Topical Application of Fingolimod Perturbs Cutaneous Inflammation.
The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.


A novel 2-hour method for rapid preparation of permanent paraffin sections when treating melanoma in situ with mohs micrographic surgery.
Distinguishing sun-induced melanocyte atypia from residual melanoma in situ (MIS) can be challenging, particularly when working with frozen sections. Immunostains such as melanoma-associated antigen recognized by T cells (MART-1) can assist, but paraffin sections provide an optimal means of analyzing melanocyte morphology. To verify the effectiveness of a 2-hour paraffin processing technique that uses microwave technology in the preparation of MIS sections. Twelve MIS debulk specimens were divided into 4 pieces with each piece processed 1 of 4 ways: our 2-hour paraffin technique with hematoxylin and eosin (H&E), conventional 24-hour paraffin processing with H&E, frozen sections with H&E, and frozen sections with MART-1 immunostaining. A Mohs surgeon and a dermatopathologist compared all specimens in a blinded fashion using a 3-point ranking scale to assess ease of visualizing normal melanocytes, ease of visualizing abnormal melanocytes, and overall ability to adequately visualize epidermal and dermal structures. A nonparametric signed rank test indicated no significant differences between our microwave technique and conventional paraffin processing in all 3 criteria (p=.29, .63, .75, respectively). Our microwave technique was significantly better than frozen H&E sections for all 3 criteria (p=.046, .004, .005, respectively). This rapid microwave tissue processing technique is comparable with conventional paraffin section processing.


Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats.
Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97-116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.


Exploring the usefulness of indicators for referring people with dementia and their informal caregivers to activating interventions: a qualitative analysis of needs assessments.
People with dementia (PWDs) and their informal caregivers frequently report difficulties in maintaining their usual activities. We had previously developed a set of indicators to estimate whether dyadic, activating interventions can meet these needs for activity. This study investigates how PWDs and informal caregivers talk about the indicators in interviews for needs assessments, and how professionals identify activity needs and preferences. Our research goal was to explore the usefulness of the indicators for assessing the activity needs of community-dwelling dyads. Such assessments are needed for appropriate referral to activating interventions. A dementia case manager assessed the needs of community-dwelling PWDs and their informal caregivers; we carried out secondary analyses on the dataset resulting from the audio-tapes and transcripts. We applied qualitative, deductive content analysis because we wanted to identify both explicit and implicit needs and preferences. We used the indicators that we had developed in previous research as codes. Both PWDs and informal caregivers do explicitly mention needs, preferences, and characteristics related to the indicators in the needs assessments. Possible implicit needs and preferences were frequently identified in their stories. Needs-driven care requires high-quality needs assessments. Both PWDs and their informal caregivers need encouragement to express their latent needs and preferences. In addition, latent needs and preferences have to be further explored in needs assessments to find out the real meaning. The outcomes of this study highlight the significance of structured needs assessments for mapping the activity needs of PWDs and their informal caregivers. Many PWDs and informal caregivers reported activity needs, which suggests that activating interventions may be appropriate. The indicators can help professionals identify activity needs so that they can discuss matching activating interventions with the dyad.


Charge transfer and polarization for chloride ions bound in ClC transport proteins: natural bond orbital and energy decomposition analyses.
ClC transport proteins show a distinct "broken-helix" architecture, in which certain α-helices are oriented with their N-terminal ends pointed toward the binding sites where the chloride ions are held extensively by the backbone amide nitrogen atoms from the helices. To understand the effectiveness of such binding structures, we carried out natural bond orbital analysis and energy decomposition analysis employing truncated active-site model systems for the bound chloride ions along the translocation pore of the EcClC proteins. Our results indicated that the chloride ions are stabilized in such a binding environment by electrostatic, polarization, and charge-transfer interactions with the backbone and a few side chains. Up to ~25% of the formal charges of the chloride ions were found smeared out to the surroundings primarily via charge transfer from the chloride's lone pair n(Cl) orbitals to the protein's antibonding σ*(N-H) or σ*(O-H) orbitals; those σ* orbitals are localized at the polar N-H and O-H bonds in the chloride's first solvation shells formed by the backbone amide groups and the side chains of residues Ser107, Arg147, Glu148, and Tyr445. Polarizations by the chloride ions were dominated by the redistribution of charge densities among the π orbitals and lone pair orbitals of the protein atoms, in particular the atoms of the backbone peptide links and of the side chains of Arg147, Glu148, and Tyr445. The substantial amounts of electron density involved in charge transfer and in polarization were consistent with the large energetic contributions by the two processes revealed by the energy decomposition analysis. The significant polarization and charge-transfer effects may have impacts on the mechanisms and dynamics of the chloride transport by the ClC proteins.


Distribution and coexistence of peptides in nerve fibers of the external muscle of the human gastrointestinal tract.
The nerve fibers that supply the external muscle of the human gastrointestinal tract were examined for their immunoreactivity to the neuropeptides enkephalin, neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide, for tyrosine hydroxylase (a catecholamine-synthesizing enzyme), and for coexistence between immunoreactivities in nerve fibers. Studies on coexistence revealed that the majority of reactive nerve fibers could be placed in one of two classes: (a) those fibers with reactivity to enkephalin or substance P, or both, and (b) fibers containing one or both of the peptides neuropeptide Y and vasoactive intestinal peptide. Many fibers immunoreactive for vasoactive intestinal peptide or neuropeptide Y, or both, were found throughout the external smooth muscle of the gastrointestinal tract, but neuropeptide Y-reactive fibers were less common in the small and large intestines than in the stomach and esophagus. Fibers immunoreactive for enkephalin or substance P, or both, were sparse in the esophagus, increased in numbers to reach maximal frequency in the pylorus, and maintained a similar frequency in the small and large intestines. Fibers with somatostatin or tyrosine hydroxylase immunoreactivity were rare. In general, sphincter regions were similar to nonsphincter regions in peptide-immunoreactive fiber numbers and types, except that the internal anal sphincter had no enkephalin-immunoreactive fibers and very few substance P-reactive fibers. Moderate numbers of fibers reactive for neuropeptide Y and vasoactive intestinal peptide were found in the internal anal sphincter. It is suggested that enkephalin and substance P are in excitatory fibers and that vasoactive intestinal peptide and neuropeptide Y are in fibers inhibitory to the external muscle.


No patients to resect or transplant: an analysis of patients with hepatocellular carcinoma admitted to a major African referral hospital.
This study aimed to describe the characteristics of patients diagnosed with hepatocellular carcinoma (HCC) at the Komfo Anokye Teaching Hospital (KATH) in Ghana and to determine their treatment options per the Barcelona Clinic Liver Cancer (BCLC) algorithm. We reviewed the medical records of patients diagnosed with HCC at KATH in the period 2007-2013. Patient demographics, medical history, investigations, management, and outcome were extracted. BCLC staging was applied to determine their treatment options. Results were expressed as descriptive statistics. The charts for 206/465 patients were available for review. The male:female ratio was 2:1 and mean age was 44.0 ± 14.5 years. Common presenting complaints were abdominal distension, abdominal pain, and jaundice. hepatitis B virus (HBV) positivity was 52 %. Almost all patients received only supportive treatment. None underwent surgery, ablation, or transarterial chemoembolization. BCLC staging could be completed for 118 patients. Using predicted INR values in cases without the result, < 8 % of patients were eligible for resection, transplantation, or ablation; 25-53 % were eligible for embolization or sorafenib therapy. Up to 72 % were eligible only for supportive care. Seventy-six percent of patients reviewed were discharged alive; 71 % of patients whose charts were not available died during an admission. Thus, of the 465-patient cohort, 50 % died in the hospital. The majority of HCC in our population is caused by HBV. Up to 61 % of patients may be eligible for curative treatment, transarterial chemoembolization, or sorafenib treatment. This percentage may be increased with a robust surveillance program for patients at increased risk for HCC. Hepatitis B vaccination must also be a public health priority.


Phospholipids as modulators of K(ATP) channels: distinct mechanisms for control of sensitivity to sulphonylureas, K(+) channel openers, and ATP.
Recent work has established membrane phospholipids such as phosphatidylinositol-4,5-bisphosphate (PIP(2)) as potent regulators of K(ATP) channels controlling open probability and ATP sensitivity. We here investigated the effects of phospholipids on the pharmacological properties of cardiac type K(ATP) (Kir6.2/SUR2A) channels. In excised membrane patches K(ATP) channels showed considerable variability in sensitivity to glibenclamide and ATP. Application of the phosphatidylinositol phosphates (PIPs) phosphatidylinositiol-4-phosphate, PIP(2), and phosphatidylinositol-3,4,5-trisphosphate reduced sensitivity to ATP and glibenclamide closely resembling the native variability. Insertion of the patch back into the oocyte (patch-cramming) restored high ATP and glibenclamide sensitivity, indicating reversible modulation of K(ATP) channels via endogenous PIPs-degrading enzymes. Thus, the observed variability seemed to result from differences in the membrane phospholipid content. PIP(2) also diminished activation of K(ATP) channels by the K(+) channel openers (KCOs) cromakalim and P1075. The properties mediated by the sulphonylurea receptor (sensitivity to sulfonylureas and KCOs) seemed to be modulated by PIPs via a different mechanism than ATP inhibition mediated by the Kir6.2 subunits. First, polycations abolished the effect of PIP(2) on ATP inhibition consistent with an electrostatic mechanism but only weakly affected glibenclamide inhibition and activation by KCOs. Second, PIP(2) had clearly distinct effects on the concentration-response curves for ATP and glibenclamide. However, PIPs seemed to mediate the different effects via the Kir6.2 subunits because a mutation in Kir6.2 (R176A) attenuated simultaneously the effects of PIP(2) on ATP and glibenclamide inhibition. Finally, experiments with various lipids revealed structural features necessary to modulate K(ATP) channel properties and an artificial lipid (dioleoylglycerol-succinyl-nitriloacetic acid) that mimicked the effects of PIPs on K(ATP) channels.


Intracellular targeting of the insulin-regulatable glucose transporter (GLUT4) is isoform specific and independent of cell type.
Insulin stimulates glucose transport in adipocytes via the rapid redistribution of the GLUT1 and GLUT4 glucose transporters from intracellular membrane compartments to the cell surface. Insulin sensitivity is dependent on the proper intracellular trafficking of the glucose transporters in the basal state. The bulk of insulin-sensitive transport in adipocytes appears to be due to the translocation of GLUT4, which is more efficiently sequestered inside the cell and is present in much greater abundance than GLUT1. The cell type and isoform specificity of GLUT4 intracellular targeting were investigated by examining the subcellular distribution of GLUT1 and GLUT4 in cell types that are refractory to the effect of insulin on glucose transport. Rat GLUT4 was expressed in 3T3-L1 fibroblasts and HepG2 hepatoma cells by DNA-mediated transfection. Transfected 3T3-L1 fibroblasts over-expressing human GLUT1 exhibited increased glucose transport, and laser confocal immunofluorescent imaging of GLUT1 in these cells indicated that the protein was concentrated in the plasma membrane. In contrast, 3T3-L1 fibroblasts expressing GLUT4 exhibited no increase in transport activity, and confocal imaging demonstrated that this protein was targeted almost exclusively to cytoplasmic compartments. 3T3-L1 fibroblasts expressing GLUT4 were unresponsive to insulin with respect to transport activity, and no change was observed in the subcellular distribution of the protein after insulin administration. Immunogold labeling of frozen ultrathin sections revealed that GLUT4 was concentrated in tubulo-vesicular elements of the trans-Golgi reticulum in these cells. Sucrose density gradient analysis of 3T3-L1 homogenates was consistent with the presence of GLUT1 and GLUT4 in discrete cytoplasmic compartments. Immunogold labeling of frozen thin sections of HepG2 cells indicated that endogenous GLUT1 was heavily concentrated in the plasma membrane. Sucrose density gradient analysis of homogenates of HepG2 cells expressing rat GLUT4 suggested that GLUT4 is targeted to an intracellular location in these cells. The density of the putative GLUT4-containing cytoplasmic membrane vesicles was very similar in HepG2 cells, 3T3-L1 fibroblasts, 3T3-L1 adipocytes, and rat adipocytes. These data indicate that the intracellular trafficking of GLUT4 is isoform specific. Additionally, these observations support the notion that GLUT4 is targeted to its proper intracellular locale even in cell types that do not exhibit insulin-responsive glucose transport, and suggest that the machinery that regulates the intracellular targeting of GLUT4 is distinct from the factors that regulate insulin-dependent recruitment to the cell surface.


Taiwan guideline on oral pre-exposure prophylaxis for HIV prevention - 2018 update.
Pre-exposure prophylaxis (PrEP) for prevention of human immunodeficiency virus infection is proved to be effective and has been implemented worldwide. This article introduces the guideline development and revised recommendations and guidance on PrEP provision in the updated Taiwan PrEP guideline. The Taiwan PrEP guideline writing group searched randomized controlled trials and guidelines published before October 2017 through Medline/PubMed, Cochrane Database, Embase and ClinicalTrials.gov database. Keywords included pre(-)exposure prophylaxis, PrEP, Truvada, tenofovir, HIV, and AIDS. Each selected article was assessed by two authors using the Grading of Recommendations Assessment, Development and Evaluation. External reviewers were invited to independently evaluate the revised manuscript per the Appraisal of Guidelines for Research and Evaluation II. Before publication, a public consultation was held to reach consensus on the updated guideline among providers, civil society, and Taiwan Centers for Disease Control. Four systematic reviews and 28 original articles were reviewed by Taiwan PrEP writing group. The second version of the Taiwan PrEP guideline was released in March 2018. We recommended daily PrEP use for the following populations: strong recommendation and high quality of evidence for men who have sex with men (MSM) and transgender women (TGW), as well as heterosexual serodiscordant couples; weak recommendation and high quality of evidence for people who inject drugs, while weak recommendation and moderate quality of evidence for at-risk heterosexual men and women. There is high-quality evidence for event-driven PrEP in MSM and likely TGW, and we additionally recognized these key populations could benefit from such dosing regimen.


Continued competency--a responsibility of the profession.
For the past decade the Continued Competency Committee of the American Association of Dental Examiners has explored issues in continued competency for the dental profession. The efforts have focused on creating policy and standards which must be met by any continued competency assessment mechanisms. Nine potential systems are under review. Some, such as examination for diplomate status in a recognized dental specialty are already in place. The development and pilot testing of four new mechanisms--simulations, continuing education with measurable outcomes, case presentation, and in-office audit--is being encouraged.


Descriptive and Quasi-Experimental Studies about Moral Emotions, Online Empathy, Anger Management, and Their Relations with Key Competencies in Primary Education.
Antisocial behaviours make social interactions difficult among students. Moral emotions, online empathy, and anger management are social and emotional variables related to prosocial and antisocial behaviours and health problems. This research aims to assess the impact of Cooperative Project-Based Learning intervention on these three variables for Primary Education students. Additionally, the relations of these variables with key competencies, such as social and emotional competencies and literacy competence, were studied. This research is made up of two studies, descriptive and quasi-experimental, during regular school hours. The descriptive study was carried out with a sample of 516 primary school students and aimed to assess the development of the three variables, taking into account personal and ethnic-cultural factors. The quasi-experimental study, with pre-test and post-test data, had the participation of 145 students to study the incidence of these variables after Cooperative Project-Based Learning intervention in Primary Education. The results show the relation among the cited variables and the positive impact of the intervention on moral emotions and anger management in the experimental group compared to the control group. Experimental group girls presented higher scores in moral emotions than control group girls. These results open new research lines in relation to the intervention as a programme to prevent the appearance of antisocial behaviours and health problems at school.


Comparison of the efficacy of pharmacological and nonpharmacological treatments in women with primary dysmenorrhea: randomized controlled parallel-group study.
To compare the effectiveness of pharmacological (PT) and nonpharmacological treatments (NPT) in women with primary dysmenorrhea (PD) and determine the most effective treatment method. We enrolled 85 PD participants with PD who were randomly classified into five groups: pharmacological groups; naproxen sodium (NS) and micronized purified flavanoid fraction (MPFF), nonpharmacological groups; motor imagery focused pelvic floor exercise (MOPEXE) and acupressure, and no treatment group; control. Initial assessment was conducted in all groups on the first day of the menstrual cycle. After the end ofthe third menstrual cycle, the specialist physiotherapist and the obstetrician conducted a final evaluation. Intensity and nature of pain were evaluated with the Short-Form McGill Pain Questionnaire (SF-MPQ), and menstrual attitudes and behaviors were evaluated using the Menstruation Attitude Questionnaire (MAQ). In the total pain dimension scores, which are the sum of the affective dimension of pain and sensory dimension scores, the pre-post treatment difference was the highest in the mean of the total pain dimension. The highest was for MOPEXE (15.12 ± 4.44), followed by MPFF (7.53 ± 6.8); acupressure (7.47 ± 5.28) and NS (4.47 ± 4.91) showed more significant change than the control group (p = 0.001). The mean difference in visual analog scale (VAS) scores was highest in MOPEXE (4.53 ± 1.5), followed by acupressure (2.35 ± 1.66); MPFF (1.88 ± 1.73) and NS (1.65 ± 1.84) scores were more significant than the control group (p = 0.001). Regarding total pain intensity, the highest was MOPEXE (2.59 ± 0.94), followed by MPFF (1.18 ± 0.88); acupressure (1.06 ± 0.83) and NS (0.82 ± 1.01) scores were more significant compared to the control group (p = 0.001). There was no significant change in the pre-post difference values in the MAQ subparameters: menstruation as deliberate event, menstruating as bothersome event, menstruation as natural event, anticipation and prediction of the onset of menstruation, and denial of any effects of menstruation; menstruation as a natural event resulted in insignificant changes in parameters (p = 0.579, p = 0.074, p = 0.892, p = 0.056, p = 0. 377). PT and NPT methods in the study were effective in coping with PD-associated pain. MPFF was more effective than the NS group in terms of relieving pain. In terms of pain, MOPEXE and acupressure groups were as effective as PT. The most effective of these treatment methods was the MOPEXE group created by the researcher.


Direct inter-subdomain interactions switch between the closed and open forms of the Hsp70 nucleotide-binding domain in the nucleotide-free state.
The 70 kDa heat-shock proteins (Hsp70s) are highly conserved chaperones that are involved in several cellular processes, such as protein folding, disaggregation and translocation. In this study, the crystal structures of the human Hsp70 nucleotide-binding domain (NBD) fragment were determined in the nucleotide-free state and in complex with adenosine 5'-(beta,gamma-imido)triphosphate (AMPPNP). The structure of the nucleotide-free NBD fragment is similar to that of the AMPPNP-bound NBD fragment and is designated as the ;closed form'. In the nucleotide-free NBD fragment the closed form is intrinsically supported through interactions between Tyr15, Lys56 and Glu268 which connect subdomains IA, IB and IIB at the centre of the protein. Interaction with the substrate-binding domain (SBD) of Hsp70 or the BAG domain of BAG1 impairs this subdomain connection and triggers the rotation of subdomain IIA around a hydrophobic helix from subdomain IA. The subdomain rotation is limited by Asp199 and Asp206 from subdomain IIA and clearly defines the open form of the NBD. The open form is further stabilized by a new interaction between Gly230 from subdomain IIB and Ser340 from subdomain IIA. The structure of the NBD in the nucleotide-free state is determined by switching of the inter-subdomain interactions.


Calotropis procera extract induces apoptosis and cell cycle arrest at G2/M phase in human skin melanoma (SK-MEL-2) cells.
Calotropis procera (family: Asclepiadaceae) contains cardiac glycosides which are cytotoxic to cancer cells. The extracts of C. procera have been reported to be cytotoxic to many cancer cell lines and this is the first report against the human skin melanoma cells (SK-MEL-2). The SK-MEL-2 cells treated with C. procera methanolic extract (CPME) were analysed for growth inhibition and apoptosis. The exposure of phosphatidylserine in apoptotic SK-MEL-2 was analysed by using the Annexin-V FITC flow cytometry method. In CPME-treated SK-MEL-2 cells, 19.6% of apoptotic and 58.3% dead cells were observed. The 15.97% and 15.85% of early apoptotic cells were found at 20 μg/mL of the ouabain and paclitaxel, respectively. Active caspases, nuclear degradation confirmed apoptotic SK-MEL-2 cells in time- and dose-dependent manner. The cell cycle analysis shows that CPME treated cells halt at G2/M phase. Significant cytotoxic activity of CPME against SK-MEL-2 may be attributed to its high cardenolide content.


Language-related potentials specific to human language cortex.
Event-related potentials following silently named object pictures were recorded directly from the exposed left hemisphere of the human cortex at sites whose relation to naming was subsequently established by electrical stimulation mapping. Two simultaneous potential changes are specific to sites where stimulation disrupts naming: slow potentials as premotor sites and focal desynchronization at posterior sites surrounding the Sylvian fissure. These anatomically specific changes are also specific to the task--present with silent naming and absent in a spatial task with the same visual input. Overt speech is also preceded by slow potentials with earliest onset at premotor sites.


Preparation of high-quality graphene oxide-carbon quantum dots composites and their application for electrochemical sensing of uric acid and ascorbic acid.
Graphene oxide-quantum dots systems are emerging as a new class of materials that hold promise for biochemical sensing applications. In this paper, the eco-friendly carbon quantum dots (CQDs) are prepared with cheap and recyclable coke powders as carbon source. The graphene oxide-carbon quantum dots (GO-CQDs) composites are synthesized using graphene oxide as the conductive skeleton to load the CQDs by a one-step calcination method. The obtained GO-CQDs composites demonstrate the successful decoration of CQDs on GO nanosheets. The CQDs acting as spacers create gaps between GO sheets, resulting in a high surface area, which electively increases the electrolyte accessibility and electronic transmission. The electrocatalytic activity and reversibility of GO-CQDs composites can be effectively enhanced by tuning the mass ratio of GO to CQDs and the heating process. Furthermore, a highly sensitive and selective electrochemical sensor for determining uric acid (UA) and ascorbic acid (AA) was developed by modifying GO-CQDs composites onto a glassy carbon electrode. The results show that the linear range, minimum detection limit, and sensitivity of the GO-CQDs electrode for UA detection are 1-150 μM, 0.01 μM, and 2319.4 μA mM-1 cm-2, respectively, and those for AA detection are 800-9000 μM, 31.57 μM, and 53.1 μA mM-1 cm-2, respectively. The GO-CQDs are employed as the electrode materials for the serum and urine samples electrochemical sensing, the results indicate that the sensor can be used for the analysis of real biological samples.


Interferon-α treatment in systemic mastocytosis.
Patients with systemic mastocytosis are rare, constitute a heterogeneous clinical entity and some may not require treatment until long after diagnosis. However, most patients who present with disabling symptoms, organ involvement and fulfill B or C findings as outlined in the 2008 WHO classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-α, as mono- or combination therapy, in the treatment algorithm may only be definitely established in multicenter studies, which are based on the principles of controlled clinical trials.


Video Distraction and Parental Presence for the Management of Preoperative Anxiety and Postoperative Behavioral Disturbance in Children: A Randomized Controlled Trial.
The anxiolytic efficacy of video watching, in the absence of parents, during the mask induction of anesthesia in young children with high separation anxiety has not been clearly established. We performed this study to determine whether the effect of video distraction on alleviating preoperative anxiety is independent of parental presence and whether a combination of both interventions is more effective than either single intervention in alleviating preoperative anxiety and postoperative behavioral disturbance in preschool children. In this prospective trial, 117 children aged 2 to 7 years scheduled for elective minor surgery were randomly allocated to 1 of 3 groups, a video distraction group (group V), a parental presence group (group P), or a combination of video distraction plus parental presence group (group VP) during induction of sevoflurane anesthesia. The Modified Yale Preoperative Anxiety Scale (mYPAS) was used to assess anxiety in the preoperative holding area (baseline), immediately after entry to the operating room, and during mask induction. Compliance during induction, emergence delirium during recovery, and negative behavioral changes at 1 day and 2 weeks postoperatively were also assessed. The mYPAS scores were comparable (P = 0.558), and the number of children exhibiting baseline anxiety (an mYPAS score > 30) were not different among the 3 groups in the preoperative holding area (P = 0.824). After intervention, the changes in mYPAS scores from baseline to induction were not different among the 3 groups (P = 0.049). The proportion of children with increased mYPAS scores was higher in group P compared with group V from baseline to operating room entry (Bonferroni-adjusted 95% confidence interval for difference, 2 to 49) but similar from baseline to induction in all 3 groups. Although children in group V were more cooperative during mask induction than those in the other 2 groups (P < 0.001 versus group P and P = 0.001 versus group VP), no significant intergroup differences were observed in the incidence of emergence delirium or new-onset negative behavioral change after surgery. Video distraction, parental presence, or their combination showed similar effects on preoperative anxiety during inhaled induction of anesthesia and postoperative behavioral outcomes in preschool children having surgery.


Total synthesis of a 28-member stereoisomer library of murisolins.
Total syntheses of two 16-member libraries of murisolin isomers are reported. In the first library, fluorous PMB (p-methoxybenzyl) groups encode configurations, and four mixtures of four dihydroxy-tetrahydrofurans are prepared by Shi epoxidation followed (optionally) by Mitsunobu reaction. The mixtures are coupled by Kocienski-Julia reaction with a single hydroxybutenolide followed by hydrogenation. Demixing and detagging provide the 16 pure stereoisomers. In the second synthesis, a single mixture of four fluorous-tagged dihydroxy-tetrahydrofurans is coupled with a four-compound mixture of hydroxybutenolides that bear derivatives of DMB (dimethoxybenzyl) groups with oligoethylene glycol (OEG) units that encode the configurations at C4 and C34. The 16-compound mixture is subjected to hydrogenation, double demixing, and detagging to provide the 16 isomerically pure murisolins. Twelve of these isomers are new, while four match samples from the first library.


Presence of severe neuroinflammation does not intensify neurofibrillary degeneration in human brain.
This study investigated the allegedly causal relationship between microglial activation and neurofibrillary degeneration (NFD) typical of Alzheimer's disease (AD) by determining if presence of extreme microglial activation coincides with intensified NFD. We performed comparative histopathological analyses of NFD and microglial reactivity in 18 primary subjects ranging from 4 to 51 years of age. Ten of these subjects (median age 34) died from infectious disease (HIV, sepsis) and CNS trauma, while eight subjects (median age 32.5) died from non-infectious conditions (controls). Second, we also examined two 52-year-old subjects with Down syndrome where one had comorbid sepsis and the other one did not. We found that all 10 subjects with infectious/traumatic diagnoses showed severe neuroinflammation, while the 8 control subjects completely lacked neuroinflammatory changes. However, all 18 primary subjects were found to show the same early-stage, pretangle neuropathology of Braak stage 1a and 1b, that is, they exhibited primarily subcortical NFD in the locus coeruleus and sporadic lesions in the transentorhinal cortex. Similarly, the two subjects with Down syndrome showed the same high levels of NFD (Braak stage VI) irrespective of the comorbid sepsis-related neuroinflammation present in one of these individuals. Collectively, our findings show that despite rampant microglial activation in all subjects with neuroinflammatory conditions the extent of NFD is at the same level as seen in non-inflamed controls. These findings demonstrate that microglial activation does not initiate or exacerbate NFD, and we conclude that CNS inflammation is unlikely to be causally involved in the development of NFD characteristic of AD dementia.


Credibility and creativity: a conversation with Kaiser Permanente's George C. Halvorson.
In 2002 Kaiser Permanente's board surprised the industry by reaching outside its organization and selecting a nonphysician leader, George C. Halvorson, then CEO of HealthPartners of Minneapolis. In this interview Halvorson talks about returning to Kaiser's strengths--its sixty-year-plus history of integrated health care organization and its power base along the Pacific Coast--and about how he and his physician colleagues intend to leverage clinical information technology to improve their subscribers' health. Halvorson also discusses the new Medicare prescription drug legislation, the sources of the current run-up in health costs, and how he intends to position Kaiser for future growth.


Identification and functional analysis of the essential and regulatory light chains of the only type II myosin Myo1p in Saccharomyces cerevisiae.
Cytokinesis in Saccharomyces cerevisiae involves coordination between actomyosin ring contraction and septum formation and/or targeted membrane deposition. We show that Mlc1p, a light chain for Myo2p (type V myosin) and Iqg1p (IQGAP), is the essential light chain for Myo1p, the only type II myosin in S. cerevisiae. However, disruption or reduction of Mlc1p-Myo1p interaction by deleting the Mlc1p binding site on Myo1p or by a point mutation in MLC1, mlc1-93, did not cause any obvious defect in cytokinesis. In contrast, a different point mutation, mlc1-11, displayed defects in cytokinesis and in interactions with Myo2p and Iqg1p. These data suggest that the major function of the Mlc1p-Myo1p interaction is not to regulate Myo1p activity but that Mlc1p may interact with Myo1p, Iqg1p, and Myo2p to coordinate actin ring formation and targeted membrane deposition during cytokinesis. We also identify Mlc2p as the regulatory light chain for Myo1p and demonstrate its role in Myo1p ring disassembly, a function likely conserved among eukaryotes.


Paliperidone: another treatment option for delusional parasitosis.
Patients with delusional parasitosis (DP) have a fixed belief of being infested by small pathogens. Typical and atypical antipsychotics are widely used for treating DP. There are limited controlled trials about the treatment of DP and the most useful antipsychotic agent is still unknown. Paliperidone treatment for DP will be demonstrated through two cases. One of these cases had previously used pimozide but had not responded to treatment. Both cases had remission from symptoms with paliperidone. There are only two case reports published about paliperidone treatment for DP. Paliperidone appears to have promise in the treatment of DP; however, more case reports and controlled trials are required.


The influence of averageness on judgments of facial attractiveness: no own-age or own-sex advantage among children attending single-sex schools.
We examined how recent biased face experience affects the influence of averageness on judgments of facial attractiveness among 8- and 9-year-old children attending a girls' school, a boys' school, and a mixed-sex school. We presented pairs of individual faces in which one face was transformed 50% toward its group average, whereas the other face was transformed 50% away from that average. Across blocks, the faces varied in age (adult, 9-year-old, or 5-year-old) and sex (male or female). We expected that averageness might influence attractiveness judgments more strongly for same-age faces and, for children attending single-sex schools, same-sex faces of that age because their prototype(s) should be best tuned to the faces they see most frequently. Averageness influenced children's judgments of attractiveness, but the strength of the influence was not modulated by the age of the face, nor did the effects of sex of face differ across schools. Recent biased experience might not have affected the results because of similarities between the average faces of different ages and sexes and/or because a minimum level of experience with a particular group of faces may be adequate for the formation of a veridical prototype and its influence on judgments of attractiveness. The results suggest that averageness affects children's judgments of the attractiveness of the faces they encounter in everyday life regardless of age or sex of face.


Comparison of promoter hypermethylation pattern in salivary rinses collected with and without an exfoliating brush from patients with HNSCC.
Salivary rinses have been recently proposed as a valuable resource for the development of epigenetic biomarkers for detection and monitoring of head and neck squamous cell carcinoma (HNSCC). Both salivary rinses collected with and without an exfoliating brush from patients with HNSCC are used in detection of promoter hypermethylation, yet their correlation of promoter hypermethylation has not been evaluated. This study was to evaluate the concordance of promoter hypermethylation between salivary rinses collected with and without an exfoliating brush from patients with HNSCC. METHODOLGY: 57 paired salivary rinses collected with or without an exfoliating brush from identical HNSCC patients were evaluated for promoter hypermethylation status using Quantitative Methylation-Specific PCR. Target tumor suppressor gene promoter regions were selected based on our previous studies describing a panel for HNSCC screening and surveillance, including P16, CCNA1, DCC, TIMP3, MGMT, DAPK and MINT31. In salivary rinses collected with and without brush, frequent methylation was detected in P16 (8.8% vs. 5.2%), CCNA1 (26.3% vs. 22.8%), DCC (33.3% vs. 29.8%), TIMP3 (31.6% vs. 36.8%), MGMT (29.8% vs. 38.6%), DAPK (14.0% vs. 19.2%), and MINT31 (10.5% vs. 8.8%). Spearman's rank correlation coefficient showed a positive correlation between salivary rinses collected with and without brush for P16 (ρ = 0.79), CCNA1 (ρ = 0.61), DCC (ρ = 0.58), TIMP3 (ρ = 0.10), MGMT (ρ = 0.70), DAPK (ρ = 0.51) and MINT31 (ρ = 0.72) (P<0.01). The percent agreement of promoter methylation between salivary rinses with brush and without brush were 96.5% for P16, 82.5% for CCNA1, 78.9% for DCC, 59.7% for TIMP3, 84.2% for MGMT, 84.2% for DAPK, and 94.7% for MINT31. Our study demonstrated strong correlations of gene promoter hypermethylation between salivary rinses collected with and without an exfoliating brush. Salivary rinse collection without using an exfoliating brush may offer a cost effective, rapid, non-invasive, and reliable means for development of epigenetic salivary rinse biomarkers.


Parallel lives: Intergroup contact, threat, and the segregation of everyday activity spaces.
Although intergroup contact can reduce prejudice, opportunities to experience such contact are often constrained by systems of segregation. Work on this problem has focused on divisions entrenched within institutions of residence, education, and employment. Our research employed a complementary approach, which treated segregation as the outcome of individuals' movements over time within everyday life spaces. Taking as a case study Catholics' and Protestants' use of public environments in north Belfast, we used GPS tracking technology, combined with GIS analytics, to explore the time geography of residents' activity space use over a 2-week period (Study 1). We also conducted a field survey to explore how psychological factors shaped their willingness to use activity spaces beyond their own communities (Study 2). Analysis based on around 1,000 hr of raw movement data revealed that north Belfast is marked by high levels of segregation, expressed via residents' limited use of public spaces, facilities, and pathways located in outgroup areas. However, use of shared spaces is also common, with Catholics spending more time in such spaces than Protestants. Structural equation modeling suggested that residents' self-reported willingness to use activity spaces outside their own communities was associated with both negative and positive intergroup contact-relationships partially mediated by realistic threat, symbolic threat, and anxiety over interaction across sectarian lines. Both kinds of contact and realistic threat were also associated with the time residents actually spent in spaces beyond their own communities. Opportunities for integrating psychological and geographic research on contact and segregation are highlighted. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G.
The interaction of the eukaryotic translation initiation factor eIF4E with the initiation factor eIF4G recruits the 40S ribosomal particle to the 5' end of mRNAs, facilitates scanning to the AUG start codon, and is crucial for eukaryotic translation of nearly all genes. Efficient recruitment of the 40S particle is particularly important for translation of mRNAs encoding oncoproteins and growth-promoting factors, which often harbor complex 5' UTRs and require efficient initiation. Thus, inhibiting the eIF4E/eIF4G interaction has emerged as a previously unpursued route for developing anticancer agents. Indeed, we discovered small-molecule inhibitors of this eIF4E/eIF4G interaction (4EGIs) that inhibit translation initiation both in vitro and in vivo and were used successfully in numerous cancer-biology and neurobiology studies. However, their detailed molecular mechanism of action has remained elusive. Here, we show that the eIF4E/eIF4G inhibitor 4EGI-1 acts allosterically by binding to a site on eIF4E distant from the eIF4G binding epitope. Data from NMR mapping and high-resolution crystal structures are congruent with this mechanism, where 4EGI-1 attaches to a hydrophobic pocket of eIF4E between β-sheet2 (L60-T68) and α-helix1 (E69-N77), causing localized conformational changes mainly in the H78-L85 region. It acts by unfolding a short 310-helix (S82-L85) while extending α-helix1 by one turn (H78-S82). This unusual helix rearrangement has not been seen in any previous eIF4E structure and reveals elements of an allosteric inhibition mechanism leading to the dislocation of eIF4G from eIF4E.


Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas.
Stimulation of the antitumor immune response by dendritic cells (DC) is critically dependent on their tightly regulated ability to produce interleukin-12 (IL-12). To enhance this effect artificially, bone marrow (BM)-derived DC were genetically engineered to produce high levels of functional IL-12 by ex vivo infection with a recombinant defective adenovirus (AdCMVIL-12). DC-expressing IL-12 injected into the malignant tissue eradicated 50-100% well established malignant nodules derived from the injection of two murine colon adenocarcinoma cell lines. Successful therapy was dependent on IL-12 transfection and was mediated only by syngeneic, but not allogeneic BM-derived DC, indicating that compatible antigen-presenting molecules were required. The antitumor effect was inhibited by in vivo depletion of CD8+ T cells and completely abrogated by simultaneous depletion with anti-CD4 and anti-CD8 mAbs. Mice which had undergone tumor regression remained immune to a rechallenge with tumor cells, showing the achievement of long-lasting systemic immunity that also was able to reject simultaneously induced concomitant untreated tumors. Tumor regression was associated with a detectable CTL response directed against tumor-specific antigens probably captured by DC artificially released inside tumor nodules. Our results open the possibility of similarly treating the corresponding human malignancies.


Machine Learning Algorithms in Suicide Prevention: Clinician Interpretations as Barriers to Implementation.
Machine learning algorithms in electronic medical records can classify patients by suicide risk, but no research has explored clinicians' perceptions of suicide risk flags generated by these algorithms, which may affect algorithm implementation. The objective of this study was to evaluate clinician perceptions of suicide risk flags. Participants (n = 139; 68 with complete data) were mental health clinicians recruited to complete online surveys from October 2018 to April 2019. Most participants preferred to know which features resulted in a patient receiving a suicide flag (94.12%) and reported that knowing those features would influence their treatment (88.24%). Clinicians were more likely to report that some algorithm features (increased thoughts of suicide) would alter their clinical decisions more than others (age, physical health conditions; χ² = 270.84, P < .001). Clinicians were more likely to report that they would create a safety/crisis response plan in response to a suicide risk flag compared to other interventions (χ² = 227.02, P < .001), and 21% reported that they would complete a no-suicide contract following a suicide risk flag. Clinicians overwhelmingly reported that suicide risk flags in electronic medical records would alter their clinical decision making. However, clinicians' likelihood of acting in response to a suicide risk flag was tied to which features were highlighted rather than the presence of the risk flag alone. Thus, the utility of a suicide risk algorithm will be reduced if clinical features underlying the algorithm are hidden from clinicians or if clinicians do not view the clinical features as intuitively meaningful predictors of suicide risk.


Safety and efficacy of the combination acetaminophen-codeine in the treatment of pain of different origin.
Pain is the most common reason people see doctors in developed Countries and a very common cause of access in Emergency Department (ED). The combination acetaminophen/codeine represents the standard medication in the second step of the WHO analgesic scale and codeine is one of the most commonly used opioid analgesic for a variety of pain conditions. However, many aspects related to safety and efficacy are still undefined. To summarize and review the results of the most relevant studies on the efficacy and safety profile of acetaminophen/codeine combination in the treatment of pain of different origin. We performed a literature search to identify and evaluate all relevant english-language randomized controlled trials (RCTs), meta-analyses and reviews about the codeine plus paracetamol combination in the treatment of pain from any source. Acetaminophen/codeine combination is effective in the treatment of moderate to severe pain in all setting analyzed in this study, which include headache, postoperative, osteoarticular and post-traumatic. The best results in terms of safety and efficacy have been obtained in postoperative pain. Efficacy of acetaminophen/codeine combination is not inferior to NSAIDs. Acetaminophen/codeine combination is effective in the treatment of pain, through a synergistic action of the two molecules, and is not inferior to NSAIDs. Side effects of acetaminophen/codeine are usually minor, differently from NSAIDs, which may induce some potentially life threatening conditions.


Quantitative Microscopy Reveals Stepwise Alteration of Chromatin Structure during Herpesvirus Infection.
During lytic herpes simplex virus 1 (HSV-1) infection, the expansion of the viral replication compartments leads to an enrichment of the host chromatin in the peripheral nucleoplasm. We have shown previously that HSV-1 infection induces the formation of channels through the compacted peripheral chromatin. Here, we used three-dimensional confocal and expansion microscopy, soft X-ray tomography, electron microscopy, and random walk simulations to analyze the kinetics of host chromatin redistribution and capsid localization relative to their egress site at the nuclear envelope. Our data demonstrated a gradual increase in chromatin marginalization, and the kinetics of chromatin smoothening around the viral replication compartments correlated with their expansion. We also observed a gradual transfer of capsids to the nuclear envelope. Later in the infection, random walk modeling indicated a gradually faster transport of capsids to the nuclear envelope that correlated with an increase in the interchromatin channels in the nuclear periphery. Our study reveals a stepwise and time-dependent mechanism of herpesvirus nuclear egress, in which progeny viral capsids approach the egress sites at the nuclear envelope via interchromatin spaces.


Reduction of in-hospital cardiac arrest with sequential deployment of rapid response team and medical emergency team to the emergency department and acute care wards.
This study aimed to determine if sequential deployment of a nurse-led Rapid Response Team (RRT) and an intensivist-led Medical Emergency Team (MET) for critically ill patients in the Emergency Department (ED) and acute care wards improved hospital-wide cardiac arrest rates. In this single-center, retrospective observational cohort study, we compared the cardiac arrest rates per 1000 patient-days during two time periods. Our hospital instituted a nurse-led RRT in 2012 and added an intensivist-led MET in 2014. We compared the cardiac arrest rates during the nurse-led RRT period and the combined RRT-MET period. With the sequential approach, nurse-led RRT evaluated and managed rapid response calls in acute care wards and if required escalated care and co-managed with an intensivist-led MET. We specifically compared the rates of pulseless electrical activity (PEA) in the two periods. We also looked at the cardiac arrest rates in the ED as RRT-MET co-managed patients with the ED team. Hospital-wide cardiac arrests decreased from 2.2 events per 1000 patient-days in the nurse-led RRT period to 0.8 events per 1000 patient-days in the combined RRT and MET period (p-value = 0.001). Hospital-wide PEA arrests and shockable rhythms both decreased significantly. PEA rhythms significantly decreased in acute care wards and the ED. Implementing an intensivist-led MET-RRT significantly decreased the overall cardiac arrest rate relative to the rate under a nurse-led RRT model. Additional MET capabilities and early initiation of advanced, time-sensitive therapies likely had the most impact.


Serotonin syndrome presenting as pulmonary edema.
Serotonin syndrome (SS) is a potentially life-threatening condition resulting from excessive central and peripheral serotonergic activity. Clinically, it is a triad of mental-status changes, neuromuscular abnormalities, and autonomic disturbances. It can be caused by intentional self-poisoning, overdose, or inadvertent drug interactions. We report the case of a 58-year-old male with type 2 diabetes mellitus and obsessive compulsive disorder who developed pulmonary edema as a possible complication of SS. SS was caused by a combination of three specific serotonin re-uptake inhibitors (fluoxetine, fluvoxamine, and sertraline), linezolid, and fentanyl. The hospital course was further complicated by difficult weaning from the ventilator. SS was identified and successfully treated with cyproheptadine and lorazepam. The case highlights the importance of effective consultation-liaison and prompt recognition of SS as the presentation may be complex in the presence of co-morbid medical illness.


Aqueous two-phase system patterning of detection antibody solutions for cross-reaction-free multiplex ELISA.
Accurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross-reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co-localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings.


The 2020 Pandemic: Current SARS-CoV-2 Vaccine Development.
Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome infecting animals and humans. Coronaviruses have been described more than 70 years ago and contain many species. Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are lethal species caused by human coronaviruses (HCoVs). Currently, a novel strain of HCoVs, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19). SARS-CoV-2 was first identified in December 2019 in Wuhan, the capital city of the Hubei province of China, and has since spread worldwide causing an outbreak in more than 200 countries. The SARS-CoV-2 outbreak was declared a pandemic on March 11th, 2020 and a public health emergency of international concern (PHEIC) in late January 2020 by the World Health Organization (WHO). SARS-CoV-2 infects the respiratory tract causing flu-like symptoms and, in some, may cause severe illness like pneumonia and multi-organ failure leading to death. Today, Covid-19 cases almost reaching 9 million, with more than 450 thousand deaths. There is an urgent demand for developing a vaccine since no effective therapies or vaccines have been approved to this day to prevent or minimize the spread of the infection. In this review, we summarized the furthest vaccines in the clinical pipeline.


Using the Borg rating of perceived exertion scale to grade the intensity of a functional training program of the affected upper limb after a stroke: a feasibility study.
Intensity of a training program is a critical variable in treatment gains poststroke, but there are no guidelines to adequately dose the intensity of functional training (FT); the recommended type of training to promote poststroke recovery. Such guidelines are made available for strength training (ST) using the 1 repetition maximum (1RM), which has been linked to individuals' self-rated level of exertion using the Borg rating of perceived exertion (BRPE) scale. The BRPE could be a valuable tool for clinicians to dose FT intensity after a stroke, but this remains to be tested. The main objective of the study was to evaluate the feasibility of the BRPE at grading FT intensity of the affected upper limb in older adults with a chronic stroke and secondarily to explore the clinical changes between FT and ST when the intensity is regulated with BRPE. Twelve participants were randomized into a FT or ST group and trained their affected upper limb (3 times/week for 4 weeks) with the intensity standardized with BRPE. Feasibility was assessed by adherence, occurrence of adverse events, and comparison of BRPE ratings between groups. Clinical changes were defined as improvements on the Fugl-Meyer motor assessment (FMA) and Wolf motor function test (WMFT). All participants adhered to FT/ST without adverse effects, and comparable BRPE ratings were noted between groups throughout the training (P≥0.42). Both groups showed significant gains at the FMA (ST: 5±4 points/FT: 6±4 points; P=0.04) and WMFT (ST: 0.4±0.3 points/FT: 0.6±0.4 points; P=0.05), which were comparable between groups (P≥0.47). The results suggest that it is feasible to use the BRPE scale to adjust FT intensity. Gains in motor function in both groups suggest that undergoing therapy, regardless of its type, might be a sufficient stimulus to produce gains when intensity is adequately adjusted. Further studies are needed to validate the current observations.


Multi-timescale reinforcement learning in the brain.
To thrive in complex environments, animals and artificial agents must learn to act adaptively to maximize fitness and rewards. Such adaptive behavior can be learned through reinforcement learning1, a class of algorithms that has been successful at training artificial agents2-6 and at characterizing the firing of dopamine neurons in the midbrain7-9. In classical reinforcement learning, agents discount future rewards exponentially according to a single time scale, controlled by the discount factor. Here, we explore the presence of multiple timescales in biological reinforcement learning. We first show that reinforcement agents learning at a multitude of timescales possess distinct computational benefits. Next, we report that dopamine neurons in mice performing two behavioral tasks encode reward prediction error with a diversity of discount time constants. Our model explains the heterogeneity of temporal discounting in both cue-evoked transient responses and slower timescale fluctuations known as dopamine ramps. Crucially, the measured discount factor of individual neurons is correlated across the two tasks suggesting that it is a cell-specific property. Together, our results provide a new paradigm to understand functional heterogeneity in dopamine neurons, a mechanistic basis for the empirical observation that humans and animals use non-exponential discounts in many situations10-14, and open new avenues for the design of more efficient reinforcement learning algorithms.


Surface diffusion and islanding in semiconductor heterostructures.
Molecular beam epitaxy (MBE) is an important technique for the creation of new, non-equilibrium semiconductor materials and structures exhibiting novel physical phenomena. Surface diffusion plays an important role in the growth of these structures, influencing such fundamental growth processes and constants as islanding, critical thickness and epitaxial temperatures. Two approaches to the general problem of surface diffusion and islanding, using the SiGe system as a prototypical semiconductor heterostructure, are discussed: The time evolution of patterned deposits, and kinetic studies of nucleation and growth. While disordered laminar growth occurs for deposition at 300 K, elevated temperatures lead to Stranski-Krastanow (SK) growth (uniform coverage theta SK with excess Ge in islands). Diffusion coefficients for Ge on Si(100) have been determined for coverages below theta SK and show a significant coverage dependence. They are extremely sensitive to contamination with carbon on the order of approximately 0.05 ML, as well as to e-beam irradiation. In situ annealing experiments were performed to study the islanding process in real time. Provided the initial coverage exceeds the thickness of the SK layer, theta SK approximately 3 ML on Si(100)2 x 1, the initially uniform but disordered layer begins to collapse into a SK-type morphology at about 250 degrees C. At a ramping rate of 0.1 degrees C/s this process is completed at approximately 400 degrees C. A temperature dependence of the SK-layer thickness has been discovered for the first time. It is in excellent agreement with theoretical predictions.


In everybody's interest but no one's assigned responsibility: midwives' thoughts and experiences of preventive work for men's sexual and reproductive health and rights within primary care.
Sexual and reproductive health and rights (SRHR) have historically been regarded as a woman's issue. It is likely that these gender norms also hinder health care providers from perceiving boys and men as health care recipients, especially within the area of SRHR. The aim of this study was to explore midwives' thoughts and experiences regarding preventive work for men's sexual and reproductive health and rights in the primary care setting. An exploratory qualitative study. Five focus group interviews, including 4-5 participants in each group, were conducted with 22 midwives aged 31-64, who worked with reproductive, perinatal and sexual health within primary care. Data were analysed by latent content analysis. One overall theme emerged, in everybody's interest, but no one's assigned responsibility, and three sub-themes: (i) organisational aspects create obstacles, (ii) mixed views on the midwife's role and responsibility, and (iii) beliefs about men and women: same, but different. Midwives believed that preventive work for men's sexual and reproductive health and rights was in everybody's interest, but no one's assigned responsibility. To improve men's access to sexual and reproductive health care, actions are needed from the state, the health care system and health care providers.


DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis.
The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated), and ATR (ATM and Rad3-related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes. In all cases, the key neuroprotective function of these kinases is uncertain. It also remains unclear how interactions between the three DNA damage-responsive kinases coordinate genome stability, particularly in a physiological context. Here, we used a genetic approach to identify the neural function of DNA-PKcs and the interplay between ATM and ATR during neurogenesis. We found that DNA-PKcs loss in the mouse sensitized neuronal progenitors to apoptosis after ionizing radiation because of excessive DNA damage. DNA-PKcs was also required to prevent endogenous DNA damage accumulation throughout the adult brain. In contrast, ATR coordinated the DDR during neurogenesis to direct apoptosis in cycling neural progenitors, whereas ATM regulated apoptosis in both proliferative and noncycling cells. We also found that ATR controls a DNA damage-induced G2/M checkpoint in cortical progenitors, independent of ATM and DNA-PKcs. These nonoverlapping roles were further confirmed via sustained murine embryonic or cortical development after all three kinases were simultaneously inactivated. Thus, our results illustrate how DNA-PKcs, ATM, and ATR have unique and essential roles during the DDR, collectively ensuring comprehensive genome maintenance in the nervous system. The DNA damage response (DDR) is essential for prevention of a broad spectrum of different human neurologic diseases. However, a detailed understanding of the DDR at a physiological level is lacking. In contrast to many in vitro cellular studies, here we demonstrate independent biological roles for the DDR kinases DNA-PKcs, ATM, and ATR during neurogenesis. We show that DNA-PKcs is central to DNA repair in nonproliferating cells, and restricts DNA damage accumulation, whereas ATR controls damage-induced G2 checkpoint control and apoptosis in proliferating cells. Conversely, ATM is critical for controlling apoptosis in immature noncycling neural cells after DNA damage. These data demonstrate functionally distinct, but cooperative, roles for each kinase in preserving genome stability in the nervous system.


Reward for Bdellovibrio bacteriovorus for preying on a polyhydroxyalkanoate producer.
Bdellovibrio bacteriovorus HD100 is an obligate predator that invades and grows within the periplasm of Gram-negative bacteria, including mcl-polyhydroxyalkanoate (PHA) producers such as Pseudomonas putida. We investigated the impact of prey PHA content on the predator fitness and the potential advantages for preying on a PHA producer. Using a new procedure to control P. putida KT2442 cell size we demonstrated that the number of Bdellovibrio progeny depends on the prey biomass and not on the viable prey cell number or PHA content. The presence of mcl-PHA hydrolysed products in the culture supernatant after predation on P. putida KT42Z, a PHA producing strain lacking PhaZ depolymerase, confirmed the ability of Bdellovibrio to degrade the prey's PHA. Predator motility was higher when growing on PHA accumulating prey. External addition of PHA polymer (latex suspension) to Bdellovibrio preying on the PHA minus mutant P. putida KT42C1 restored predator movement, suggesting that PHA is a key prey component to sustain predator swimming speed. High velocities observed in Bdellovibrio preying on the PHA producing strain were correlated to high intracellular ATP levels of the predator. These effects brought Bdellovibrio fitness benefits as predation on PHA producers was more efficient than predation on non-producing bacteria.


A biomechanical and histological analysis of standard versus hydroxyapatite-coated pins for external fixation.
This sheep study was designed to make a comparative evaluation of two external fixation pin types each with and without hydroxyapatite (HA) coating. The two pins had different taper, pitch, and self drilling capabilities. Twenty Orthofix standard, self-tapping pins (group A), 20 Orthofix HA-coated, self-tapping pins (group B), 20 X-caliber, self-drilling, self-tapping pins (group C), and 20 X-caliber HA-coated, self-drilling, self-tapping pins (group D) were selected. Four pins were implanted in the right femurs of 20 adult sheep that were euthanized at 6 weeks. Mean pin insertion torque was 2745 +/- 822 Nmm in group A, 2726 +/- 784 Nmm in group B, 2818 +/- 552 Nmm in group C, and 2657 +/- 732 Nmm in group D (ns). Mean pin extraction torque was 1567 +/- 541 Nmm in group A, 2524 +/- 838 Nmm in group B, 1650 +/- 650 Nmm in group C, and 2517 +/- 726 Nmm in group D. HA-coated pins (group B and D) had a significantly greater mean pin extraction torque compared to similar uncoated pins (group A and C) (p < 0.0005). Histological analysis showed good osteointegration of the two coated pin types. This study shows that HA-coating is more important for optimal pin fixation than the particular combination of design parameters used in each pin type.


Device-scale perpendicular alignment of colloidal nanorods.
The self-assembly of nanocrystals enables new classes of materials whose properties are controlled by the periodicities of the assembly, as well as by the size, shape, and composition of the nanocrystals. While self-assembly of spherical nanoparticles has advanced significantly in the past decade, assembly of rod-shaped nanocrystals has seen limited progress due to the requirement of orientational order. Here, the parameters relevant to self-assembly are systematically quantified using a combination of diffraction and theoretical modeling; these highlight the importance of kinetics on orientational order. Through drying-mediated self-assembly, we achieve unprecedented control over orientational order (up to 96% vertically oriented rods on 1 cm(2) areas) on a wide range of substrates (ITO, PEDOT:PSS, Si(3)N(4)). This opens new avenues for nanocrystal-based devices competitive with thin film devices, as problems of granularity can be tackled through crystallographic orientational control over macroscopic areas.


Using normalisation process theory to understand workflow implications of decision support implementation across diverse primary care settings.
Effective implementation of technologies into clinical workflow is hampered by lack of integration into daily activities. Normalisation process theory (NPT) can be used to describe the kinds of 'work' necessary to implement and embed complex new practices. We determined the suitability of NPT to assess the facilitators, barriers and 'work' of implementation of two clinical decision support (CDS) tools across diverse care settings. We conducted baseline and 6-month follow-up quantitative surveys of clinic leadership at two academic institutions' primary care clinics randomised to the intervention arm of a larger study. The survey was adapted from the NPT toolkit, analysing four implementation domains: sense-making, participation, action, monitoring. Domains were summarised among completed responses (n=60) and examined by role, institution, and time. The median score for each NPT domain was the same across roles and institutions at baseline, and decreased at 6 months. At 6 months, clinic managers' participation domain (p=0.003), and all domains for medical directors (p<0.003) declined. At 6 months, the action domain decreased among Utah respondents (p=0.03), and all domains decreased among Wisconsin respondents (p≤0.008). This study employed NPT to longitudinally assess the implementation barriers of new CDS. The consistency of results across participant roles suggests similarities in the work each role took on during implementation. The decline in engagement over time suggests the need for more frequent contact to maintain momentum. Using NPT to evaluate this implementation provides insight into domains which can be addressed with participants to improve success of new electronic health record technologies. NCT02534987.


Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid.
Patients who undergo thyroidectomy for medullary carcinoma of the thyroid gland (MTC) often have elevations of postoperative serum calcitonin levels, which are indicative of metastatic or residual disease. It has been extremely difficult to localize tumor in these patients with standard diagnostic studies such as ultrasonography, computed tomography, or magnetic resonance imaging scans. Previous studies have suggested that planar technetium 99m (V) dimercaptosuccinic acid (DMSA) scintigraphic scans can localize MTC in these patients. We have recently increased the sensitivity of planar scintigraphic images by using single-photon emission tomography (SPECT). This study was performed to compare the sensitivity of planar DMSA scans with that of SPECT DMSA scans. Two normal volunteers and three patients with occult MTC after previous total thyroidectomy underwent planar and SPECT DMSA scans. Each patient subsequently underwent surgical exploration based on the DMSA scans. Physiologic DMSA uptake was noted in the nasopharynx, axial skeleton, breast, liver, spleen, heart, kidneys, urinary bladder, great vessels, and skeletal muscles in both normal volunteers and patients with occult MTC. Planar DMSA scans and dynamic computed tomographic scans failed to localize MTC in any of these patients who had minimal disease. SPECT DMSA scans correctly localized cervical MTC in two of three patients, as proved by subsequent surgical resection. One patient who had a negative cervical exploration is presumed to have had a false-positive SPECT DMSA scan. SPECT DMSA scans appear to be a sensitive, safe, and noninvasive localization technique for patients with occult MTC who have undergone previous thyroidectomy.


Use of nanoclay as an environmentally friendly flame retardant synergist in polyamide-6.
Due to their very high levels of flame retardancy, chlorinated and brominated flame retardants had been the most widely used flame retardant additives in plastics industry. However, these flame retardants lead to formation of very toxic volatiles and by-products during fire. Therefore, the recent trend is to replace all of them with non-halogenated flame retardants. In this respect, the use of nanoclays as a synergist flame retardant is becoming more and more important. Thus, the main aim of this work was to investigate the synergistic flame retardant effect of nanoclays with phosphorous compounds in polyamide-6 composites. For this purpose, exfoliated clay nanocomposites of flame retarded/glass fiber reinforced polyamide-6 were prepared by melt compounding. A flame retardant based on phosphorus compounds was used at various levels in glass fiber reinforced polyamide-6 and nanocomposites. Flammability and fire behaviors were evaluated by limiting oxygen index, UL94 and cone calorimeter tests. Substitution of a certain fraction of the flame retardant with nanoclays was found to significantly reduce the peak heat release rate and delay the ignition in cone calorimeter. Moreover, remarkable improvements were obtained in limiting oxygen index along with maintained UL94 ratings.


Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.
The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency.


Genes, race, and culture in clinical care: racial profiling in the management of chronic illness.
Race, although an unscientific concept, remains prominent in health research and clinical guidelines, and is routinely invoked in clinical practice. In interviews with 58 primary care clinicians we explored how they understand and apply concepts of racial difference. We found wide agreement that race is important to consider in clinical care. They explained the effect of race on health, drawing on common assumptions about the biological, class, and cultural characteristics of racial minorities. They identified specific race-based clinical strategies for only a handful of conditions and were inconsistent in the details of what they said should be done for minority patients. We conclude that using race in clinical medicine promotes and maintains the illusion of inherent racial differences and may result in minority patients receiving care aimed at presumed racial group characteristics, rather than care selected as specifically appropriate for them as individuals.


Learning in the 2-bottle alcohol preference test.
The 2-bottle preference test is a popular protocol for characterizing a rodent's selection of a variety of solutions. Little attention has been paid, however, to the role of learning in this procedure. We explored the role of learning in 2-bottle alcohol preference (AP) in mice by recording changes between days and periods (every 3 days the alcohol and water tubes were interchanged) throughout a 15-day standard exposure protocol in use in our laboratory. Male and female ethanol-naive mice of 2 BALB strains (cJ and cByJ), both characterized by low AP scores in the 2-bottle test, exhibited decreases in AP among days but the magnitude of the change depended on test period: relatively large reductions in AP between Day 1 and the subsequent 2 days of the first 3-day test period, smaller decreases between days during Period 2, while there were no significant differences between days during Periods 3 and 4. Thus, the ability of the mice to adapt to changes in tube position improved with increasing experience with the test until asymptote was reached. Study of mice from a C57BL/6JXBALB/cCrgl intercross with a wide range of AP scores showed that learning in the 2-bottle test was not restricted to inbred animals. In this genetically heterogeneous group, learning was shown to be flexible according to an animal's idiosyncratic pattern of alcohol intake: mice characterized by low AP scores on the basis of their 15-day mean AP index exhibited decreases across Days and Periods similar to those shown by the BALB mice (who also had low alcohol consumption) but F(2) mice characterized by high overall AP scores exhibited increases in AP across Periods. Two-bottle AP scores are known to be affected by genetic influences and environmental variation before test administration. The present data provide evidence of learning within the 2-bottle test situation and this phenomenon may help understand the biobehavioral mechanisms underlying preference behavior.


Characterization of the autophosphorylation of chicken gizzard caldesmon.
Caldesmon, an actin- and calmodulin-binding protein of smooth muscle, is a protein serine/threonine kinase capable of Ca2+/calmodulin-dependent autophosphorylation [Scott-Woo & Walsh (1988) Biochem. J. 252, 463-472]. Phosphorylation nullifies the inhibitory effect of caldesmon on the actin-activated Mg2+-ATPase activity of smooth-muscle myosin [Ngai & Walsh (1987) Biochem. J. 244, 417-425]. We have characterized the kinase activity of caldesmon of chicken gizzard smooth muscle. Autophosphorylation requires Ca2+/calmodulin, but is unaffected by other second messengers (Ca2+/phospholipid/diacylglycerol, cyclic AMP or cyclic GMP), and is inhibited by the calmodulin antagonists chlorpromazine and compound 48/80, with 50% inhibition at 39.8 microM and 12.0 ng/ml respectively. Half-maximal activation of autophosphorylation occurs at 60-80 nM-Ca2+ and 0.14 microM-calmodulin, and maximal activity at 0.14-0.18 microM-Ca2+ and 1 microM-calmodulin; activation is gradually lost at higher Ca2+ and calmodulin concentrations. Autophosphorylation is pH-dependent, with maximal activity over the range pH 7-9, and requires free Mg2+ in addition to the MgATP2- substrate. The Km for ATP is 15.6 +/- 4.1 microM (mean +/- S.D., n = 4), and kinase activity is inhibited by increasing ionic strength [half-maximal inhibition at I = 0.094 +/- 0.009 M (mean +/- S.D., n = 4)]. Autophosphorylation does not affect the rate of hydrolysis of caldesmon (free or bound to calmodulin) by alpha-chymotrypsin. However, a slight difference in peptides generated from phospho- and dephospho-forms of caldesmon is observed. The binding of phospho- or dephospho-caldesmon to F-actin protects the protein against chymotryptic digestion, but does not alter the pattern of peptide generation. Characterization of proteolytic fragments of caldesmon generated by alpha-chymotrypsin and Staphylococcus aureus V8 protease enables localization of the phosphorylation sites and the kinase active site within the caldesmon molecule.


Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.
Structured approaches like the adverse outcome pathway (AOP) framework offer great potential for depicting complex toxicological processes in a manner that can facilitate informed integration of mechanistic information in regulatory decisions. While this concept provides a structure for organizing evidence and facilitates consistency in evidence integration; the process, inputs, and manner in which AOPs and AOP networks are developed is still evolving. Following the OECD guiding principles of AOP development, we propose three AOPs for male reproductive tract abnormalities and derive a putative AOP network. The AOPs were developed using a fundamental understanding of the developmental biology of the organs of interest, paying close attention to the gestational timing of key events (KEs) to very specifically inform the domain of life stage applicability for the key event relationships (KERs). Chemical stressor data primarily from studies on low molecular weight phthalates (LMWPs) served to 'bound' the pathways of focus in this dynamic period of development and were integrated with the developmental biology data through an iterative process to define KEs and conclude on the extent of evidence in support of the KERs. The AOPs developed describe the linkage between 1) a decrease in Insl3 gene expression and cryptorchidism, 2) the sustained expression of Coup-tfII and hypospadias and 3) the sustained expression of Coup-tfII and altered Wolffian duct development/ epididymal agenesis. A putative AOP network linking AOP2 and AOP3 through decreased steroidogenic biosynthetic protein expression and converging of all AOPS at the population level impaired fertility adverse outcome is proposed. The network depiction specifies and displays the KEs aligned with their occurrence in gestational time. The pathways and network described herein are intended to catalyze collaborative initiatives for expansion into a larger network to enable effective data collection and inform alternative approaches for identifying stressors impacting this sensitive period of male reproductive tract development.


[Pancreas structure in fetuses and newborn infants who died in the perinatal period].
In the pancreas of fetuses at weeks 22-40 of prenatal development (n = 111) and of newborn infants who died during the first week of postnatal life (n = 38) the changes were detected that were characterized by exocrine part hypoplasia, retardation of acinar pancreatocyte differentiation, connective tissue outgrowth, pancreatic (Langerhans) islet hyperplasia and hypertrophy. The results of the study have shown that with the increase of the total risk sum of the perinatal period pathology development (expressed in balls), the relative content of the insular part of the organ and the number of large pancreatic islets (larger than 100 microm in diameter) decreased. The morphological features detected in this study indirectly reflect endo-ecologically discomfortable conditions of fetus development within the fetoplacental unit which increase the risk of polyendocrinopathy development and fetal intrauterine growth retardation. These polyendocrinopathies increase further the risk of endocrine disturbance occurence in childhood.


Dermatoglyphic patterns in Alzheimer's disease.
Selected dermatoglyphic variables were analyzed in 50 patients with presumed Alzheimer's disease (AD), 50 patients with dementia referable to other causes, and 100 control patients without known dementia matched for age, sex, and race. AD patients have a significantly increased frequency of ulnar loops on the fingertips, Simian creases on the palms, palmar hypothenar patterns; and large distal loops in the hallucal region. A trend involving an increased frequency of radial loops on the fourth and fifth digits, Sydney lines on the palms, and small distal loops on the soles was also observed. The presence of eight or more ulnar loops or bilateral hypothenar patterns separates AD patients from controls with 84% sensitivity and 63% specificity, supporting the discriminant value of dermatoglyphics in the categorization of patients and in the potential identification of asymptomatic persons at increased risk for AD by dermatoglyphic criteria. The dermatoglyphic patterns observed in the AD patients correspond remarkably with patterns repeatedly observed in Down's syndrome and parents of Down's syndrome children, suggesting that a common genetic factor modulates epidermal ridge formation during fetal development, meiotic non-disjunction during gametogenesis, and accelerated neuronal senescence.


Patient satisfaction with transgender health services.
Measuring patient satisfaction (i.e., patients' subjective evaluation of health care services received) is increasingly important in assessing health care outcomes because of the current emphasis on greater partnership between providers (therapist, doctor, staff) and consumers (patients) in health care. In care of transgender persons, achieving good patient satisfaction is particularly challenging given the primary role mental health professionals play as arbiters of who has access to sex reassignment and when such candidates are ready. Dependence on a mental health professional in this "gate-keeping" role is perceived by some members of the transgender community as unnecessarily pathologizing. This study compared satisfaction ratings of 180 transgender and 837 other sexual health patients with psychotherapeutic, psychiatric, and sexual medicine services provided at a university-based sexual health clinic. Five consecutive surveys conducted during 1993-2002 showed high patient satisfaction. We found few significant differences between transgender and other sexual health patients, except that in 1995, transgender patients had higher satisfaction on their perceived ability to handle the problems that originally had led them to therapy. Survey results helped target areas in need of improvement (e.g., friendliness and courtesy of staff, handling of phone calls), and efforts by the providers to improve services resulted in significant increases in patient satisfaction. These findings put individual complaints in perspective and showed that despite the challenges inherent in providing transgender care good satisfaction can be achieved. We encourage providers to implement quality assurance and improvement procedures to give patients the opportunity to provide feedback and have a voice in shaping their own health care.


[Relationship between visceral diseases and oral health].
The paper analyzes the literature showing that there is not only a phylogenetic relationship, but also a functional one between visceral diseases and oral health. It gives data on the unity of the occurrence of somatic and dental diseases. There is evidence for cause-and-effect relationships between them, which arise from immune imbalance, interleukin dysregulation, and nonspecific inresistance. There was a negative comorbidity of visceral diseases and oral health, namely, a relationship of dental diseases to the patients' general condition, as well as the impact of the foci of chronic oral infection on the development of systemic diseases. Mechanisms of a relationship between oral infection and secondary systemic manifestations are also described. It has been established that transient bacteremia odontogenic is detected at a dental visit and conditions for its transformation to any infectious diseases are also outlined. Unified systems approaches to treating polymorbidity are found to be needed.


Assessing toxicity of the insecticide thiacloprid on Chironomus riparius (Insecta: Diptera) using multiple end points.
Since data documentation on neonicotinic toxicity to nontarget organisms should be enhanced, we investigate the effects of thiacloprid, a novel neonicotinoid insecticide, on the sediment-dwelling nontarget insect Chironomus riparius. Further, we wanted to validate the sensitivity of end points on different biological levels and obtain the greatest amount of information regarding the effects of this compound by using a battery of several end points such as larval mortality, behavior, body weight gain, emergence rate, time of development, gender ratio, Hsp70 stress protein level, and larval mouthpart deformities after exposure at a concentration range of 0.1 to 1000 microg/L thiacloprid. C. riparius was impacted starting at concentrations of 0.5 microg/L, a concentration that can be considered environmentally relevant. Larval mortality, behavior, emergence, and Hsp70 protein level were sensitive indicators for the toxic effect of thiacloprid, whereas gender ratio and mouthpart morphology were not affected. In our case life-cycle end points like survival rate (LC(50): 1.57 microg/L) and emergence rate (EC(50): 0.54 microg/L) proved to be more sensitive than tested physiological end points for the neurotoxic insecticide.


A gradient of acute gastroenteritis was characterized, to assess risk of long-term health sequelae after drinking bacterial-contaminated water.
A municipal water system became contaminated with Escherichia coli O157:H7 and Campylobacter spp. Beginning 2 years after an outbreak, all residents from the region were invited to participate in a cohort study assessing the risk of long-term sequelae. We aimed to develop a method to grade the accuracy and severity of self-reported acute symptoms. We corroborated participant survey responses with health records at the time of the outbreak. Of the 4,135 participants, 1,388 were asymptomatic during the outbreak, 1,752 had symptoms of acute self-limited gastroenteritis that could neither be confirmed nor refuted by prior health records, and 995 had symptoms that necessitated medical attention (and thus were confirmed by prior health records). The gradient related to the severity of acute symptoms. Compared to those with unconfirmed gastroenteritis, participants with confirmed gastroenteritis were more likely to describe fever, bloody diarrhea, and prolonged diarrhea (all P < .03). The gradient also correlated with long-term plausible outcomes, including chronic gastrointestinal symptoms, chronic symptoms of arthritis or depression, and the avoidance of municipal water ingestion after the outbreak (P for trend consistently < .03). Conversely, for the outcome of chronic tinnitus, an association was neither expected nor observed (P for trend = .26). We successfully characterized a gradient to be used in future primary analyses assessing the risk of long-term health sequelae after an outbreak.


Adult intradural primary spinal cord tumors.
Primary spinal cord tumors represent 4.5% of all central nervous system neoplasms. They are either intradural intramedullary or intradural extramedullary. Intramedullary tumors are predominantly intrinsic gliomas (astrocytomas and ependymomas). Spinal ependymomas can usually be completely removed by separating the tumor from the spinal cord and, when complete, no further therapy is required. Astrocytomas, by contrast, infiltrate the myelon, and therefore surgery is frequently incomplete. Intradural extramedullary tumors are mostly benign (WHO grade 1) and comprise either peripheral nerve sheath tumors (neurofibromas and schwannomas) or meningiomas. Complete resection can be performed on both lesions and is often curative. Radiotherapy is indicated for primary malignant tumors (WHO grade 3 and higher) and for patients in whom surgery is contraindicated. For grade 1 and 2 tumors, the role of radiotherapy is controversial. Chemotherapy is reserved for recurrent primary spinal cord tumors with no other options. However, the lack of clinical trials for these tumors is problematic. Consequently, treatment is similar to that for intracranial histologies. Early recognition of the signs and symptoms of primary spinal cord tumors facilitates early treatment, potentially minimizes neurologic morbidity, and improves outcome. Primary treatment for almost all spinal cord tumors is surgery, with predictors of outcome being preoperative functional status, grade of tumor, and extent of resection.


Planetary ball milling and supercritical fluid technology as a way to enhance dissolution of bicalutamide.
Dissolution of bicalutamide processed with polyvinylpyrrolidone by either supercritical carbon dioxide or ball milling has been investigated. Various compositions as well as process parameters were used to obtain binary systems of the drug with the carrier. Thermal analysis and powder X-ray diffractometry confirmed amorphization of bicalutamide mechanically activated by ball milling and the decrease in crystallinity of the supercritical carbon dioxide-treated drug. Both methods led to reduction of particles size what was confirmed by scanning electron microscopy and laser diffraction measurements. Moreover, the effect of micronisation was found to depend on the parameters of applied process. Fourier transform infrared spectroscopy revealed the appearance of intermolecular interactions between drug and carrier molecules that play an important role in the stabilization of amorphous form of the active compound. Changes in crystal structure combined with reduced size of particles of bicalutamide dispersed within polymer matrix were found to improve dissolution of bicalutamide by 4 to 10-fold in comparison to untreated drug. It is of particular importance as poor dissolution profiles are considered to be the major limitation in bioavailability of the drug.


Coil embolization of intracranial aneurysms with ipsilateral carotid stenosis: technical considerations.
Simultaneous occurrence of carotid atherosclerotic disease and ipsilateral cerebral aneurysm is known because of common risk factors. When interventional neuroradiologists encounter such cases, issue of 'in which order to treat these lesions ' is raised. If carotid artery disease is treated first, then acute increase in perfusion pressure and high dose antiplatelets might increase the risk of aneurysm rupture. If aneurysm coiling is performed first, the stroke risk may increase due to manipulations through plaque and compromise of cerebral flow secondary to catheter placement through stenotic vessel. Even though aneurysm coiling first is a rational approach, there are technical problems like crossing the carotid lesion safely and making sure that placement of catheter through the stenosed vessel will not compromise the cerebral blood flow. This technical report describes our protocol in performing safe and successful coil embolization in three cases with moderate carotid stenosis and ipsilateral intracranial aneurysm. Our emphasis is mainly on technical considerations with the aim of avoiding cerebral embolism during crossing of carotid plaque and to avoid compromise of cerebral blood flow using 'syngo iflow'. These technical considerations may have important implications in treatment of intracranial aneurysm in patients with moderate ipsilateral cervical carotid stenosis.