Towards a compact spherical tokamak fusion pilot plant.
The question of size of a tokamak fusion reactor is central to current fusion research especially with the large device, ITER, under construction and even larger DEMO reactors under initial engineering design. In this paper, the question of size is addressed initially from a physics perspective. It is shown that in addition to size, field and plasma shape are important too, and shape can be a significant factor. For a spherical tokamak (ST), the elongated shape leads to significant reductions in major radius and/or field for comparable fusion performance. Further, it is shown that when the density limit is taken into account, the relationship between fusion power and fusion gain is almost independent of size, implying that relatively small, high performance reactors should be possible. In order to realize a small, high performance fusion module based on the ST, feasible solutions to several key technical challenges must be developed. These are identified and possible design solutions outlined. The results of the physics, technical and engineering studies are integrated using the Tokamak Energy system code, and the results of a scoping study are reviewed. The results indicate that a relatively small ST using high temperature superconductor magnets should be feasible and may provide an alternative, possibly faster, 'small modular' route to fusion power. This article is part of a discussion meeting issue 'Fusion energy using tokamaks: can development be accelerated?'.


Damage targeted to the mitochondrial interior induces autophagy, cell cycle arrest and, only at high doses, apoptosis.
It is generally accepted that permeabilization of the outer mitochondrial membrane is a crucial event in the induction of apoptosis. In order to know how the cell would respond to the damage targeted not to the outer mitochondrial membrane, but to the mitochondrial interior, we followed the changes in cell morphology and some biochemical parameters triggered by ROS in the mitochondrial inner space. The experiments were carried out in epidermoid carcinoma A431 cells. For stimulated production of singlet oxygen in the inner space of mitochondria, we employed photodynamic treatment (PDT) mediated by a cationic photosensitizer 7-diamino-2,8-dimethyl-5-phenylphenazinium chloride (Safranin O, Safr), accumulating in the inner space of mitochondria. At low to intermediate cytotoxic doses (up to CD50 reducing cellular viability by 50%), Safr-PDT did not reveal hallmarks of dead cells, and the decrease of cellular viability could be attributed to cell cycle inhibition, and enhanced autophagy. High Safr-PDT doses (beyond CD70) did induce cell death by apoptosis involving release of cytochrome c and caspase-3 activation, in addition to enhanced autophagy.


The comparative absorption and excretion of chemical vapors by the upper, lower, and intact respiratory tract of rats.
Upper respiratory tract (URT) absorption of several compounds with differing water solubilities and potentials to cause lesions of the nasal mucosa were studied in rats. Absorption of propylene glycol monomethyl ether (PGME), PGME acetate (PGMEAc), ethyl acrylate (EA), epichlorohydrin (EPI), styrene (STY), nitroethane (NE), ethylene dibromide (EDB), and methylene chloride (MeCl2) vapors by the isolated URT was compared to that by the isolated lower respiratory tract (LRT) and the intact animal. Nearly all PGME and PGMEAc and 30-70% of EA, EPI, STY, NE, and EDB were absorbed when passed through the URT. In general, similar levels were absorbed by both the isolated LRT and intact animal. It was estimated that intact animals received more than 90% of their total dose of PGME and PGMEAc, and 50% of EA, NE, EPI, and EDB via the URT. Further, the dosage per unit of surface area in the URT may be 5000-6000 times that of the LRT. However, the extent of URT absorption was not related to the ability to cause lesions of the nasal mucosa. Absorption of compounds by the URT was not a simple function of water solubility or of blood or water/air partitioning coefficients suggesting that a more complex mechanism for controlling absorption may exist. In one case, it was demonstrated that URT enzymatic activity could influence the absorption of certain compounds by the URT.


Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.
Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016.


Cytokine dermatitis and febrile seizure from imiquimod.
Cytokine dermatitis is a well-known and common clinical adverse effect of imiquimod 5% cream (Aldara, 3M). Data from initial Phase III clinical trials reveal a minority of study drug patients experience systemic adverse effects, including fever, arthralgia, headache, myalgia, and lymphadenopathy. These adverse effects are caused, presumably, from increased absorption of study drug over the area of dermatitis, leading to systemic cytokine release. Furthermore, the incidence of systemic reactions was rarely statistically increased above control patients. We describe herein a case of severe cytokine dermatitis in a 2-year-old female patient treated with daily imiquimod for molluscum contagiosum who subsequently developed febrile seizure. We believe this to be the first reported case of seizure associated with imiquimod 5% cream (Aldara, 3M) in a pediatric setting.


Tie-2 and angiopoietin-2 expression at the fetal-maternal interface: a receptor ligand model for vascular remodelling.
The blood vessels at the fetal-maternal interface widen dramatically during pregnancy in order to increase blood flow to nourish the developing fetus. This vessel remodelling destroys normal vessel integrity and encompasses the dissolution of vessel muscle and elastic tissue. It also includes the displacement of endothelial cells by fetal trophoblasts that invade the maternal arteries of the uterus. Interaction between the endothelial cell receptor, Tie-2, and its recently discovered antagonist ligand, angiopoietin-2 (Ang-2), has been implicated in the loosening of vessel structure. Using Northern blot hybridization and RNA in-situ hybridization analysis the expression pattern of Tie-2, and Ang-2 in the placenta throughout pregnancy, was investigated. We found Ang-2 expressed in the syncytiotrophoblast during the first trimester. In addition to the expected expression of the Tie-2 receptor in both fetal and maternal endothelial cells, we observed Tie-2 expression in endovascular invasive trophoblasts. These cells of epithelial origin invade the uterine spiral arteries and acquire endothelial cell properties. The temporal- and lineage-specific pattern of expression of Tie-2 and Ang-2 suggests that this receptor-ligand pair functions during the critical phase of development of the fetal vasculature and reworking of the maternal vessels during normal placentation.


[Novel germline SAMD9 mutation in an elderly patient with myelodysplastic syndrome].
An 80-year-old Japanese male patient presented to our hospital with complaints of fatigue. His peripheral blood tests revealed pancytopenia with predominant lymphocytes and without blasts. The bone marrow (BM) aspiration was unsuccessful due to a dry tap, and the subsequent BM biopsy revealed hypocellular marrow with fibrosis. He was diagnosed with myelodysplastic syndrome (MDS) with excess blasts (EB)-2 based on CD34-positive cells. The chromosome analysis of the BM revealed monosomy 7, and the SAMD9 W22* mutation was detected (variant allele frequency [VAF] of 51.22%) using next-generation sequencing. An identical mutation was observed in the buccal mucosa (VAF of 50%), which was confirmed as a germline mutation. The SAMD9 gene mutation is reported as one of the causative genes for MIRAGE syndrome and child-onset MDS. The present case was considered a loss-of-function mutation due to the near full-length SAMD9 deletion. This is the first adult case of MDS with SAMD9 W22* as a germline mutation.


Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library.
Structure-guided phage display was used to select for combinations of interface residues for antibody C(H)3 domains that promote the formation of stable heterodimers. A C(H)3 "knob" mutant was made by replacement of a small residue, threonine, with a larger one, tryptophan: T366W. A library of C(H)3 "hole" mutants was then created by randomizing residues 366, 368 and 407, which are in proximity to the knob on the partner C(H)3 domain. The C(H)3 knob mutant was fused to a peptide flag and the C(H)3 hole library was fused to M13 gene III. Phage displaying stable C(H)3 heterodimers were recovered by panning using an anti-flag antibody. Phage-selected C(H)3 heterodimers differed in sequence from the previously designed heterodimer T366W-Y407'A, and most clones tested were more stable to guanidine hydrochloride denaturation. The thermal stability of individual C(H)3 domains secreted from Escherichia coli was analyzed by differential scanning calorimetry. One heterodimer, T366W-T366'S:L368'A:Y407'V, had a t(m) of 69.4 degrees C, which is 4.0 deg.C higher than that for the designed heterodimer and 11.0 deg.C lower than that for the wild-type homodimer. The phage-selected C(H)3 mutant maintained the preference for forming heterodimers over homodimers as judged by near-quantitative formation of an antibody/immunoadhesin hybrid in a cotransfection assay. Phage optimization provides a complementary and more comprehensive strategy to rational design for engineering homodimers for heterodimerization.


The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association.
In this report, we introduce the CDKN2A Database, an online database of germline and somatic variants of the CDKN2A tumor suppressor gene recorded in human disease through the year 2002, annotated with evolutionary, structural, and functional information. The CDKN2A Database improves upon existing resources by: 1) including both somatic mutations and germline variants, thereby adding the perspective of somatic cell carcinogenesis to that of hereditary cancer predisposition; 2) including information that assists with the interpretation of allelic variants, such as other primary data (sequences, structures, alignments, functional measurements, and literature references) and annotations (extensive text, figures, and a tree-based phylogenetic classification); and 3) providing the information in a format that allows a user to either download the database or to easily manipulate it online. We describe the database structure, content, current uses, and potential implications (http://biodesktop.uvm.edu/perl/p16).


Association of State Legislation of Human Papillomavirus Vaccination with Vaccine Uptake Among Adolescents in the United States.
We assessed the association of state legislation with adolescent human papillomavirus (HPV) vaccination rates in states that legislated information dissemination or administration of HPV vaccination. Using insurance claims, we calculated monthly HPV vaccination rates (November 2009-December 2017) among adolescents in states that passed HPV vaccination legislation during that period: Missouri (July 2010), Kentucky (February 2012), Indiana (March 2013), Oregon (June 2013). We used segmented regression to estimate levels and trends of HPV vaccination rates, comparing pre-legislation to post-legislation segments, adjusting for seasonal vaccination patterns and changes to the vaccination recommendation among males during the study period. Indiana's legislation allowed pharmacists to administer HPV vaccination; legislation in Kentucky, Missouri, and Oregon included provisions HPV and cervical cancer education. No statistically significant increases in HPV vaccination levels or trends were observed in the post-legislation segments among adolescents overall; however, a significant post-legislation increase in vaccination trends was observed among boys in Missouri (β = 0.16, p = 0.03). Evidence for a positive impact of legislation on HPV vaccination rates is limited. The scarcity of policies that directly facilitate or promote HPV vaccination, and the breadth of exemptions to school vaccination requirements, may limit the effectiveness of these policies. Continuing efforts to introduce and pass legislation that directly facilitates HPV vaccination, combined with promoting existing evidence-based interventions, can provide opportunities to identify the most effective strategies to increase adolescent HPV vaccination rates.


Type B aortic dissection with rupture of the left common iliac artery: a case report.
Type B aortic dissection involves the appearance of a false lumen distal to the left subclavian artery and extending distally into the descending thoracic aorta and into the abdominal aorta. Complications of the dissection include rupture of the thoracic aorta, leg ischemia, visceral ischemia, and renal failure. A 37-year-old man presented with complaints of sudden onset of chest pain, left leg pain, and numbness. Examination revealed no femoral, popliteal, or distal pulses with decreased sensory and motor function on the left lower extremity. A CT scan revealed an aortic dissection at the proximal descending aorta extending into the iliac arteries with a left retroperitoneal hematoma at the iliac bifurcation. An MRI confirmed the dissection distal to the left subclavian artery into the iliac artery with a distal occlusion. Exploration revealed rupture of the left iliac artery dissection with arterial occlusion and a contained hematoma. The common iliac artery was ligated and an 8-mm Dacron bypass graft from the right common femoral artery to the left femoral artery was performed. Type B aortic dissection can present as rupture of the common iliac artery. Revascularization of the extremity with a femoral-femoral crossover graft is the recommended procedure in the absence of visceral ischemia. The surgeon should have a keen suspicion of this rare complication and its management.


Rectal benzodiazepines for premedication in children. Review and personal experience.
Modern anesthetic techniques have modified the aims of premedication in pediatric practice. Anxiolysis, amnesia and easiness of induction are now the the main targets. This paper reviews both the literature and the personal experience of the authors on the subject. Many authors now prefer a benzodiazepine. Rectal instillation of benzodiazepine in solution avoids the trauma of the intramuscular route and produces a faster and more predictable effect, than suppositories. Diazepam (.1 to .2 mg/kg) and flunitrazepam (40 to 80 micrograms/kg) have been extensively used in this indication. Diazepam's duration of elimination being much longer than that of flunitrazepam, this last drug is preferred by many pediatric anesthetists. Midazolam (.4 to .5 mg/kg) has a much faster onset and shorter duration of action. It should thus be preferred if the environment enables the administration of premedication within 10 to 15 minutes of induction.


Subtrochanteric osteotomy effectively treats femoroacetabular impingement after slipped capital femoral epiphysis.
Femoroacetabular impingement causing pain and deformity often follows in situ pinning for severe, stable (Grade III) slipped capital femoral epiphysis. We asked whether a transverse percutaneous subtrochanteric osteotomy using external fixation could decrease pain, restore function and motion, and improve radiographic outcome. We performed a transverse subtrochanteric osteotomy with external fixation in 13 patients who had prior in situ pinning for severe slipped capital femoral epiphysis. All patients had decreased function, limited range of motion, pain with ambulation, and a limp after in situ pinning. We evaluated the patients using Southwick's categorical classification. The patients' ages ranged from 11 to 17 years; there were five boys and eight girls. The minimum followup was 32 months (average, 43 months; range, 32-92 months). Considering pain as a criterion, 11 patients had good or excellent results (two fair). Twelve patients had good results (one fair) for function, 11 had good results (two fair) for limping, and 11 had good or excellent results (two fair) for motion. Radiographic parameters showed nine good results and four fair results. Subtrochanteric three-dimensional correction using a percutaneous transverse osteotomy and external fixation effectively improved symptoms of femoroacetabular impingement after pinning of a severe slipped capital femoral epiphysis. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.


Complete removal of vagus nerve stimulator generator and electrodes.
Vagus nerve stimulation has become widely used in the palliative treatment of refractory epilepsy. Removal of a vagus nerve stimulator may be desirable or even necessary due to lack of efficacy, intolerable side effects, signs of infection, or failure of the device. Unless the lead or the helical electrodes are defective, only the generator is explanted and the electrodes are usually left behind for fear of damaging nerve or surrounding structures. The authors review their experience with complete removal of the stimulating electrodes and pacemaker-like generator device in 9 consecutive patients, 3 of whom were children. Using microsurgical techniques, the authors were able to completely remove the stimulator, including electrodes in all patients. All nerves remained morphologically intact. One case of temporary and one of permanent clinically silent ipsilateral vocal cord paresis were observed.


Cell proliferation and cell sheet detachment from the positively and negatively charged nanocomposite hydrogels.
The charged nanocomposite hydrogels (NC gels) were synthesized by copolymerization of positively or negatively chargeable monomer with N-isopropylacrylamide (NIPAm) in the aqueous suspension of hectorite clay. The ionic NC gels preserved the thermo-responsibility with the phase-transition temperature below 37°C. The L929 cell proliferation was sensitive to charge polarity and charge density. As compared to the PNIPAm NC gel, the cationic NC gels with <5 mol % of 2-(dimethylamino)ethyl methacrylate (DMAEMA) showed improved cell proliferation, whereas the cells grew slowly on the gels with negatively charged 2-acrylamido-2-methylpropane sulfonic acid (AMPSNa). By lowering temperature, rapid cell sheet detachment was observed from the surface of ionic NC gels with 1 mol % of ionizable monomers. However, lager amount of AMPSNa or DMAEMA did not support rapid cell sheet detachment, probably owing to the adverse swelling effects and/or enhanced electrostatic attraction.


Modification of the theory of dual radiation action for attenuated fields. I. Basic formalism.
A modification of the Theory of Dual Radiation Action is described to take into account the effects of an attenuated beam of radiation across the sensitive site of the cell. It is shown that, unlike the case of uniform radiation, the coefficient of the dose-squared (intertrack) term is not constant, but varies in a manner dependent on the attenuation coefficient of the radiation and the geometry of the site.


External Validation of the IOTA Classification in Women with Ovarian Masses Suspected to Be Endometrioma.
The study aimed to perform external validation of the International Ovarian Tumor Analysis (IOTA) classification of adnexal masses as benign or malignant in women with suspected endometrioma. A retrospective study including women referred to an endometriosis tertiary referral center for dedicated transvaginal ultrasound (TVUS). Adnexal masses were evaluated using the IOTA classification simple descriptors, simple rules and expert opinion. The reference standard was definitive histology after mass removal at laparoscopy. In total, 621 women were evaluated and divided into four groups: endometrioma on TVUS and confirmed on surgery (Group 1 = 181), endometrioma on TVUS but other benign cysts on surgery (Group 2 = 9), other cysts on TVUS but endometrioma on surgery (Group 3 = 2), masses classified as other findings or suspicious for malignancy on TVUS and confirmed on surgery (Group 4 = 5 potentially malignant, 11 benign). This gave a sensitivity 98.9%, specificity 64%, positive 95.3% and negative 88.9% predictive values, positive 2.74 and negative 0.02 likelihood ratios and 94.7% overall accuracy. The surgical diagnosis for the five masses suspected to be malignant was: borderline serous tumor (2), borderline mucinous tumor (2), and endometrioid lesion with complex hyperplasia without atypia (1). The conclusions were that the IOTA classification simple descriptors, simple rules and expert opinion performs well for classifying adnexal masses suspected to be endometrioma. The most common potentially malignant masses in these women were borderline ovarian tumors.


Dendritic cell function in lupus: Independent contributors or victims of aberrant immune regulation.
Dendritic cells (DCs) represent an important component of the immune system connecting the innate and adaptive immune responses. They are able to trigger strong immunity as well as tolerance against certain antigens, and therefore it is obvious that they have a central role in the expression of immunological diseases. However, because DCs are sparse, heterogeneous and plastic, their exact role in complex autoimmune diseases, such as systemic lupus erythematosus (SLE) remains not well defined. In this review, we make an attempt to summarize critically recent knowledge on the role of conventional DCs in the expression of autoimmunity and pathology in SLE.


TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression.
Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.


The importance of story-telling: research protocols in aboriginal communities.
AN ORAL TRADITION AND STORY TELLING CULTURE are still central to aboriginal personal and community identity, and provide major means of remembering and conveying personal and community experience with university researchers. These stories describe stark accounts of betrayal and upset, as well as descriptions of positive experiences. They provide dramatic reminders to researchers of the importance of respectful and collaborative relationships with traditional community leaders and their members.


A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria: usefulness for the detection of platelet antibodies.
The tendency of platelets and leukocytes to lyse after their interaction with antibody and complement was studied by measuring the release of (51)Cr from cells labeled with this isotope. Platelets from six patients with paroxysmal nocturnal hemoglobinuria (PNH) were 15-230 times more sensitive to antibodies and 10-32 times more sensitive to complement than normal platelets or platelets from patients with other types of thrombocytopenic or hemolytic disorders. Mixed white blood cell (WBC) preparations from patients with PNH were 3-20 times more sensitive to anti-WBC antibodies and 5-10 times more sensitive to C' than were WBC preparations from normal subjects, but PNH lymphocytes showed normal immunologic reactivity. PNH platelets, like PNH erythrocytes, lysed more readily than normal platelets in acidified serum and in media of reduced ionic strength, but these characteristics were not demonstrable with PNH WBC's under the conditions of study. In PNH, platelets appear to comprise a single population with respect to their sensitivity to immune lysis, yet their survival time as measured with (51)Cr falls within normal limits. PNH granulocytes likewise appear to consist of a single, uniformly sensitive population. It is concluded that, in PNH, platelets and granulocytes share the membrane defect characteristic of erythrocytes in this disorder. These observations support the concept that PNH arises as the result of a somatic mutation in a primitive cell capable of differentiating into erythroblast, myeloblast, and megakaryoblast lines. PNH platelets or enzymatically treated normal platelets permit the detection of some types of platelet antibodies in dilutions up to 2000-fold greater than is possible with currently available methods, a finding suggesting that the immune lysis technique will prove useful for the study of platelet immunology.


Prediction and preliminary screening of HLA-A*0201-restricted epitope peptides of human GPC3.
In response to the limited therapeutic option for hepatocellular carcinoma (HCC), immunotherapy as a promising approach points out a new direction to the cure of tumours through specific recognition and elimination of tumour cells by the immunity-enhanced autologous immunocytes of patients. Few effective tumour antigens, however, are alternative in addition to alpha fetoprotein or tumour cell lysates. Recent studies have demonstrated that glypican-3 (GPC3) is not only a promising diagnostic marker, but also ideal therapeutic target to HCC. In this study, potential HLA-A*0201 GPC3 peptides were screened with three epitope prediction software, the binding affinity of 13 predicted epitopes with high scores was determined by T2 cells binding assay and four optimal epitopes were identified. This is the first study in which the optimal HLA-A*0201 GPC3 epitopes were screened from a large number of candidates predicted by three software. The optimized HLA-A*0201 GPC3 peptides will provide new epitope candidates for HCC immunotherapy.


Decellularized human liver scaffold-based three-dimensional culture system facilitate hepatitis B virus infection.
Hepatitis B virus (HBV) study is hampered by lacking of idea cell model which support effective HBV infection and meanwhile recapitulate hepatocyte biology function in vivo. In this study, we developed decellularized human liver scaffolds for cell culture and further applied for HBV infection. As a result, primary human hepatocytes (PHHs) engrafted into liver scaffolds and maintained differentiation with stable albumin secretion and liver-specific gene expression. Comparing to mono-layer cell culture, scaffold-based three-dimensional (3D) culture system significantly augment HBV DNA (including cccDNA), RNA level as well as HBsAg secretion. Moreover, HepG2-NTCP cells cultured on 3D system exhibited higher infection efficiency and longer infection period in vitro. In addition, HBV DNA level was suppressed when anti-HBV medicine Entecavir (ETV) introduced into HepG2-NTCP 3D system. Herein, we evaluated the potential of decellularized human liver scaffold-based in 3D cell culture and disclosed that scaffold-based 3D culture system can facilitate HBV infection in vitro. This 3D culture system could be further applied in HBV-related study. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1744-1753, 2019.


Modelling multi-type transmission of pneumococcal carriage in Bangladeshi families.
The burden of pneumococcal carriage is largest in developing countries from which, however, detailed studies on pneumococcal transmission are missing. In this study we followed nasopharyngeal carriage in Bangladeshi infants (n=99) from birth, with 2-week sampling intervals until age 4 months, and monthly thereafter until age 1 year, and also their family members at the same intervals. We assessed the dependence of pneumococcal acquisition rates on age, serotype, serotype-specific exposure (i.e. transmission) and current state of carriage (yes/no). A statistical model of pneumococcal transmission, taking into account incompletely observed data, was applied to estimate rates of acquisition and clearance for a large number of serotypes at the same time. Serotypes that were common in the study population were more often acquired from the community than rarer serotypes. However, when conditioning on serotype-specific exposure within the family, transmission rates were similar between different serotypes. Exposure within families signified more than tenfold increase in the rate of acquisition.


Integrating CKD Into US Primary Care: Bridging the Knowledge and Implementation Gaps.
Chronic kidney disease (CKD) affects 37 million American adults who experience high rates of cardiovascular events and are at risk of kidney failure and mortality. Routine primary care case finding for CKD with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (uACR) should focus on risk conditions, particularly diabetes, hypertension, and cardiovascular disease, as recommended by clinical practice guidelines. The diagnosis of CKD is associated with many important aspects of care, including patient awareness, patient engagement, and improved implementation of evidence-based interventions. Individualized care that tailors CKD interventions proportional to the adverse outcome risk or the eGFR and uACR heat map is a major challenge for primary CKD care, because the condition is heterogeneous in terms of both the cause and the severity. The coordinated care approach to CKD management is necessary to deploy best practice in chronic disease management that engages the interdisciplinary team. An integrated system supports the time-constrained primary clinician with CKD registry functions, clinical decision support tools, quality improvement initiatives, and payment model incentives to drive reduction in adverse outcomes and containment of expenditures. A CKD population health strategy can be built to address primary care education and implementation gaps from the perspectives of testing, detection of disease, interventions, and coordinated system-integrated care. Registry function and data monitoring of the burden of CKD, delivery interventions, and outcomes are key features. Implementation of the Race-free 2021 CKD-(Epidemiology Collaboration) EPI eGFR reporting recommendations by engaging local nephrology, administrative, clinical laboratory, and health equity leaders should help drive the population health design strategy and the data assessment.


Influence of time of day and partial sleep loss on muscle strength in eumenorrheic females.
Disrupted sleep is the most common form of sleep deprivation in travellers, shift workers, athletes the night before important competitions and among parents of infants. The influence of partial sleep loss on muscle strength might differ according to the time of testing on the following day. This study was therefore designed to assess the interaction between the effects of partial sleep loss and time of day on muscle strength in females. Eight sedentary eumenorrheic females (mean +/- SD; age 30 +/- 6 years, height 1.62 +/- 0.06 m and body mass 67 +/- 5.0 kg) took part in the study, in a counterbalanced design. Measurements of muscle strength were carried out at 06:00 and 18:00 hours after the one control night (no sleep loss) and the one night of partial sleep loss, during menses. Muscle strength measures included isokinetic (at 1.05, 3.14 rad s(-1); 90 degrees range of motion) and isometric peak torque (at 60 degrees of knee flexion) of knee extensors and flexors (dominant leg). In addition, isometric force of knee extensors with super-imposed electrical twitches (50 Hz, 250 V, 200 mus pulse width) was measured using the same procedure in order to control for motivation. Rectal temperature was measured during the 30 min before muscle strength measurements. Partial sleep loss consisted of allowing 2.5 h sleep (between 03:00 and 05:30 h), whilst in the control condition (no sleep loss) subjects retired between 22:30 and 23:30 h, rising at 05:30 hours. All measurements were conducted at just one phase of the menstrual cycle (menses) to prevent any masking effect due to different phases of the menstrual cycle. In both conditions (with and without partial sleep loss) a diurnal variation was observed in peak torque of knee flexors at 1.05 (F(1,7) = 5.5, p < 0.05) and 3.14 rad s(-1) (F(1,7) = 8.0, p < 0.05); values at 18:00 hours were 4.5 and 5.9% higher than at 06:00 hours, respectively. No significant diurnal variation was observed for the other muscle strength measures. No significant effect of partial sleep loss or interaction effect (sleep x time of day) was observed for muscle strength measures. However, the performance rhythms were in phase with the circadian rhythm in rectal temperature. Partial sleep deprivation over one night did not have any adverse effect on maximal muscle strength, nor on diurnal variations of muscle strength indices. As the effect of time of day was observed with some of the muscle strength measures, it is suggested that, in designing future studies using females, the control of time of day is essential.


Clonal dissemination of Klebsiella pneumoniae ST512 carrying blaKPC-3 in a hospital in southern Italy.
Strains of Klebsiella pneumoniae producing KPC-carbapenemase have emerged as one of the most important multidrug-resistant Gram-negative nosocomial pathogens. Here, we report the first isolation and subsequent dissemination of a K. pneumoniae ST512 producing KPC-3 carbapenemase in a hospital in southern Italy. Isolates were obtained from blood, throat swabs, sputum, catheters, and urine of patients admitted to different hospital wards. Antimicrobial MICs were determined for all isolates by automated systems and confirmed by Etest. Carbapenemase production was confirmed by the modified Hodge test and by a disc synergy test, and carbapenemase genes were investigated by PCR. All isolates were characterized by pulse-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analysis. Most isolates were multidrug resistant with exception of some isolates intermediately susceptible to gentamicin, tigecycline, and trimethoprim-sulfamethoxazole. PCR analysis showed that isolates harbored the bla(KPC-3) gene associated with bla(TEM) and bla(SVH). PFGE and MLST showed that all isolates belonged to the same ST512 clone recently described in Israel.


Ectopic activation of Mycobacterium tuberculosis-specific CD4+ T cells in lungs of CCR7-/- mice.
Initiation of an adaptive cellular immune response depends on intimate interactions with APCs and naive T lymphocytes. We previously reported that activation of naive Mycobacterium tuberculosis-specific CD4+ T cells depends on dendritic cell (DC) transport of live bacteria from the lungs to the mediastinal lymph node (MDLN). Because the migratory paths of DCs are largely governed by the chemokine receptor CCR7, which is expressed on DCs upon maturation by proinflammatory stimuli, we examined the quantitative contribution of CCR7-dependent DC migration in the context of tuberculosis. We found that early trafficking of DCs from the lungs to the MDLN depended on CCR7-mediated signaling, but alternative mechanism(s) are used later in infection. Impaired migration of DCs in CCR7(-/-) mice resulted in delayed dissemination of bacteria to MDLN and spleen and in delayed kinetics of activation of adoptively transferred Ag85B-specific CD4+ T cells. Furthermore, in contrast to control mice, we found that naive Ag85B-specific CD4+ T cells are activated to proliferate in the lungs of CCR7(-/-) mice and, when infected with higher doses of bacteria, resistance to M. tuberculosis infection in CCR7(-/-) mice is compromised compared with wild-type mice.


Safe zone for transacetabular screw fixation using a Kerboull cross-plate: A CT-scan templating prospective study.
Implantation of Kerboull acetabular reinforcement cross-plates (Kerboull plate) carries a risk for injury to vascular structures and pelvic organs. To our knowledge, there is no study assessing anatomical assessment related to this risk with this specific design. Therefore, we performed a prospective study to answer the following four questions: 1) What is the minimum distance and angle between the plate and iliac vessels? 2) What is the distance between the plate and the inner cortex of the ilium? 3) What is the ratio of views with muscle tissue present on the inner surface of the ilium? 4) What are the boundaries of the safe zone for transacetabular screw fixation for a Kerboull plate? A safe zone for fixation screws would be defined by a narrow range of insertion angles. This is a CT-based 3D templating prospective study. Simulations were performed for 18 patients fitted with a Kerboull plate. An original Kerboull plate (Stryker, Mahwah, NJ, USA) was placed at a 45° abduction angle relative to the X-axis (alignment A) and the palette was placed vertically to the X-axis (alignment B). We measured the distance from the centre of the plate to the inner surface of the cortex of the ilium, the shortest distance to vessels and the angle of existing vessels, and the ratio of muscles on the inner surface of the ilium. The shortest distance to the vascular structures increased with increasing angle of insertion of the fixation screws, 85.8±12.1mm for A and 111.4±12.0mm for B at 45°. The distance to the inner cortex was further increased for screws inserted in posterior direction. At insertion angles ≥40°, the screws passed through muscle before invading the pelvis in most cases. However, at anterior-posterior angle (AP angles) ≤-10°, the risk of direct insertion of screws into the sacroiliac joint increased. The safe zone for transacetabular screws would be insertion at an angle≥40°, with an AP angle between 0° and -10° (slight posterior direction). Level IV prospective diagnostic study.


Sequence and structural analysis of the presumed downstream promoter of the canine mdr1 gene.
The product of the canine mdr1 gene, P-glycoprotein (P-gp), plays an important role in chemotherapeutic drug resistance of several canine tumours. Increased expression of P-gp by tumour cells is associated with the multidrug-resistant phenotype. Because of its importance in cancer chemotherapy, a great deal is known about the regulation of mdr1 gene expression in human cancer patients and rodent cancer models. In contrast, there is no information regarding the regulation of P-gp expression in dogs. Initial information regarding the regulation of mdr1 gene expression can be gained by evaluating the mdr1 promoter. The downstream promoter of the canine mdr1 gene was sequenced. Several regulatory elements were identified, including an AP-1 site, AP-2 site and SP-1 site. The presumed canine mdr1 promoter was similar to that of other species; however, low overall sequence homology may suggest that aspects of P-gp regulation are distinctive in dogs.


[How to think a phenomenological clinic].
The emergence of Phenomenology cannot to be understood outside the context of naturalism, the crisis affecting the philosophy and the scientific foundation of psychology toward the end of the 19th century. Binswanger thinks Husserl's attempt to found the experience of the things themselves in intentional living structures can to be useful to guide the psychiatric examination. For that, he seeks in the fundamental dimensions of existence, the conditions of possibility of being sick, which are also those of the same psychiatry. While the phenomenological psycho(patho)logy has not born of direct confrontation with patients, it doesn't mean that it doesn't have internal references with practice. It's proposed then a semiological Eidetic founded in multiple modes of intentionality, or "basic categories", opposite of semiology supported on psychic functions. From etiology to the anthropological a priori of mental illnesses, from the symptom to the phenomenon, here are two possible readings in the field of the clinic.


Evidence-Based Management of Common Gallstone-Related Emergencies.
Gallstone-related disease is among the most common clinical problems encountered worldwide. The manifestations of cholelithiasis vary greatly, ranging from mild biliary colic to life-threatening gallstone pancreatitis and cholangitis. The vast majority of gallstone-related diseases encountered in an acute setting can be categorized as biliary colic, cholecystitis, choledocholithiasis, and pancreatitis, although these diagnoses can overlap. The management of these diseases is uniquely multidisciplinary, involving many specialties and treatment options. Thus, care may be compromised due to redundant tests, treatment delays, or inconsistent management. This review outlines the evidence for initial evaluation, diagnostic workup, and treatment for the most common gallstone-related emergencies. Key principles include initial risk stratification of patients to aid in triage and timing of interventions, early initiation of appropriate antibiotics for patients with evidence of cholecystitis or cholangitis, patient selection for endoscopic biliary decompression, and growing evidence in favor of early laparoscopic cholecystectomy for clinically stable patients.


Medical consequences of terrorism. The conventional weapon threat.
As long as gunpowder and explosives are used to solve disagreements between nations, ethnic groups, and individuals, victims of blast injury continue to arrive occasionally at trauma centers around the world. Bombs planted in crowded urban locations or suicide bombings continue to stress civilian EMS and urban medical systems. Although the clinical presentation depends on whether the blast occurs in open or confined quarters, open air, or water, the pattern of injury inflicted on the body is relatively consistent. The proximity to the detonating device is probably much more important than the size of the bomb. If not injured by secondary, tertiary, or other miscellaneous mechanisms of most conventional bombs with 1 to 20 kg of TNT, people at distances exceeding 6 m will probably not experience substantial blast-induced injury. Three systems are prone to injury. The first is the auditory system, with damage to the eardrum in milder cases and inner-ear injury in more severe cases. The alimentary tract with contusions, hematoma, and occasional perforation of a hollow viscus is the second system involved. Solid organs are rarely damaged in survivors of blast injury. Close proximity to the blast can impose traumatic amputation of limbs (i.e., arms and legs) and ear lobes. Most of these victims succumb to their injuries in the immediate post-injury phase, but the hallmark of blast injury is the involvement of the respiratory system. With expeditious evacuation performed by efficiently coordinated and highly skilled EMS personnel, more patients with blast injuries arrive with signs of life to the medical facility. At the medical facility, the staff need to triage many victims into urgent and nonurgent groups. Only lifesaving procedures should be performed during the initial phase. Later, medical care is directed at patients moved to ICUs. Prompt evacuation after necessary lifesaving procedures in the field; proper triage and distribution; prudent hospital triage and surgical care; and, last but not least, expert critical care provide the best possible outcome in such circumstances.


Treatment of early Parkinson's disease.
The early treatment of Parkinson's disease (PD) consists of nonpharmacologic treatment, consideration of neuroprotective therapy, and initial symptomatic treatment. Education for the patient and family, access to support groups, regular exercise, and good nutrition are essential to the overall management of PD. Disease-modifying therapies, such as agents that provide neurorescue or neuroprotection, will provide a major advance in the treatment of PD. Intervention at the genetic/environmental level or that affects the cascade of pathophysiologic events, protein aggregation, or apoptosis could result in neuroprotection. Many agents are now being investigated for neuroprotective potential. A major paradigm shift has recently occurred because of the recent basic and clinical data indicating that dopamine agonists, rather than levodopa, should be the initial symptomatic therapy in PD. However, levodopa may be started first in some patients because of patient age, cognitive status, or cost of drugs.


Preventing and reversing vacuum-induced optical losses in high-finesse tantalum (V) oxide mirror coatings.
High-finesse optical cavities placed under vacuum are foundational platforms in quantum information science with photons and atoms. We study the vacuum-induced degradation of high-finesse optical cavities with mirror coatings composed of SiO₂-Ta₂O₅ dielectric stacks, and present methods to protect these coatings and to recover their initial low loss levels. For separate coatings with reflectivities centered at 370 nm and 422 nm, a vacuum-induced continuous increase in optical loss occurs if the surface-layer coating is made of Ta₂O₅, while it does not occur if it is made of SiO₂. The incurred optical loss can be reversed by filling the vacuum chamber with oxygen at atmospheric pressure, and the recovery rate can be strongly accelerated by continuous laser illumination at 422 nm. Both the degradation and the recovery processes depend strongly on temperature. We find that a 1 nm-thick layer of SiO₂ passivating the Ta₂O₅ surface layer is sufficient to reduce the degradation rate by more than a factor of 10, strongly supporting surface oxygen depletion as the primary degradation mechanism.


[Normal cardiac diameters in cine-MRI of the heart].
To measure the normal diameters of cardiac cavities in standard cardiac views using cine MRI. Fifty-six volunteers were examined (27 male, 29 female) on a 1.5 T MR unit with ECG-triggered single shot free precision (SSFP) cine MR sequences and parallel image acquisition. Standardized echocardiographic planes were used to depict the heart of all volunteers (short axis, 4-chamber view, left and right 2-chamber views). The different diameters of the cardiac cavities were measured using a fixed protocol. For the estimation of ventricular dilatation, the important female/male cross diameters of the left ventricle are 45.2 +/- 3.4/51.6 +/- 4.6 mm diastolic and 30.5 +/- 3.5/33.8 +/- 3.6 mm systolic, and of the right ventricle 30.7 +/- 3.8/37.1 +/- 5.9 mm diastolic and 22.3 +/- 3.8/28.1 +/- 4.4 mm systolic. For the determination of a left ventricular hypertrophy, relevant septal wall thickness measured in the short axis of the left ventricle of female/male volunteers are 8.0 +/- 1.0/9.9 +/- 1.2 mm diastolic and 10.9 +/- 1.4/13.6 +/- 1.9 mm systolic. The measured normal values of male volunteers were generally higher than those of female volunteers. The thickness of the ventricular septum correlated well when measured in the short axis and 4-chamber view. When measured in the 4-chamber view, the longitudinal diameter of the ventricles had a higher value in diastole and a lower value in systole, compared to the 2-chamber views of the right and left cardiac cavities. The atrial longitudinal diameters were higher in the 4-chamber view compared to the 2-chamber views, without any difference in systole or diastole. Diameters of cardiac cavities are easily and quickly measured. Using the tables with the normal values published here, it is simple to estimate an abnormal size of the heart.


Basic fibroblast growth factor in human prostate cancer cells.
To increase our understanding of the potential role of basic fibroblast growth factor (bFGF) in malignant progression of prostate cancer, we determined the production of bFGF, the expression of FGF receptor (flg), and the response to exogenous bFGF in LNCaP, DU 145, and PC 3 cells. We observed that these three prostate cancer cell lines, which differed in their dependence on androgens for growth in vitro and in their in vivo behavior in nude mice, could be distinguished as follows: (a) androgen-sensitive LNCaP cells, which do not metastasize in nude mice, did not produce measurable amounts of bFGF, expressed small but measurable amounts of FGF receptor mRNA, and did respond to exogeneous bFGF; (b) androgen-insensitive, moderately metastatic DU 145 cells did produce measurable amounts of biologically active bFGF, expressed large amounts of FGF receptor mRNA, and responded to exogeneous bFGF and the heparin-binding fractions from DU 145 cell extracts; (c) androgen-insensitive and highly metastatic PC3 cells also produced measurable amounts of bFGF but did not demonstrate a growth response to either the heparin-binding fractions from PC3 cell extracts or exogenous bFGF, even though large amounts of FGF receptor mRNA were expressed in PC 3 cells. These results suggest the possibility that differences in production of, and response to, bFGF may be associated with different biological behavior.


Improved signal-to-noise ratio in parametric images by cluster analysis.
Parametric images are formed by analyzing the concentration history of every voxel in PET data sets. Because PET concentration data at the voxel level are rather noisy, noise propagation into the parametric image is often quite noticeable. To address this problem, a model-based clustering method has been developed to generate parametric images. The basic idea of the clustering method is to average over voxels whose concentration histories have the same shape. We applied the method to a two-parameter (K1, k2) compartment model of local cerebral blood flow. The statistic R = integral tC(t) dt/integral C(t) dt= integral te-k2t multiply sign in circle Ca(t) dt/integral e-k2t multiply sign in circle Ca(t) dt classifies curves in terms of k2, where C(t) and Ca(t) denote the tissue and blood concentration histories, respectively, and multiply sign in circle is the convolution operator. Simulation studies of noise propagation in the clustering statistic showed that 30% voxel noise yielded a 2% standard deviation in R. Parametric images of blood flow and partition coefficient were computed for an O15 study, with and without clustering. Cluster size affected bias, statistical precision, and computation time. With clusters of 400 voxels, the variance of the flow parameter was around 1/50 smaller with clustering, with negligible bias and a computation time of 30 s on a 64-MHz workstation for 15 x 128 x 128 images with MATLAB 5.1.


Changes in cognitive functioning from 75 to 80 years of age: a 5-year follow-up in two Nordic localities.
The purpose of the study was to analyze changes and stability in cognitive functions among older persons aged from 75 to 80 years, as well as differences in this development between two Nordic localities. The number of subjects taking part in the follow-up phase was 188 in Jyväskylä, Finland, and 184 in Göteborg, Sweden. Cognitive functions were assessed using conventional memory tests (Digit Span Forward and Backward for assessing primary working memory; Visual Reproduction for visual memory) and intelligence tests (Digit Symbol for assessing psychomotor speed; Word Fluency for verbal ability; Raven's Matrices for non-verbal reasoning). With few exceptions, the mean test scores declined significantly among the retested men and women in both localities. Analyses showed that generally over half of the subjects maintained their level of performance over the 5-year period, while a part of the deteriorating minority had a steep decline. There were significant differences in the test performance between the localities both at the baseline and follow-up assessments, but few differences between women and men. On the whole, however, the groups of older women and men from the two Nordic localities had a similar pattern of cognitive development from 75 to 80 years of age.


Field trials with Vectolex (Bacillus sphaericus) and Vectobac (Bacillus thuringiensis (H-14)) against Anopheles gambiae and Culex quinquefasciatus breeding in Zaire.
Under field conditions in Kinshasa, Zaire, an aqueous suspension of Bacillus thuringiensis (H-14), Vectobac (12-AS), lost most of its larvicidal activity at all concentrations after 48 h against Culex quinquefasciatus breeding in polluted gutter water and Anopheles gambiae breeding in clear water irrigation ponds. However, good control of Cx. quinquefasciatus was obtained using a granular formulation of B. sphaericus, Vectolex-G (ABG-6185), at concentrations of 10-30 kg/ha. High concentrations of Vectolex-G gave excellent control of An. gambiae breeding in irrigation ponds. The Vectobac-G was less active against An. gambiae than Vectolex-G, in spite of good dispersion of Vectobac-G particles.


Optically active histidin-2-ylidene stabilised gold nanoparticles.
Drawing from the natural amino acid chiral pool, l and d histidines were utilized as chiral NHC ligands in the synthesis of NHC-stabilized chiroptical gold nanoparticles. Centrifugal size selection afforded monodisperse gold nanoparticles which display mirrored signals in CD spectroscopy.


The effects of mortality salience and conceptual focus in CISM providers: implications for mental health response to mass fatality disasters.
On the basis of terror management theory (TMT) and cognitive-experiential self-theory (CEST), research has demonstrated that when individuals are experientially (rather than rationally)focused, mortality salience (MS) can engender world view defense in the form of increased in-group bias, increased favoritism toward others who uphold cultural values, and greater derogation of those who threaten them. The goal of the present study was to replicate previously observed effects of mortality salience on world view defense in a sample of disaster responders, specifically Criticallncident Stress Management (CISM) providers, and to examine the potential moderating effect of conceptual mode (rational versus experiential) on these effects. Sixty-two participants at the International Critical Incident Stress Foundation's 2011 World Congress were selected for participation in the study. Subsequent manipulation checks revealed that neither,manipulation (mortality salience: MS versus non-MS or conceptual mode: rational versus experiential) was effective. This failure is discussed in terms of the potentially mortality salient nature of conference proceedings that preceded data collection, the depletion of self-control resources required to maintain a rational focus on conference presentations, participants 'need to maintain their focus during future conference presentations, and profession-related practice effects that may have made it easier for some participants to maintain a rational focus.


Endoscopic laser treatment of intrahepatic stones.
Application of the Nd:YAG laser to cholangioscopic lithotomy allows lithotomy for stones that are difficult to remove by conventional methods. Also, when the laser is used in conjunction with PTCD under echo guidance, treatment is completed within a shorter period of time by endoscopic lithotomy than by surgery cases of residual intrahepatic stones, recurrent stones, and for some primary cases. Further, laser irradiation under cholangioscopy is also effective for dilatation of strictured anastomosis after hepaticojejunostomy. It is expected that in the future, preoperative endoscopic lithotomy by laser for hepatolithiasis will come into wide use.


Implementation of a multidisciplinary, team-based model to treat chronic hepatitis C in the primary care setting: Lessons learned.
Hepatitis C virus (HCV) is the most common blood-borne virus in the U.S., and its incidence continues to rise. With approval of direct-acting antiviral medications, treatment for Chronic Hepatitis C (CHC) has become highly efficacious with a minimal side effect profile. Primary care physicians are well-positioned to address this increased demand, yet most do not feel comfortable treating CHC. In this case report, we describe implementation of a multidisciplinary team-based approach for treating CHC at multiple primary care sites across a large safety net health system. We focus on the evolving nature of implementation of our model through iterative Plan-Do-Study-Act (PDSA) cycles, highlighting the importance of developing an interdependent, multidisciplinary team, providing training, and ongoing support of Primary Care Hepatitis C Specialists, responding to the evolving nature of CHC treatment and policies, and ensuring high quality treatment. This process allowed us to continually grow and adapt our approach to make it feasible and successful. We share our "lessons" learned for others looking to bring CHC treatment, and potentially other specialty-based treatment, into the primary care setting.


Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2.
Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.


Long-term results using ossicular grafts.
Sculpted autologous ossicle and cortical bone grafts were the first materials successfully used to reconstruct the ossicular chain in chronic ear surgery. Over the last 20 years, the use of biocompatible implants has been popularized; as a result, bone grafts have fallen into disfavor with most otologists. To determine if autologous bone grafts remain stable with time, 115 cases in which autologous bone grafts were used between 1971 and 1984 were reviewed. Eighty patients underwent Type III tympanoplasty, stapes arch present. Thirty-five underwent Type IV tympanoplasty, stapes arch absent. Minimum follow-up was 2 years; 30 patients were followed for > or = 10 years. In Type III tympanoplasty, overall the initial air/bone gap was 19.7 dB at 6 months, with 59% of those with improved hearing at 15 dB air/bone gap or better. Hearing remained stable for 10 years with overall hearing of 19.2 dB air/bone gap and 50% with an air/bone gap of < or = 15 dB. In Type IV tympanoplasty, the average air/bone gap was 26 dB at 6 months, with 70% of those having improved hearing with < or = 20 dB air/bone gap. At 10 years, the overall air/bone gap was 29.3 dB, with only 28% maintaining an air/bone gap of < or = 20 dB. Poor eustachian tube function and collapse of the middle ear air space were found to be the primary causes for long-term failure. The initial hearing results using autologous bone are comparable with those achieved with synthetic prosthesis. Hearing results using autologous bone remained stable through 5 years. Beyond 5 years, Type III tympanoplasty remained stable, while there was deterioration in Type IV tympanoplasty due to poor eustachian tube function.


Cavernous sinus involvement by extramedullary plasmacytoma of the sphenoid sinus. An argument for the use of adjuvant chemotherapy.
A 63-year-old man with cavernous sinus involvement from extramedullary plasmacytoma (EMP) of the sphenoid sinus is described. Transient resolution of retro-orbital headache and continued progression of the locally extensive tumor were noted after chemotherapy was given following a poor response to 5400 cGy of local irradiation. To determine whether adjunctive chemotherapy will improve the outcome of these particular patients, we propose that a randomized trial comparing radiotherapy to chemoradiation be conducted.


Reduced concentrations of galanin, arginine vasopressin, neuropeptide Y and peptide YY in the temporal cortex but not in the hypothalamus of brains from schizophrenics.
Postmortem investigations were performed in brains from 14 schizophrenic patients and 21 controls matched for age and autopsy latency. Concentrations of galanin, delta-sleep-inducing peptide (DSIP), corticotropin-releasing factor (CRF), arginine vasopressin (AVP), neuropeptide Y (NPY) and peptide YY (PYY) were determined in the hypothalamus and grey matter from the temporal cortex. A significant positive correlation between age and the concentrations of galanin and CRF was found in the controls. No sex differences were found except a higher mean of CRF in the hypothalamus of the women. In the temporal cortex of the schizophrenic brains, galanin, AVP, NPY and PYY were significantly reduced. DSIP reduction only bordered on significance. CRF was not reduced. Comparing neuroleptic-treated vs non-treated schizophrenics, the treatment factor could not explain the reduced concentrations of neuropeptides in the temporal lobe. A comparison of controls with schizophrenics showed no significant differences in hypothalamic neuropeptide concentrations.


Expression proteomics identifies biochemical adaptations and defense responses in transgenic plants with perturbed polyamine metabolism.
Soluble proteins from leaves of transgenic tobacco plants with perturbed polyamine metabolism, caused by S-adenosylmethionine decarboxylase overexpression, were analysed by comparative proteomics. A group of proteins was found to be increasingly repressed, in parallel with the degree of polyamine perturbation, in each of the three independent transgenic lines. These were identified as isoforms of chloroplast ribonucleoproteins, known to be involved in chloroplast mRNA stability, processing and translation. Another group of eight proteins strongly induced in the most metabolically perturbed line was identified as multiple, uncharacterised isoforms of the defense protein PR-1, a known marker for systemic acquired resistance.


Muscle histopathology and plasma aspartate aminotransferase, creatine kinase and myoglobin changes with exercise in horses with recurrent exertional rhabdomyolysis.
Six horses with a history of recurrent exertional rhabdomyolysis (RER) (Horses A-F) and 7 control horses performed a submaximal and later a near-maximal treadmill exercise test. Blood samples were obtained before, during and after exercise and muscle biopsies were taken before and after exercise. At rest, plasma aspartate aminotransferase (AST) activities in horses with RER were above 95% confidence intervals for control horses. During submaximal exercise, 3 horses with RER (A, B and C) had much greater increases in plasma AST, creatine kinase (CK) and myoglobin concentrations than did Horses D, E and F and control horses. Clinical signs of muscle stiffness and pain were only obvious in Horse A. During near-maximal exercise, only Horse C showed a substantial increase in CK activity and myoglobin concentrations without any associated clinical signs of rhabdomyolysis. Muscle biopsies from Horses A, B and C contained necrotic type II fibres which, on electron microscopic examination, contained disrupted myofibrils and swollen mitochondria. These results suggest that, in RER, subclinical episodes of muscle fibre necrosis and associated increases in plasma AST, CK and myoglobin occur with exercise more frequently than could be detected clinically. Furthermore, the pattern of increase in muscle enzymes and myoglobin concentrations in the 6 horses with RER suggested that the high plasma AST and CK activities commonly observed at rest in symptom-free Standardbred horses are probably a result of repeated subclinical episodes of rhabdomyolysis after exercise, rather than leakage due to abnormal sarcolemmal permeability.


The effect of milk proteins on appetite regulation and diet-induced thermogenesis.
There is increasing evidence to support that a high-protein diet may promote weight loss and prevent weight (re)gain better than a low-protein diet, and that the effect is due to higher diet-induced thermogenesis (DIT) and increased satiety. However, data on the effect of different types of protein are limited. In the present study we compare the effect of whey, casein and milk on DIT and satiety. Seventeen slightly overweight (29 ± 4 kg/m(2)) male subjects completed the study. The study had a randomized, crossover design, where the effect on 4 h postprandial energy expenditure (EE), substrate oxidation and subjective appetite sensation of three isocaloric test meals containing either a whey drink, a casein drink or skim milk was examined. Energy intake (EI) at a subsequent ad libitum lunch was also measured. There was no significant effect on subjective appetite sensation, but EI at lunch was lower after the milk test meal than after the casein (9%; P=0.0260) and the whey (9%; P=0.0258) test meals. Postprandial lipid oxidation was significantly higher after the casein test meal compared with the whey test meal (P=0.0147) when adjusted for baseline values. There was no significant difference in effect on EE, protein oxidation or carbohydrate oxidation. Milk reduced subsequent EI more than isocaloric drinks containing only whey or casein. A small but significant increase in lipid oxidation was seen after casein compared with whey.


Urinary nerve growth factor in women with overactive bladder syndrome.
• To measure urinary nerve growth factor (NGF) in women with overactive bladder (OAB)-dry and OAB-wet and investigate the association of urinary NGF expression with these factors. • Differentiation between OAB-wet and OAB-dry was based on symptoms and a 3-day voiding diary. • Urinary NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). • The urinary NGF levels were compared among controls, OAB-dry and OAB-wet subgroups, and also between OAB patients ≥ 55 years and < 55 years, as well as between patients with a body mass index (BMI, kg/m²) < 20, 20-30 and > 30. • A total of 113 women with OAB-dry, 106 with OAB-wet and 84 controls were enrolled. The urinary NGF/creatinine (Cr) levels were significantly highest in OAB-wet (2.13 ± 3.87) and second highest in OAB-dry (0.265 ± 0.59) compared to controls (0.07 ± 0.21). • Analysis of urinary NGF or NGF/Cr levels among controls, OAB-dry and OAB-wet groups by age and BMI showed no significant differences, except for the OAB-dry group. • Urinary NGF/Cr was not significantly correlated with age (P = 0.088) or BMI (P = 0.886) in women with OAB-dry and OAB-wet. • Urinary NGF levels were significantly higher in women with OAB-dry and even higher in women with OAB-wet. • The urinary NGF level was not associated with ageing, menopause or higher BMI either in controls or OAB patients.


[Correlation of the inner diameter parameters of the spermatic vein in different positions and states of the varicocele patient with the results of seminal examination].
To study the correlation of the inner diameter parameters of the spermatic vein in different positions and states of the varicocele (VC) patient with the results of seminal examination. A total of 149 VC patients underwent ultrasonography, routine semen examination, and sperm morphological analysis. The parameters obtained from ultrasonography included the bilateral testis volume in a supine position, the largest spermatic vein diameter in a supine position at rest (DSR), the largest spermatic vein diameter in a supine position following Valsalva manoeuvre (DSV), the largest spermatic vein diameter in an upright position at rest (DUR), and the largest spermatic vein diameter in an upright position following Valsalva manoeuvre (DUV). Then we calculated the parameters △DS=DSV-DSR, △DU=DUV-DUR, △DR=DUR-DSR, and △DV=DUV-DSV and analyzed the correlation of the above parameters with the results of semen examination using the ROC curve. Based on the results of semen examination, 119 (79.87%) of the patients were allocated to the abnormal group and the other 30 (20.13%) to the normal group. Statistically significant differences were observed between the two groups in △DU (P=0.007), △DR (P=0.0001), and △DV (P=0.04), but not in DSR (P=0.35), DSV (P=0.34), DUR (P=0.06), DUV (P=0.12), and △DS (P=0.64), nor in the volume of the testis affected (P=0.323). The area under the ROC curve was 0.55 for DSR, 0.57 for DSV, 0.64 for DUR, 0.62 for DUV, 0.49 for △DS, 0.28 for △DU, 0.86 for △DR, and 0.69 for △DV. The corresponding cutoff values were 2.25, 2.51, 2.48, 2.63, 0.30, 0.23, 0.25, and 0.20, the corresponding sensitivities of semen detection were 50.42%, 65.55%, 60.50%, 60.50%, 49.90%, 29.41%, 79.83%, and 65.55%, and the corresponding specificities were 56.67%, 63.33%, 63.33%, 63.33%, 56.67%, 33.33%, 80%, and 63.33%, respectively. The difference between the largest spermatic vein diameters in supine and upright positions at rest provides a high diagnostic accuracy for semen detection and helps to predict abnormality in seminal examination for VC patients.


Neuroinflammation, Pain and Depression: An Overview of the Main Findings.
Chronic pain is a serious public health problem with a strong affective-motivational component that makes it difficult to treat. Most patients with chronic pain suffer from severe depression; hence, both conditions coexist and exacerbate one another. Brain inflammatory mediators are critical for maintaining depression-pain syndrome and could be substrates for it. The goal of our paper was to review clinical and preclinical findings to identify the neuroinflammatory profile associated with the cooccurrence of pain and depression. In addition, we aimed to explore the regulatory effect of neuronal reorganization on the inflammatory response in pain and depression. We conducted a quantitative review supplemented by manual screening. Our results revealed inflammatory signatures in different preclinical models and clinical articles regarding depression-pain syndrome. We also identified that improvements in depressive symptoms and amelioration of pain can be modulated through direct targeting of inflammatory mediators, such as cytokines and molecular inhibitors of the inflammatory cascade. Additionally, therapeutic targets that improve and regulate the synaptic environment and its neurotransmitters may act as anti-inflammatory compounds, reducing local damage-associated molecular patterns and inhibiting the activation of immune and glial cells. Taken together, our data will help to better elucidate the neuroinflammatory profile in pain and depression and may help to identify pharmacological targets for effective management of depression-pain syndrome.


Murine Peyer's patches favor development of an IL-10-secreting, regulatory T cell population.
Peyer's patches (PP) are believed to be the principal sites for induction of tolerance to Ags from food and commensal flora, yet the phenotype of T cells activated within the PP is largely unexplored. We hypothesize that exposure to Ags within the PP promotes differentiation of T cells with immunoregulatory functions. Cytokine production and cell surface marker expression of murine PP mononuclear cells (MC) are compared with those from mesenteric lymph nodes and peripheral lymph nodes (PLN). In response to stimulation through the TCR/CD3 complex, PP MC exhibit vigorous proliferation, modest production of IL-2, and significantly elevated synthesis of IL-10. Exogenous IL-12 enhances both IL-10 and IFN-gamma secretion by activated PP MC. Cell surface marker analysis reveals that PP T cells consist of activated and memory subpopulations compared with the predominantly naive T cells identified in the PLN and mesenteric lymph nodes. Upon stimulation, only CD45RB(low)CD4(+) PP T cells produce IL-10, whereas secretion of IL-2, IL-4, and IFN-gamma was not detected. Furthermore, PP MC, but not PLN MC, stimulated through the TCR/CD3 complex suppress proliferation of purified PLN T cells in vitro, evidence for a regulatory function among PP lymphocytes. We conclude that PP favor differentiation of an IL-10-producing, regulatory CD45RB(low)CD4(+) T cell population and that inhibition of T cell proliferation by activated PP MC may reflect regulatory activity consistent with T regulatory cells.


Right atrial isomerism in children older than 3 years.
There is a high mortality in infants with right atrial isomerism (RAI). However, less is known about outcome in older children with RAI. This study sought to evaluate those patients with RAI who survived older than 3 years of age without surgical intervention. A total of 33 consecutive patients (20 males) were enrolled in the study, mean age 6 years (range 3-32). None of the patients had surgical intervention for the RAI before age 3. Cardiac abnormalities include altered cardiac position (39 %), atrioventricular valve anomaly (87 %), single or functional single ventricle (55 %), pulmonary/subpulmonary obstruction (97 %), abnormal origin of the aorta (100 %), bilateral superior vena cava (67 %), and anomalous pulmonary venous drainage (66 %). Surgical intervention was performed after 3 years of age in 20 patients (61 %). None of them planned or had biventricular repair performed. 10 patients underwent the total cavopulmonary connection procedure, including four (40 %) who had atrioventricular valve (AVV) repair at the same time [all with common atrioventricular valve (CAVV)]. One patient died the day after the operation. A total of 69 % of patients with a CAVV had moderate or severe regurgitation, while 27 % with a single atrioventricular valve had moderate or severe regurgitation. Patients with RAI who have survived to early childhood without surgical intervention have complex cardiac abnormalities. Survival after single stage total cavopulmonary connection is good but AVV repair is common.


Neural Mechanisms of Hearing Recovery for Cochlear-Implanted Patients: An Electroencephalogram Follow-Up Study.
Patients with severe profound hearing loss could benefit from cochlear implantation (CI). However, the neural mechanism of such benefit is still unclear. Therefore, we analyzed the electroencephalogram (EEG) and behavioral indicators of auditory function remodeling in patients with CI. Both indicators were sampled at multiple time points after implantation (1, 90, and 180 days). First, the speech perception ability was evaluated with the recording of a list of Chinese words and sentences in 15 healthy controls (HC group) and 10 patients with CI (CI group). EEG data were collected using an oddball paradigm. Then, the characteristics of event-related potentials (ERPs) and mismatch negative (MMN) were compared between the CI group and the HC group. In addition, we analyzed the phase lag indices (PLI) in the CI group and the HC group and calculated the difference in functional connectivity between the two groups at different stages after implantation. The behavioral indicator, speech recognition ability, in CI patients improved as the implantation time increased. The MMN analysis showed that CI patients could recognize the difference between standard and deviation stimuli just like the HCs 90 days after cochlear implantation. Comparing the latencies of N1/P2/MMN between the CI group and the HC group, we found that the latency of N1/P2 in CI patients was longer, while the latency of MMN in CI users was shorter. In addition, PLI-based whole-brain functional connectivity (PLI-FC) showed that the difference between the CI group and the HC group mainly exists in electrode pairs between the bilateral auditory area and the frontal area. Furthermore, all those differences gradually decreased with the increase in implantation time. The N1 amplitude, N1/P2/MMN latency, and PLI-FC in the alpha band may reflect the process of auditory function remodeling and could be an objective index for the assessment of speech perception ability and the effect of cochlear implantation.


Hypoxia and its therapeutic possibilities in paediatric cancers.
In tumours, hypoxia-a condition in which the demand for oxygen is higher than its availability-is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.


Tilt performance of the ground settlement sensor configured in a fiber-optic low-coherent interferometer.
Ground settlement (GS) is one of the causes that destroy the durability of reinforced concrete structures. It could lead to a deterioration in the structural basement and increase the risk of collapse. The methods used for GS monitoring were mostly electronic-based sensors for reading the changes in resistance, resonant frequencies, etc. These sensors often bear low accuracy in the long term. Our published work demonstrated that a fiber-optic low-coherent interferometer configured in a Michelson interferometer was designed as a GS sensor, and a micro-meter resolution in the room environment was approached. However, the designed GS sensor, which in principle is based on a hydraulic connecting vessel, has to suffer from a tilt degeneration problem due to a strictly vertical requirement in practical installment. Here, we made a design for the GS sensor based on its robust tilt performance. The experimental tests show that the sensor can work well within a ±5° tilt. This could meet the requirements in most designed GS sensor installment applications.


DNA-probes for the differentiation of Capnocytophaga species.
We designed oligonucleotides to differentiate between the seven currently known Capnocytophaga species. The oligonucleotides were labelled non-radioactively at the 3' end with digoxigenin. The specificity could be demonstrated in a dot-blot hybridization assay by using the type strains, reference strains, and 37 clinical Capnocytophaga isolates as well as 11 representative strains of other taxa as a template. The sensitivity of the assay was calculated with 10(3) bacteria per dot.


Endothelin-1 stimulates the release of arachidonic acid and prostaglandins in rabbit iris sphincter smooth muscle: activation of phospholipase A2.
We have investigated the effects of endothelin-1 (ET1) on phospholipid hydrolysis and 3H-arachidonic acid (AA) release and prostaglandin synthesis in the rabbit iris sphincter smooth muscle. ET1 actions are concentration- and time dependent with an EC50 for AA release of 1 nM and t1/2 value of 1.5 min. We have identified the AA metabolites released by ET1, employing HPLC, as both cyclooxygenase and lipoxygenase products. The AA released by ET1 appears to derive mainly from the phosphoinositides through phospholipase A2, rather than phospholipase C activation. A key role for phospholipase A2 in AA release in the sphincter muscle is supported by the following observations. (1) Pretreatment of the labeled sphincter with the phorbol ester, PDBu (100 nM) inhibited ET1-stimulated IP3 formation, but it potentiated ET1-stimulated AA release. (2) Pretreatment of the labeled tissue with isoproterenol (5 M) inhibited ET1-stimulated IP3 production without altering AA release. (3) The potency for ET1-stimulated AA release (EC50 = 1 nM) was much higher than that for IP3 formation (EC50 = 45 nM). (4) There were considerable increases, rather than decreases, in 1, 2-diacyl-glycerol formation (1.2-folds) and its phosphorylated product, phosphatidic acid (2.6-folds) by ET1. It is concluded that in the rabbit iris sphincter ET1 is a potent agonist for AA release and eicosanoid synthesis and that AA is released from phosphoinositides mainly through activation of phospholipase A2.


Ostial right coronary chronic total occlusion: Transesophageal echocardiographic guidance for retrograde aortic re-entry.
As antegrade options are limited, intervention upon the ostial right coronary artery (RCA) chronic total occlusion (CTO) warrants a retrograde approach. Landmarks for an aggressive approach are concerning as passage of stiff guidewires or electrocautery near the RCA ostium may result in wire passage into structures other than the aorta. We report the first use of transesophageal echocardiography (TEE) to assist retrograde passage of a guidewire into the aorta. For the ostial RCA CTO, TEE guidance may be considered to assist retrograde passage of aggressive guidewires into the aorta.


MiR-18a-3p improves cartilage matrix remodeling and inhibits inflammation in osteoarthritis by suppressing PDP1.
Osteoarthritis (OA) is a degenerative disease characterized by synovial inflammation. MiR-18a-3p was reported to be downregulated in knee anterior cruciate ligament of OA patients. In the present study, the specific functions and mechanism of miR-18a-3p in OA were explored. An in vitro model of OA was established using 10 ng/ml IL-1β to treat ATDC5 cells, and medial meniscus instability surgery was performed on Wistar rats to establish in vivo rat model of OA. RT-qPCR revealed that miR-18a-3p was downregulated in IL-1β-stimulated ATDC5 cells. MiR-18a-3p overexpression inhibited secretion of inflammatory cytokines and concentration of matrix metalloproteinases, as shown by ELISA and western blotting. The binding relation between miR-18a-3p and pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) was detected by luciferase reporter assays. MiR-18a-3p targeted PDP1 and negatively regulated PDP1 expression. Results of rescue assays revealed that PDP1 upregulation reserved the suppressive effect of miR-18a-3p overexpression on levels of inflammatory cytokines and matrix metalloproteinases in IL-1β-stimulated ATDC5 cells. H&E staining was used to observe pathological changes of synovial tissues in the knee joint of Wistar rats. Safranin O-fast green/hematoxylin was used to stain cartilage samples of knee joints. MiR-18a-3p overexpression suppressed OA progression in vivo. Overall, miR-18a-3p improves cartilage matrix remodeling and suppresses inflammation in OA by targeting PDP1.


Status migrainosus inpatient treatment with eptinezumab (SMITE): study protocol for a randomised controlled trial.
Status migrainosus is a disabling complication of migraine, which frequently results in hospitalisation. For patients who fail to respond to simple analgesia, triptans and intravenous prochlorperazine or chlorpromazine, there are limited treatment options, and a paucity of high-quality evidence to guide clinical practice. Eptinezumab, an intravenous monoclonal antibody specific for the calcitonin gene-related peptide ligand which achieves maximal plasma concentration immediately following administration and may improve migraines from day one. Intravenous lignocaine is an anaesthetic medication used in treatment of status migrainosus, often requiring prolonged admissions and with potential cardiac adverse events. The aim of this study is to assess the efficacy and safety of eptinezumab in the treatment of status migrainosus in comparison to intravenous lidocaine. Status migrainosus inpatient treatment with eptinezumab is a randomised, controlled, single-centre clinical trial conducted in a parallel design with an active comparator conducted in Melbourne, Australia. This study randomises forty patients (1:1) to receive either eptinezumab or an infusion of intravenous lignocaine for up to 5 days. It will assess the effect of eptinezumab compared with intravenous lignocaine in aborting status migrainosus, with the primary outcome of time from infusion until resolution of pain. It will explore several secondary measures including change in health resource utilisation, effect on patient reported outcomes of migraine disability and the safety and tolerability of each medication. This study has been reviewed and approved by the Human Research Ethics Committee of Alfred Health, local reference number 443/21, and all participants will provide informed consent for participation in the trial and dissemination of results. The trial registration number is ACTRN12621001616864. The results of this study will be disseminated through peer-reviewed journals, conference presentations and social media.


Equity-focused knowledge translation: a framework for "reasonable action" on health inequities.
To identify gaps in procedural approaches to knowledge translation and outline a more relational approach that addresses health inequities based on creating collaborative environments for reasonable action. A literature review encompassing approaches to critical inquiry of the institutional conditions in which knowledge is created combined with a process for encouraging reflexive professional practice provide the conceptual foundation for our approach, called equity-focused knowledge translation (EqKT). The EqKT approach creates a matrix through which teams of knowledge stakeholders (researchers, practitioners, and policymakers) can set common ground for taking collaborative action on health inequities. Our approach can contribute to the call by the WHO Commission on the Social Determinants of Healths for more reasonable action on health inequities by being incorporated into numerous public health settings and processes. Further steps include empirical applications and evaluations of EqKT in real world applications.


How does cachexia influence survival in cancer, heart failure and other chronic diseases?
Metabolic, immunological and neurohormonal disturbances, body wasting, and poor patient performance frequently accompany chronic disease. Ultimately, cachexia may develop in 10-15% of patients, who usually perish soon after. We currently have neither a globally accepted definition of cachexia nor any treatment to prevent or treat cachexia. Cachexia remains an unresolved issue in modern medicine. Despite its significant prevalence and poor prognosis, debate on the global definition of cachexia continues. We require a clinical definition, which should include the significant weight loss and its dynamics. There is accumulating evidence that various chronic diseases share pathophysiological mechanisms that lead to wasting and ultimately cachexia. Reversal of traditional cardiovascular risk factors is of value not only in chronic heart failure but also in chronic kidney disease and chronic obstructive pulmonary disease. Future trials to improve prognosis in patients with cachexia will require a global definition of cachexia and identification of key underlying mechanisms. Results with neurohormonal antagonists are intriguing, and clinical use of these agents would be feasible. While searching for treatments for full-blown cachexia, we should also aim to identify treatments directed at the causes in order to prevent its development.


Schizophrenia: Developmental Variability Interacts with Risk Factors to Cause the Disorder: Nonspecific Variability-Enhancing Factors Combine with Specific Risk Factors to Cause Schizophrenia.
A new etiological model is proposed for schizophrenia that combines variability-enhancing nonspecific factors acting during development with more specific risk factors. This model is better suited than the current etiological models of schizophrenia, based on the risk factors paradigm, for predicting and/or explaining several important findings about schizophrenia: high co-morbidity rates, low specificity of many risk factors, and persistence in the population of the associated genetic polymorphisms. Compared with similar models, e.g., de-canalization, common psychopathology factor, sexual-selection, or differential sensitivity to the environment, this proposal is more general and integrative. Recently developed research methods have proven the existence of genetic and environmental factors that enhance developmental variability. Applying such methods to newly collected or already available data can allow for testing the hypotheses upon which this model is built. If validated, this model may change the understanding of the etiology of schizophrenia, the research models, and preventionbrk paradigms.


PENALIZED VARIABLE SELECTION PROCEDURE FOR COX MODELS WITH SEMIPARAMETRIC RELATIVE RISK.
We study the Cox models with semiparametric relative risk, which can be partially linear with one nonparametric component, or multiple additive or nonadditive nonparametric components. A penalized partial likelihood procedure is proposed to simultaneously estimate the parameters and select variables for both the parametric and the nonparametric parts. Two penalties are applied sequentially. The first penalty, governing the smoothness of the multivariate nonlinear covariate effect function, provides a smoothing spline ANOVA framework that is exploited to derive an empirical model selection tool for the nonparametric part. The second penalty, either the smoothly-clipped-absolute-deviation (SCAD) penalty or the adaptive LASSO penalty, achieves variable selection in the parametric part. We show that the resulting estimator of the parametric part possesses the oracle property, and that the estimator of the nonparametric part achieves the optimal rate of convergence. The proposed procedures are shown to work well in simulation experiments, and then applied to a real data example on sexually transmitted diseases.


Catheter-based transendocardial gene delivery for therapeutic myocardial angiogenesis.
Currently it is unknown which is the most effective and safest delivery strategy for therapeutic myocardial angiogenesis. The enhancing effect of direct intramyocardial injection of angiogenic factors using either open-chest or catheter-based approaches on collateral function has been reported to occur in experimental models and among patients. This report reviews the rationale and current experience of using a catheter-based approach as a promising platform for proangiogenic intramyocardial gene delivery strategy.


Agile, Easily Applicable, and Useful eHealth Usability Evaluations: Systematic Review and Expert-Validation.
Electronic health (eHealth) usability evaluations of rapidly developed eHealth systems are difficult to accomplish because traditional usability evaluation methods require substantial time in preparation and implementation. This illustrates the growing need for fast, flexible, and cost-effective methods to evaluate the usability of eHealth systems. To address this demand, the present study systematically identified and expert-validated rapidly deployable eHealth usability evaluation methods. Identification and prioritization of eHealth usability evaluation methods suitable for agile, easily applicable, and useful eHealth usability evaluations. The study design comprised a systematic iterative approach in which expert knowledge was contrasted with findings from literature. Forty-three eHealth usability evaluation methods were systematically identified and assessed regarding their ease of applicability and usefulness through semi-structured expert interviews with 10 European usability experts and systematic literature research. The most appropriate eHealth usability evaluation methods were selected stepwise based on the experts' judgements of their ease of applicability and usefulness. Of these 43 eHealth usability evaluation methods identified as suitable for agile, easily applicable, and useful eHealth usability evaluations, 10 were recommended by the experts based on their usefulness for rapid eHealth usability evaluations. The three most frequently recommended eHealth usability evaluation methods were Remote User Testing, Expert Review, and Rapid Iterative Test and Evaluation Method. Eleven usability evaluation methods, such as Retrospective Testing, were not recommended for use in rapid eHealth usability evaluations. We conducted a systematic review and expert-validation to identify rapidly deployable eHealth usability evaluation methods. The comprehensive and evidence-based prioritization of eHealth usability evaluation methods supports faster usability evaluations, and so contributes to the ease-of-use of emerging eHealth systems.


The nature of spontaneous changes in growth rate in isolated coleoptile segments.
About 4 hours after they are cut from the seedling, corn (Zea mays L.) coleoptile segments mounted vertically show a strong increase in growth rate. This increase occurs in water or various buffers near pH 7 and is not accompanied by the accumulation of a growth promoter in the medium. The increase in growth rate is prevented by 1 mmp-fluorophenylalanine and is strongly inhibited by 0.1 mmp-chlorophenoxyisobutyric acid.The increased growth rate is accompanied by a 95% increase in the ability of tissue extracts to catalyze the conversion of (14)C-tryptophan to (14)C-indole-3-acetic acid and by a nearly 3-fold increase in indole-3-acetic acid oxidase activity. The increase in growth rate is also observed in segments from coleoptiles grown aseptically.The spontaneous increase in growth rate is completely but reversibly inhibited by 1 mum indole-3-acetic acid. Cytokinins have little effect on the spontaneous growth response, whereas gibberellic acid is observed to extend the latent period and reduce the magnitude of the response. It is tentatively concluded that the increase in endogenous growth rate may result from increased auxin production upon derepression of the auxin biosynthesis pathway after isolating the tissue from the normal supply of auxin from the tip.


[Ambulatory celioscopy].
Outpatient laparoscopic surgery implies a selection for surgical procedures in order to prevent the risk of postoperative bleeding and/or bowel injury. Anesthetists are concerned with the safety of the airway (tracheal intubation or laryngeal mask). Prevention of nausea and vomiting and analgesia are the more important points in the postoperative period. Due to the prolongation of these symptoms during 48 hours or more, the treatments must be adapted (oral route).


Part B: Revisions to the COMFA outdoor thermal comfort model for application to subjects performing physical activity.
The purpose of this paper is to improve the accuracy of the COMFA outdoor thermal comfort model for application to subjects performing physical activity. A sensitivity analysis was performed to identify conditions where the COMFA model produced erroneous estimates of the heat and moisture exchanges between the human body and the ambient environment, based on data from subjects performing moderate-to-vigorous physical activity. Errors occurred at high metabolic rates (> 400 W m(-2)), high wind speeds (> 4 m s(-1)) and warm air temperatures (> 28 degrees C). Revisions to the clothing resistance (r(c)), clothing vapour resistance (r(c upsilon)), skin tissue resistance (r(t)), and skin temperature (T(sk)) equations were proposed. The revised assessment revealed that subjects had a wide range of thermal acceptability (B = -20 W m(-2) to +150 W m(-2)), which was offset to the warm-end of the comfort scale. The revised model (COMFA*) performed well, predicting the actual thermal sensation of subjects in approximately 70% of cases. This study effectively integrated current empirical research related the effect of wind and activity on the clothing microclimate to improve the application of an outdoor thermal comfort model for subjects performing physical activity.