins (Rd) from Clostridium pasteurianum (Cp), the structural rearrangements upon reduction suggest specific mechanisms by which electron transfer reactions of rubredoxin should be facilitated. First, expansion of the [Fe-S] cluster and concomitant contraction of the NH...S hydrogen bonds lead to greater electrostatic stabilization of the extra negative charge. Second, a gating mechanism caused by the conformational change of Leucine 41, a nonpolar side chain, allows transient penetration of water molecules, which greatly increases the polarity of the redox site environment and also provides a source of protons. Our method of producing crystals of Cp Rd from a reducing solution leads to a distribution of water molecules not observed in the crystal structure of the reduced Rd from Pyrococcus furiosus. How general this correlation is among redox proteins must be determined in future work. The combination of our high-resolution crystal structures and molecular dynamics simulations provides a molecular picture of the structural rearrangement that occurs upon reduction in Cp rubredoxin.


Weight science: evaluating the evidence for a paradigm shift.
Current guidelines recommend that "overweight" and "obese" individuals lose weight through engaging in lifestyle modification involving diet, exercise and other behavior change. This approach reliably induces short term weight loss, but the majority of individuals are unable to maintain weight loss over the long term and do not achieve the putative benefits of improved morbidity and mortality. Concern has arisen that this weight focus is not only ineffective at producing thinner, healthier bodies, but may also have unintended consequences, contributing to food and body preoccupation, repeated cycles of weight loss and regain, distraction from other personal health goals and wider health determinants, reduced self-esteem, eating disorders, other health decrement, and weight stigmatization and discrimination. This concern has drawn increased attention to the ethical implications of recommending treatment that may be ineffective or damaging. A growing trans-disciplinary movement called Health at Every Size (HAES) challenges the value of promoting weight loss and dieting behavior and argues for a shift in focus to weight-neutral outcomes. Randomized controlled clinical trials indicate that a HAES approach is associated with statistically and clinically relevant improvements in physiological measures (e.g., blood pressure, blood lipids), health behaviors (e.g., eating and activity habits, dietary quality), and psychosocial outcomes (such as self-esteem and body image), and that HAES achieves these health outcomes more successfully than weight loss treatment and without the contraindications associated with a weight focus. This paper evaluates the evidence and rationale that justifies shifting the health care paradigm from a conventional weight focus to HAES.


Cerebellar Contributions to the Basal Ganglia Influence Motor Coordination, Reward Processing, and Movement Vigor.
Both the cerebellum and the basal ganglia are known for their roles in motor control and motivated behavior. These two systems have been classically considered as independent structures that coordinate their contributions to behavior via separate cortico-thalamic loops. However, recent evidence demonstrates the presence of a rich set of direct connections between these two regions. Although there is strong evidence for connections in both directions, for brevity we limit our discussion to the better-characterized connections from the cerebellum to the basal ganglia. We review two sets of such connections: disynaptic projections through the thalamus and direct monosynaptic projections to the midbrain dopaminergic nuclei, the VTA and the SNc. In each case, we review the evidence for these pathways from anatomic tracing and physiological recordings, and discuss their potential functional roles. We present evidence that the disynaptic pathway through the thalamus is involved in motor coordination, and that its dysfunction contributes to motor deficits, such as dystonia. We then discuss how cerebellar projections to the VTA and SNc influence dopamine release in the respective targets of these nuclei: the NAc and the dorsal striatum. We argue that the cerebellar projections to the VTA may play a role in reward-based learning and therefore contribute to addictive behavior, whereas the projection to the SNc may contribute to movement vigor. Finally, we speculate how these projections may explain many of the observations that indicate a role for the cerebellum in mental disorders, such as schizophrenia.


Cellular neoplastic transformation induced by 916 MHz microwave radiation.
There has been growing concern about the possibility of adverse health effects resulting from exposure to microwave radiations, such as those emitted by mobile phones. The purpose of this study was to investigate the cellular neoplastic transformation effects of electromagnetic fields. 916 MHz continuous microwave was employed in our study to simulate the electromagnetic radiation of mobile phone. NIH/3T3 cells were adopted in our experiment due to their sensitivity to carcinogen or cancer promoter in environment. They were divided randomly into one control group and three microwave groups. The three microwave groups were exposed to 916 MHz EMF for 2 h per day with power density of 10, 50, and 90 w/m(2), respectively, in which 10 w/m(2) was close to intensity near the antenna of mobile phone. The morphology and proliferation of NIH/3T3 cells were examined and furthermore soft agar culture and animal carcinogenesis assay were carried out to determine the neoplastic promotion. Our experiments showed NIH/3T3 cells changed in morphology and proliferation after 5-8 weeks exposure and formed clone in soft agar culture after another 3-4 weeks depending on the exposure intensity. In the animal carcinogenesis study, lumps developed on the back of SCID mice after being inoculated into exposed NIH/3T3 cells for more than 4 weeks. The results indicate that microwave radiation can promote neoplastic transformation of NIH/3T3cells.


Characterisation of betatrophin concentrations in childhood and adolescent obesity and insulin resistance.
Betatrophin, a novel hormone, is correlated with insulin resistance and promotes pancreatic β-cell growth in mice. The aim of this study was to determine circulating betatrophin levels in overweight or obese children and adolescents. The following pairs of subjects were included: (i) normal-weight healthy (n = 27) and overweight or obese (n = 28); (ii) non-insulin-resistant overweight or obese (n = 25) and insulin-resistant obese (n = 15); (iii) normal-weight males (n = 18) and females (n = 20); (4) 5 to 8 yr olds (n = 20) and 8 to 14 yr olds (n = 18). Circulating betatrophin levels were measured using enzyme-linked immunosorbent assay (ELISA). In addition, clinical data were recorded and anthropometrical measurements were performed. Circulating betatrophin levels were increased significantly in obese children and adolescents with insulin resistance (365.77 ± 30.86 pg/mL) compared with overweight or obese subjects without insulin resistance (274.25 ± 26.52 pg/mL; p < 0.05). However, no differences in betatrophin levels were seen between lean and overweight or obese children (323.18 ± 25.91 vs. 348.27 ± 18.91 pg/mL, respectively; p > 0.05). In the normal-weight cohort, males had higher serum betatrophin level than did females, and subjects <8 yr old had lower serum betatrophin levels compared with those >8 yr. Surprisingly, betatrophin concentrations were correlated negatively with body mass index (BMI), but not with the BMI Z-score, in non-insulin-resistant children and adolescents. These results demonstrated that circulating betatrophin levels were increased in insulin-resistant obese children or adolescents and might act as a potential biomarker of insulin resistance in these populations. Furthermore, serum betatrophin concentrations might vary during the development of children and adolescents, as well as between genders.


Validity of Social Support Scales Utilized Among HIV-Infected and HIV-Affected Populations: A Systematic Review.
Social support enhances self-management and prevention of behaviors and is typically assessed using self-report scales; however, little is known about the validity of these scales in HIV-infected or affected populations. This systematic review aims to identify available validated social support scales used in HIV-infected and HIV-affected populations. A systematic literature search using key search terms was conducted in electronic databases. After rounds abstract screenings, full-text reviews, and data abstraction 17 studies remained, two of which assessed multiple social support scales, which increased number of scales to 19. Most scales assessed positive social support behaviors (n = 18). Most scales assessed perceived social support (n = 14) compared to received social support. Reliability ranged from 0.67 to 0.97. The most common forms of validation reported were content validity and construct validity and the least was criterion-related validity. Future research should seek to build evidence for validation for existing scales used in HIV-infected or HIV-affected populations.


Clinical predictors of upgrading to Gleason grade 4 or 5 disease at radical prostatectomy: potential implications for patient selection for radiation and androgen suppression therapy.
A survival benefit has been suggested by the Radiation Therapy Oncology Group (RTOG) for the addition of androgen suppression to external beam radiation therapy for patients with locally advanced and high-grade disease. This study was performed to identify clinical factors that predicted high-grade disease at prostatectomy (i.e., Gleason grade 4 or 5) in patients with clinically localized and low-grade disease (i.e., Gleason grades 1-3) at biopsy. These pretreatment factors may allow for the identification of patients likely to derive a survival benefit from the addition of androgen suppression to external beam radiation therapy while awaiting the results of the prospective randomized trials. Concordance testing of both the primary and secondary biopsy and prostatectomy Gleason grades was performed in 693 patients with clinical Stage T1c, 2 prostate cancer managed with a radical prostatectomy (RP). For the subset of 420 patients with low-grade disease (i.e., Gleason grade < or =3) a logistic regression multivariable analysis was performed to evaluate the ability of the preoperative prostate-specific antigen (PSA), clinical stage, and ultrasound determined prostate gland volume to predict for upgrading to high-grade disease (i.e., Gleason grade 4 or 5). Forty percent of men with low-grade disease at biopsy were found to have high-grade disease at RP. Men who have at least a 50% chance of being upgraded from biopsy Gleason grade < or =3 to prostatectomy Gleason grade > or =4 disease included those with prostate gland volumes < or =75 cm3 and a PSA > 20 ng/ml or a PSA >10 and < or =20 and clinical Stage T2b,2c. For men with prostate gland volumes >75 cm3, only those with both PSA > 20 ng/ml and clinical Stage T2b,2c were at a significant risk of upgrading. Until the randomized data become available, clinical factors may be useful in identifying patients with clinically localized prostate cancer who are likely to benefit from combined androgen suppression and external beam radiation therapy.


Endoscopy findings in HIV-infected children from sub-Saharan Africa.
The causes of persistent gastro-intestinal symptoms in HIV-infected children from sub-Saharan Africa remain poorly documented. The clinical, radiological and endoscopic findings of all HIV-infected children who underwent upper GI endoscopy at Red Cross Children's Hospital, Cape Town, South Africa, from February 2003 to October 2005 were documented. Twenty-six HIV-infected children underwent endoscopy; median age 1 year (range: 0.17-10.9 years). The majority had advanced HIV disease; 18 (69%) were WHO Stage 4; median CD4 10.7% (range: 1-39.8%). Presenting symptoms included persistent vomiting (18), dysphagia (4) and GIT bleed (6). Observational and histological findings showed poor correlation. Pathogens were identified in 10 children: cytomegalovirus infection in seven (two with cryptosporidium co-infection), Candida in two, Helicobacter pylori in one. Age and CD4 count were not associated with the pathogens. Endoscopy findings influenced clinical management in 21 (81%) cases. Upper-GI endoscopy identified a diverse spectrum of disease and provided information that would be clinically relevant to most HIV-infected children with upper gastro-intestinal symptoms.


Preferential expression in mushroom bodies of the catalytic subunit of protein kinase A and its role in learning and memory.
Involvement of the cAMP cascade in Drosophila learning and memory is suggested by the aberrant behavioral phenotypes of the mutants dunce (cAMP phosphodiesterase) and rutabaga (adenylyl cyclase). Line DCO581, isolated via an enhancer detector screen for genes preferentially expressed in the mushroom bodies, contains a transposon in the first exon of the catalytic subunit gene (DCO) of protein kinase A (PKA). RNA in situ hybridization and immunohistochemistry show that DCO is preferentially expressed in the mushroom bodies. The DCO581 insertion and an independently isolated hypomorphic allele (DCOB10) each produce homozygous lethality and a 40% decrease in PKA activity in heterozygotes. This decrease has mild effects on learning but no effect on memory. However, the 80% reduction in activity obtained by constructing heteroallelic yet viable DCO581/DCOB10 animals results in a dramatic learning and memory deficit. These results suggest that PKA plays a crucial role in the cAMP cascade in mushroom bodies to mediate learning and memory processes.


The after-school needs and resources of a low-income urban community: surveying youth and parents for community change.
Using a collaborative research approach, this project describes a partnership between community residents and university researchers to develop a comprehensive survey of the after-school needs of a low-income urban community in a large Midwestern city. Surveying parents and children was considered particularly important because the current literature on after-school does not include much input from them, the key stakeholders in programming. By surveying pre- and young adolescent youth (N = 416) and parents (N = 225) in the community, information was gathered to document the need for after-school programming, tap program preferences, and uncover barriers to participation and enrollment. Survey findings revealed significant differences between youth and parent perspectives. Disagreements between youth and parent survey responses suggest that after-school programs in the community should offer a balance of academic, recreational, and social activities, as well as a tutoring or homework component. Further, in order to increase participation and attendance rates, community after-school programs need to address the following barriers to participation: safety, transportation, family responsibilities (e.g., care for siblings, household chores), and access to information about available programs. These findings guided the planning of future after-school programs. The survey results and comparisons between youth and parent data will be presented.


Development and Pilot Testing of an Assessment Tool for Performance of Invasive Mediastinal Staging.
To develop and evaluate a surgical trainee competency assessment instrument for invasive mediastinal staging, including cervical mediastinoscopy and endobronchial ultrasound (EBUS), a comprehensive instrument was developed, the Thoracic Competency Assessment Tool-Invasive Staging (TCAT-IS), using expert review and simulated and clinical pilot-testing. Validity and reliability evidence were collected, and item analysis was performed. Initially, a 27-item instrument was developed, which underwent expert review with members of the Canadian Association of Thoracic Surgeons (n = 86) in 2014 to 2015 (response rate, 57%). TCAT-IS was refined to 29 items in 4 competency areas: preoperative, general operative, mediastinoscopy, and EBUS. Further refinements were made based on simulated use. The final version was then used to assess competency of 5 thoracic trainees performing invasive mediastinal staging in live patients. Participants were assessed during 20 mediastinoscopy and 8 EBUS procedures, with 47 total assessments completed. Reliability (Cronbach's alpha = 0.94), interrater reliability (κ = 0.80), and correlation with an established global competency scale (κ = 0.75) were high. The most difficult items were "set up and adjust EBUS equipment" and "identify vascular anatomy (EBUS)." Feedback questionnaires from trainees (response rate, 80%) and surgeons (response rate, 100%) were consistently positive regarding user friendliness, utility as an assessment tool, and educational benefit. Participants believed the tool "facilitated communicating feedback to the trainee with specific areas to work on." TCAT-IS is an effective tool for assessing competence in invasive staging and may enhance instruction. This initial test establishes early validity and reliability evidence, supporting the use of TCAT-IS in providing structured, specific, formative assessments of competency.