Biologic canine and human intervertebral disc repair by notochordal cell-derived matrix: from bench towards bedside.
The socioeconomic burden of chronic back pain related to intervertebral disc (IVD) disease is high and current treatments are only symptomatic. Minimally invasive strategies that promote biological IVD repair should address this unmet need. Notochordal cells (NCs) are replaced by chondrocyte-like cells (CLCs) during IVD maturation and degeneration. The regenerative potential of NC-secreted substances on CLCs and mesenchymal stromal cells (MSCs) has already been demonstrated. However, identification of these substances remains elusive. Innovatively, this study exploits the regenerative NC potential by using healthy porcine NC-derived matrix (NCM) and employs the dog as a clinically relevant translational model. NCM increased the glycosaminoglycan and DNA content of human and canine CLC aggregates and facilitated chondrogenic differentiation of canine MSCs in vitro. Based on these results, NCM, MSCs and NCM+MSCs were injected in mildly (spontaneously) and moderately (induced) degenerated canine IVDs in vivo and, after six months of treatment, were analyzed. NCM injected in moderately (induced) degenerated canine IVDs exerted beneficial effects at the macroscopic and MRI level, induced collagen type II-rich extracellular matrix production, improved the disc height, and ameliorated local inflammation. MSCs exerted no (additive) effects. In conclusion, NCM induced in vivo regenerative effects on degenerated canine IVDs. NCM may, comparable to demineralized bone matrix in bone regeneration, serve as 'instructive matrix', by locally releasing growth factors and facilitating tissue repair. Therefore, intradiscal NCM injection could be a promising regenerative treatment for IVD disease, circumventing the cumbersome identification of bioactive NC-secreted substances.


Temporal and spatial variability of pelagic wild fish assemblages around Atlantic bluefin tuna Thunnus thynnus farms in the eastern Adriatic Sea.
The abundance and size structure of wild fishes aggregated around the sea-cages of two commercial Thunnus thynnus farms, including control locations, were assessed and compared over a 1 year period. The T. thynnus farms were located in the eastern Adriatic Sea, offshore of the islands of Ugljan and Brač. Fish assemblages were evaluated through visual census using scuba at 2 month intervals at two sites within each farm. The data suggest that wild fish assemblages at the study sites differed greatly; 20 species occurred at the Ugljan farm and 17 at the Brač farm, while only seven species were observed at the control locations. The abundance and diversity of wild fish assemblages were greater at the farms in comparison to control locations. The most abundant families were Sparidae and Belonidae (>80% of aggregated fishes). At both farms, the abundance and diversity of wild fishes were highest during summer, while diversity was lowest in winter and was mainly characterized by schools of bogue Boops boops and garfish Belone belone. Variability was also detected in spatial assemblages between farms; B. boops and B. belone were the most abundant species for the overall study at the Brač farm, while B. belone and saddled bream Oblada melanura were the most abundant at the Ugljan farm. The settlement also played a significant role in farm-associated fish assemblages, as both juveniles and advanced juveniles were common residents at farms. The majority of species which settled at the farms belonged to the sparids. Results indicate that aggregations of wild fishes at T. thynnus farms are persistent year-round, though the assemblage compositions and size structures of dominant species vary in respect to location and season.


Activating mutations in ALK provide a therapeutic target in neuroblastoma.
Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.


Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children.
The p.V37I (c.109G>A) mutation in the GJB2 gene is the common frequent cause of congenital deafness; however, its pathogenicity is debated. The present study investigated the prevalence of p.V37I in Chinese infants and young children and associated clinical characteristics. The subjects of the present study were screened for mutations in GJB2 (235delC, 299delAT, 176dell6, 35delG), SLC26A4 (IVS7-2A>G, 2168A>G), GJB3 (538C>T), and in the mitochondrial 12S rRNA gene (1555A>G, 1494C>T). Subjects with p.V37I underwent an audiological evaluation. GJB2 exon sequencing revealed that 20 subjects had p.V37I compound heterozygous mutations, one of whom had a family history; the mutations included c.235delC/p.V37I (n = 12), c.299AT/p.V37I (n = 7), and c.176del16/p.V37I (n = 1). Of the 20 subjects, 12 were referred for Universal Newborn Hearing Screening (UNHS). Nine of the 20 subjects had mild hearing loss in the better ear and 5 had moderate hearing loss in the better ear while 4 had normal hearing. Among subjects with the c.235delC/p.V37I mutation, 5 had mild hearing loss and 2 had moderate hearing loss while 3 had normal hearing. Among subjects with the c.299AT/p.V37I mutation, 3 had mld hearing loss and 3 had moderate hearing loss while 1 had normal hearing. One subject with the c.176del16/p.V37I mutation had mild hearing loss. Few studies have reported on the clinical characteristics of Chinese infants with p.V37I compound heterozygous mutations identified via screening for deafness genes and GJB2 sequencing. The c.235delC/p.V37I mutation was the most prevalent mutation found in subjects. The degree of hearing loss associated with p.V37I compound heterozygous mutations was mainly mild to moderate.


Making the most of open windows: establishing health in all policies in South Australia.
Significant improvements in population health are likely to arise when the social determinants ofhealth are addressed. This creates a challenge for health systems, as the policy levers to influence the determinants largely lie outside of their direct control. Health agencies have been attempting to develop responses that affect these policy levers with mixed success. Success often requires particular conditions or "windows of opportunity" to be present before even small systemic change can be made. The government of South Australia has developed a practical, policy-oriented response to address the determinants of health--Health in All Policies--and has been successfully working across government for the past five years, using a policy learning process to implement this approach. This article will focus on how the South Australian Health in All Policies initiative started and the conditions that enabled South Australia to establish a centralized governance structure, harness a group of cross-sector policy entrepreneurs, and conduct health lens projects across a range of policy issues. The authors will comment on the nature of these conditions and their relevance for other governments struggling to reduce the burden of chronic disease and growing health budgets by addressing the social determinants of health.


Atomic Force Microscope Studies of Fullerene Films: Highly Stable C60 fcc (311) Free Surfaces.
Atomic force microscopy and x-ray diffractometry were used to study 1500 A-thick films of pure C(60) grown by sublimation in ultrahigh vacuum onto a CaF(2) (111) substrate. Topographs of the films did not reveal the expected close-packed structures, but they showed instead large regions that correspond to a face-centered cubic (311) surface and distortions of this surface. The open (311) structure may have a relatively low free energy because the low packing density contributes to a high entropy of the exposed surface.


The association of patient education level with outcomes after elective lumbar surgery: a Michigan Spine Surgery Improvement Collaborative study.
Socioeconomic factors have been shown to impact a host of healthcare-related outcomes. Level of education is a marker of socioeconomic status. This study aimed to investigate the relationship between patient education level and outcomes after elective lumbar surgery and to characterize any education-related disparities. The Michigan Spine Surgery Improvement Collaborative registry was queried for all lumbar spine operations. Primary outcomes included patient satisfaction determined by the North American Spine Society patient satisfaction index, and reaching the minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score and return to work up to 2 years after surgery. Multivariate Poisson generalized estimating equation models reported adjusted risk ratios. A total of 26,229 lumbar spine patients had data available for inclusion in this study. On multivariate generalized estimating equation analysis all comparisons were done versus the high school (HS)/general equivalency development (GED)-level cohort. For North American Spine Society satisfaction scores after surgery the authors observed the following: at 90 days the likelihood of satisfaction significantly decreased by 11% (p < 0.001) among < HS, but increased by 1% (p = 0.52) among college-educated and 3% (p = 0.011) among postcollege-educated cohorts compared to the HS/GED cohort; at 1 year there was a decrease of 9% (p = 0.02) among < HS and increases of 3% (p = 0.02) among college-educated and 9% (p < 0.001) among postcollege-educated patients; and at 2 years, there was an increase of 5% (p = 0.001) among postcollege-educated patients compared to the < HS group. The likelihood of reaching a minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score at 90 days increased by 5% (p = 0.005) among college-educated and 9% (p < 0.001) among postcollege-educated cohorts; at 1 year, all comparison cohorts demonstrated significance, with a decrease of 12% (p = 0.007) among < HS, but an increase by 6% (p < 0.001) among college-educated patients and 14% (p < 0.001) among postcollege-educated compared to the HS/GED cohort; at 2 years, there was a significant decrease by 19% (p = 0.003) among the < HS cohort, an increase by 8% (p = 0.001) among the college-educated group, and an increase by 16% (p < 0.001) among the postcollege-educated group. For return to work, a significant increase was demonstrated at 90 days and 1 year when comparing the HS or less group with college or postcollege cohorts. This study demonstrated negative associations on all primary outcomes with lower levels of education. This finding suggests a potential disparity linked to education in elective spine surgery.


Folic acid and risk of prostate cancer: results from a randomized clinical trial.
Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.


Treatment of Graf Type IIa Hip Dysplasia: A Cut-off Value for Decision Making
The rate of spontaneous normalization in type IIa hips is reported to be high, whereas dysplsia persists or worsens in 5%-10% of cases. To evaluate the natural course of type IIa hips using Graf's own perspective of physiological immaturity and maturational deficit. A single center, retrospective cohort study. This was an institutional review board-approved retrospective review of all patients diagnosed with type IIa hip dysplasia at a single institution from 2012 to 2014. All patients included in the study had hip ultrasonography at about 6 weeks and 3 months of age. To assess reliability in α and β angles, ultrasonography measurements were carried out on the same image individually by all observers. The α and β angles were used as the main outcome measurements to evaluate hip maturation at the last follow-up. A receiver operating characteristics curve was drawn at the 3 month ultrasonography to evaluate the cut-off values for α and β angles for persistent dysplasia. Sixty-four patients and 88 affected hips (63% unilateral and 37% bilateral) were included. The mean age at diagnosis was 6.4±2.7 weeks. Fifty-four hips were type IIa(+) (physiologically immature) and 34 hips were type IIa(-) (maturational deficit) at the initial ultrasonography evaluation. Improvement to type I was seen in 52 type IIa(+) and 17 type IIa(-) hips. Receiver operating characteristic analyses showed that patients do well if the α angle was >55° (area under the curve: 0.86; p<0.001 for the left hip and area under the curve: 0.72; p=0.008 for the right hip). The cut-off α angle value of 55° on initial ultrasonography should be considered to prevent future dysplasia. An α angle <55° on the initial ultrasonography was an independent predictor of worsening sonographic findings.


Comparative evaluation of three gingival displacement materials for efficacy in tissue management and dimensional accuracy.
Displacement of gingiva is essential for obtaining accurate impressions for the fabrication of fixed prostheses, particularly when the finish line is at or within the gingival sulcus. Various newer impression materials have been introduced to achieve gingival displacement while recording the impressions. A comparative evaluation of these new gingival displacement materials was deemed necessary for efficacy in tissue management and dimensional accuracy. Ten individuals were selected according to the inclusion and exclusion criteria for gingival displacement using retraction cord impregnated with aluminum chloride and two polyvinyl siloxane impression materials (Aquasil and NoCord VPS impression system) according to Latin block design. Intraoral scanner and Vernier caliper were used to study and compare the dimensional accuracy of each die obtained following which the dies were sectioned and evaluated under optical microscope with image analyzer to measure the amount of gingival retraction. Statistical analysis showed that the amount of gingival retraction obtained by using retraction cord impregnated with aluminum chloride as gingival retraction agent was maximum as compared to NoCord followed by Aquasil. All three gingival displacement techniques could produce gingival displacement >0.2 mm which is the optimum amount of retraction required for impression making. All the three materials are found to be dimensionally accurate.


Dietary iron intake is positively associated with hemoglobin concentration during infancy but not during the second year of life.
Iron status during infancy and early childhood reflects highly dynamic processes, which are affected by both internal and external factors. The regulation of iron metabolism seems to be subjected to developmental changes during infancy, although the exact nature of these changes and their implications are not fully understood. We wanted to explore the association between dietary iron intake and indicators of iron status, and to assess temporal changes in these variables. This was done by secondary analysis of data from a recently conducted dietary intervention trial in which healthy, term, well-nourished infants were randomly assigned to consume iron-fortified infant cereals with regular or low phytate content, or iron-fortified infant formula. Dietary iron intake from 6 to 8 mo and from 9 to 11 mo was associated with hemoglobin (Hb) concentration at 9 mo (r = 0.27, P < 0.001) and 12 mo (r = 0.21, P = 0.001), respectively, but iron intake from 12 to 18 mo was not associated with Hb at 18 mo. In contrast, iron intake from 6 to 11 mo was not associated with serum ferritin (S-Ft) at 9 or 12 mo, whereas iron intake from 12 to 17 mo was positively associated with S-Ft at 18 mo (r = 0.14, P = 0.032). These shifts in associations between dietary iron intake, and Hb and S-Ft, respectively, may be due to developmental changes in the channeling of dietary iron to erythropoiesis relative to storage, in the absence of iron deficiency anemia. These observations should be taken into consideration when evaluating iron nutritional status during infancy and early childhood.


Increase of S-100 protein-positive stellate cells in the anterior pituitary of chronic alcoholic patients with fatty liver or fatty cirrhosis.
Healthy subjects 40 years old were used as controls in a study of stellate cells (S-100 protein-containing cells, or S-100 cells) in subjects with chronic alcoholism and fatty liver or fatty cirrhosis. S-100 cells were sparsely found in the adenohypophysis of control subjects, and these cells sometimes formed small clusters. However, in chronic alcoholics with fatty liver or fatty cirrhosis, the number of stellate cells in the anterior pituitary tended to be 17 times higher than it was in the control group. No increase in the number of S-100 positive cells that constitute the large and small follicles in the intermediate pituitary. The physiological function of the S-100 protein has not yet been identified. The fact that an increase in prolactin-secreting and growth hormone-secreting cells, as well as a decrease in gonadotrophs were observed in the hypophysis of alcoholics suggests that the function of stellate cells may be closely related to these phenomena. Our results also imply that the stellate cells found in the anterior and intermediate pituitary differ in function although they both produce S-100 proteins.


Phototherapy with Narrow-Band UVB in Adult Guttate Psoriasis: Results and Patient Assessment.
Acute guttate psoriasis (AGP) is a distinctive clinical entity with good response to treatment with narrow-band ultraviolet B (NB-UVB). To investigate the results of NB-UVB phototherapy in adult patients with adult guttate psoriasis. We carried out a prospective, open, and observational study. Patients over 18 years with more than 5% of body surface area affected were included. The PASI was assessed prior to and after treatment. The follow-up period was 18 months. After treatment, patients completed a simple questionnaire to assess their overall impression of the treatment. The 67 adult patients with AGP included in this study had an initial PASI of 8.55 (SD 5.03). Patients were treated with a mean of 19.9 sessions (SD 13.5) and mean doses of 14 mJ/cm2 (SD 10.5). Of the 67 patients, 52 achieved PASI90 with 96.15% of PASI reduction, and of these, 46 (88%) maintained PASI90 during the 18 months of follow-up. Patients were very satisfied with the treatment. AGP is a defined clinical entity with a variable course. Phototherapy with NB-UVB appears to be a very good option for treatment of AGP because of the good results obtained and patient satisfaction.


PEG-PLA-PEG block copolymeric nanoparticles for oral immunization against hepatitis B.
PLA/PLGA nanoparticles are well known as efficient vaccine delivery systems, but they have got limitation in oral vaccine delivery because of their sensitivity to harsh gastric environment. The aim of present study was to improve the stability of PLA nanoparticles in such environment by copolymerizing PLA with PEG. Nanoparticles were formulated using different block copolymers AB, ABA and BAB (where 'A' is PLA and 'B' is PEG) encapsulating hepatitis B surface antigen (HBsAg) to evaluate their efficacy as oral vaccine delivery system. The results of in vitro studies engrave the efficiency of copolymeric nanoparticles to retain encapsulated antigen and average particle size even after 2 h incubation in simulated gastric fluid and simulated intestinal fluid. Fluorescence microscopic studies indicated efficient uptake of copolymeric nanoparticles by gut mucosa of immunized mice model as compared to control. Finally copolymeric and PLA nanoparticles, encapsulating HBsAg, were evaluated for their adjuvancity in generating immune response after oral administration. PLA nanoparticles could not generate an effective immune response due to stability issues. On the other hand, oral administration of copolymeric nanoparticles exhibited effective levels of humoral immunity along with the mucosal (sIgA) and cellular immune response (T(H)1). The results of in vitro and in vivo studies demonstrate that BAB nanoparticles depict enhanced mucosal uptake leading to effective immune response as compared to other copolymeric nanoparticles. Present study indicates the efficacy of BAB nanoparticles as a promising carrier for oral immunization.


Synthetic Polymers Provide a Robust Substrate for Functional Neuron Culture.
Substrates for neuron culture and implantation are required to be both biocompatible and display surface compositions that support cell attachment, growth, differentiation, and neural activity. Laminin, a naturally occurring extracellular matrix protein is the most widely used substrate for neuron culture and fulfills some of these requirements, however, it is expensive, unstable (compared to synthetic materials), and prone to batch-to-batch variation. This study uses a high-throughput polymer screening approach to identify synthetic polymers that supports the in vitro culture of primary mouse cerebellar neurons. This allows the identification of materials that enable primary cell attachment with high viability even under "serum-free" conditions, with materials that support both primary cells and neural progenitor cell attachment with high levels of neuronal biomarker expression, while promoting progenitor cell maturation to neurons.


Integrating pharmacogenetic information and clinical decision support into the electronic health record.
Pharmacogenetics (PG) examines gene variations for drug disposition, response, or toxicity. At the National Institutes of Health Clinical Center (NIH CC), a multidepartment Pharmacogenetics Testing Implementation Committee (PGTIC) was established to develop clinical decision support (CDS) algorithms for abacavir, carbamazepine, and allopurinol, medications for which human leukocyte antigen (HLA) variants predict severe hypersensitivity reactions. Providing PG CDS in the electronic health record (EHR) during order entry could prevent adverse drug events. Medical Logic Module (MLM) programming was used to implement PG CDS in our EHR. The MLM checks to see if an HLA sequence-based gene test is ordered. A message regarding test status (result present, absent, pending, or test not ordered) is displayed on the order form, and the MLM determines if the prescriber can place the order, place it but require an over-ride reason, or be blocked from placing the order. Since implementation, more than 725 medication orders have been placed for over 230 patients by 154 different prescribers for the three drugs included in our PG program. Prescribers commonly used an over-ride reason when placing the order mainly because patients had been receiving the drug without reaction before implementation of the CDS program. Successful incorporation of PG CDS into the NIH CC EHR required a coordinated, interdisciplinary effort to ensure smooth activation and a positive effect on patient care. Prescribers have adapted to using the CDS and have ordered PG testing as a direct result of the implementation.


Novel in Situ Techniques for Studies of Model Catalysts.
Motivated mainly by catalysis, gas-surface interaction between single crystal surfaces and molecules has been studied for decades. Most of these studies have been performed in well-controlled environments and have been instrumental for the present day understanding of catalysis, providing information on surface structures, adsorption sites, and adsorption and desorption energies relevant for catalysis. However, the approach has been criticized for being too far from a catalyst operating under industrial conditions at high temperatures and pressures. To this end, a significant amount of effort over the years has been used to develop methods to investigate catalysts at more realistic conditions under operating conditions. One result from this effort is a vivid and sometimes heated discussion concerning the active phase for the seemingly simple CO oxidation reaction over the Pt-group metals in the literature. In recent years, we have explored the possibilities to perform experiments at conditions closer to those of a technical catalyst, in particular at increased pressures and temperatures. In this contribution, results from catalytic CO oxidation over a Pd(100) single crystal surface using Near Ambient Pressure X-ray Photo emission Spectroscopy (NAPXPS), Planar Laser-Induced Fluorescence (PLIF), and High Energy Surface X-ray Diffraction (HESXRD) are presented, and the strengths and weaknesses of the experimental techniques are discussed. Armed with structural knowledge from ultrahigh vacuum experiments, the presence of adsorbed molecules and gas-phase induced surface structures can be identified and related to changes in the reactivity or to reaction induced gas-flow limitations. In particular, the application of PLIF to catalysis allows one to visualize how the catalyst itself changes the gas composition close to the model catalyst surface upon ignition, and relate this to the observed surface structures. The effect obscures a straightforward relation between the active phase and the activity, since in the case of CO oxidation, the gas-phase close to the model catalyst surface is shown to be significantly more oxidizing than far away from the catalyst. We show that surface structural knowledge from UHV experiments and the composition of the gas phase close to the catalyst surface are crucial to understand structure-function relationships at semirealistic conditions. In the particular case of Pd, we argue that the surface structure of the PdO(101) has a significant influence on the activity, due to the presence of Coordinatively Unsaturated Sites (CUS) Pd atoms, similar to undercoordinated Ru and Ir atoms found for RuO2(110) and IrO2(110), respectively.


Cell-specific expression of hepatocyte growth factor in liver. Upregulation in sinusoidal endothelial cells after carbon tetrachloride.
The cellular origin of hepatocyte growth factor (HGF), a polypeptide implicated in liver regeneration, was examined in normal liver and in hepatic regeneration induced by carbon tetrachloride. In normal liver, HGF and its mRNA were abundant in lipocytes, with smaller amounts present also in sinusoidal endothelial and Kupffer cells. In regenerating liver, HGF gene expression increased exclusively in endothelial cells. HGF mRNA levels rose sixfold in these cells, peaking at 6 h after toxin administration and returning to near normal by 24 h. The rise in HGF mRNA was accompanied by a 5.4-fold increase in HGF secretion. CCl4 did not alter HGF expression by either Kupffer cells or lipocytes; nor did it induce HGF expression by hepatocytes. Nonparenchymal liver cells contained two HGF transcripts: one predicting a full-length molecule of 728 amino acids; and the other encoding a functional five-amino acid deletion variant of HGF. The variant was less abundant than the full-length transcript, but increased in parallel with native HGF mRNA in response to CCl4. The response of nonparenchymal cells to HGF was examined by plating endothelial cells and lipocytes in the presence of recombinant human HGF. Under the conditions examined, the growth factor exerted neither mitogenic nor scatter factor activity on these cells.


Effectiveness of coenzyme Q10 in prophylactic treatment of migraine headache: an open-label, add-on, controlled trial.
Despite the huge health and economic burden of migraine headache, few medications have been approved for its prophylactic treatment, most of which can potentially induce serious adverse effects. Coenzyme Q10 (CoQ10) is a supplement and has shown preliminary benefits in migraine prophylaxis. We aimed to assess this effect in an adult population. This is an open-label, parallel, add-on, match-controlled trial. Eighty patients diagnosed with migraine headache based on International Headache Society criteria were allocated to receiving only their current preventive drugs or their current preventive drugs plus 100 mg CoQ10 daily, matching for their baseline characteristics, and were assessed for frequency and severity of attacks, and ≥50 % reduction in attack frequency per month. Thirty-six and 37 patients were analyzed in CoQ10 and control groups, respectively. Number of attacks per month dropped significantly in the CoQ10 group (mean decrease: 1.6 vs. 0.5 among CoQ10 and control groups, respectively, p < 0.001). A significant reduction was also evident in the severity of headaches (mean decrease: 2.3 vs. 0.6 among CoQ10 and control groups, respectively, p < 0.001). For ≥50 % reduction in the frequency of attacks per month, the number needed to treat was calculated as 1.6. No side effects for CoQ10 were observed. This study suggests that CoQ10 might reduce the frequency of headaches, and may also make them shorter in duration, and less severe, with a favorable safety profile.


Sensitivity of yeast strains with long G-tails to levels of telomere-bound telomerase.
The Saccharomyces cerevisiae Pif1p helicase is a negative regulator of telomere length that acts by removing telomerase from chromosome ends. The catalytic subunit of yeast telomerase, Est2p, is telomere associated throughout most of the cell cycle, with peaks of association in both G1 phase (when telomerase is not active) and late S/G2 phase (when telomerase is active). The G1 association of Est2p requires a specific interaction between Ku and telomerase RNA. In mutants lacking this interaction, telomeres were longer in the absence of Pif1p than in the presence of wild-type PIF1, indicating that endogenous Pif1p inhibits the active S/G2 form of telomerase. Pif1p abundance was cell cycle regulated, low in G1 and early S phase and peaking late in the cell cycle. Low Pif1p abundance in G1 phase was anaphase-promoting complex dependent. Thus, endogenous Pif1p is unlikely to act on G1 bound Est2p. Overexpression of Pif1p from a non-cell cycle-regulated promoter dramatically reduced viability in five strains with impaired end protection (cdc13-1, yku80Delta, yku70Delta, yku80-1, and yku80-4), all of which have longer single-strand G-tails than wild-type cells. This reduced viability was suppressed by deleting the EXO1 gene, which encodes a nuclease that acts at compromised telomeres, suggesting that the removal of telomerase by Pif1p exposed telomeres to further C-strand degradation. Consistent with this interpretation, depletion of Pif1p, which increases the amount of telomere-bound telomerase, suppressed the temperature sensitivity of yku70Delta and cdc13-1 cells. Furthermore, eliminating the pathway that recruits Est2p to telomeres in G1 phase in a cdc13-1 strain also reduced viability. These data suggest that wild-type levels of telomere-bound telomerase are critical for the viability of strains whose telomeres are already susceptible to degradation.


DNA and RNA references for qRT-PCR assays in exfoliated cervical cells.
The noncritical use of housekeeping genes, RNA mass, or cell number for normalization in quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assays has come under scrutiny in recent years, highlighting the need to evaluate references in the immediate context of the relevant samples and experimental design. The purpose of this study was to select appropriate references for normalizing qRT-PCR assays of gene expression in exfoliated cervical cells. We used total nucleic acid extracts from 30 samples, representing the full spectrum of pre-invasive cervical neoplasia. We determined the DNA content by quantitative PCR for the single-copy gene beta-globin and total RNA content using quantitative image analysis of ribosomal bands. In addition, qRT-PCR for 13 candidate housekeeping genes was performed. We used two analysis methods, geNorm and Norm-Finder, to identify the best combination of reference genes and then correlated housekeeping gene expression with DNA content and gel representation of ribosomal RNA. ACTB was the most stable single gene. The addition of PGK1 and RPLP0 increased the robustness in qRT-PCR applications not stratified by disease. These genes also showed the highest correlation with DNA contents in the same samples. If special attention to intraepithelial lesions is appropriate, RPL4 and PGK1 are recommended as the best combination of two genes.


Osthole regulates TGF-β1 and MMP-2/9 expressions via activation of PPARα/γ in cultured mouse cardiac fibroblasts stimulated with angiotensin II.
Our previous studies have demonstrated that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, can prevent isoprenaline-induced myocardial fibrosis in mice, but the underlying mechanism is still unclear. The mouse cardiac fibroblasts (CFs) stimulated with angiotensin II (Ang II) were cultured and treated with different concentrations of osthole. The mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α/γ, transforming growth factor β1 (TGF-β1), and matrix metalloproteinase (MMP)-2/9 were detected by reverse transcription polymerase chain reaction method, and the protein expressions of nuclear factor-κB (NF-κB) and TGF-β1 were detected by Western blot method, respectively. Following treatment of cells with osthole at 2.5, 5, 10 and 20 μg/mL, the NF-κB and TGF-β1 expressions were dose-dependently decreased, while the expressions of PPARα/γ and MMP-2/9 were dose-dependently increased. After the cells were preincubated with PPARα antagonist (MK886) or/and PPARγ antagonist (GW9662), the inhibitions of osthole on the NF-κB and TGF-β1 expressions were decreased or completely halted and the increment of osthole on the MMP-2/9 expressions were also decreased or completely cancelled. Osthole could inhibit the NF-κB and TGF-β1 expressions by activation of PPARα/γ, and subsequently enhance the MMP-2/9 expressions in cultured CFs, and these effects of osthole may play the beneficial roles in the prevention and treatment of myocardial fibrosis.


Broad parameter optimization of polarization-diversity 2D grating couplers for silicon photonics.
Polarization-diversity couplers, which are designed to couple the unknown polarization state of an optical fiber into the TE-polarized modes of integrated waveguides, are important for the development of practical all-optical circuits. We describe the use of a full 3D finite difference time domain (FDTD) calculation campaign to rigorously optimize the 2D photonic crystal grating that couples a single-mode telecom fiber to the silicon waveguides of a Silicon-on-Insulator (SOI) platform. With this approach we identify the unique optimum combination of etch-depth, hole-radius, and grating-pitch of the photonic crystal array for best performance at 1550 nm. The mean (polarization-averaged) coupling efficiency of 48% (-3.2dB) exceeds reported efficiencies of analogous couplers, and has only a marginal dependence on the polarization state of the input fiber (48 ± 3%). In addition, 3D-FDTD calculations are used to characterize the propagation direction, mode-profile, and polarization of light coupled from the fiber into the SOI slab. Such information is crucial for component design and goes beyond previously available results from existing approximations and simulations of 2D-grating coupler performance. Calculations of photonic mode dispersion in the grating coupler, by means of guided-mode expansion, indicate that the coupling is due to an optically active resonant guided mode in the photonic crystal array. This points towards a fast optimization scheme that enhances both the performance and the physical interpretation of 3D-FDTD simulations.


Out of synch with society: an update on delayed sleep phase disorder.
Delayed sleep phase disorder is the most common of the circadian rhythm sleep disorders. Its treatment involves exploiting the intrinsic biological properties of the circadian pacemaker to advance biological rhythms, most notably the sleep-wake cycle, to a time which affords the individual an appropriate sleep opportunity compatible with normal societal functioning. This review highlights several new studies published in the last 18 months concerning sleep and circadian physiology relevant to the disorder and its management. In addition to new information regarding the epidemiology and associations of the disorder, the pathophysiological importance of light exposure across the entire day, with special relevance to the phase-delaying effects of artificial evening light, is being unravelled. Furthermore, disorder-specific differences in period length and sleep homeostasis are being considered as pathophysiological contributors to delayed sleep phase disorder. The molecular effects of chronic sleep deprivation and circadian misalignment are currently being explored as potential mechanistic markers of the deleterious health consequences associated with these states. Advances in our understanding of the dynamics of circadian physiology, sleep-wake regulation and the deleterious effects of misalignment and sleep deprivation, are spurring on efforts to find optimal treatment paradigms for patients presenting to sleep clinics with delayed sleep phase disorder.


Recruiting and retaining GPs and patients in intervention studies: the DEPS-GP project as a case study.
Recruiting and retaining GPs for research can prove difficult, and may result in sub-optimal patient participation where GPs are required to recruit patients. Low participation rates may affect the validity of research. This paper describes a multi-faceted approach to maximise participation of GPs and their patients in intervention studies, using an Australian randomised controlled trial of a depression/suicidality management intervention as a case study. The paper aims to outline experiences that may be of interest to others considering engaging GPs and/or their patients in primary care studies. A case study approach is used to describe strategies for: (a) recruiting GPs; (b) encouraging GPs to recruit patients to complete a postal questionnaire; and (c) encouraging GPs to recruit patients as part of a practice audit. Participant retention strategies are discussed in light of reasons for withdrawal. The strategies described, led to the recruitment of a higher than expected number of GPs (n = 772). Three hundred and eighty three GPs (49.6%) followed through with the intent to participate by sending out a total of 77,820 postal questionnaires, 22,251 (28.6%) of which were returned. Three hundred and three GPs (37.0%) participated in the practice audit, which aimed to recruit 20 patients per participating GP (i.e., a total of 6,060 older adults). In total, 5,143 patients (84.9%) were represented in the audit. Inexpensive methods were chosen to identify and recruit GPs; these relied on an existing database, minor promotion and a letter of invitation. Anecdotally, participating GPs agreed to be involved because they had an interest in the topic, believed the study would not impinge too greatly on their time, and appreciated the professional recognition afforded by the Continuing Professional Development (CPD) points associated with study participation. The study team established a strong rapport with GPs and their reception staff, offered clear instructions, and were as flexible and helpful as possible to retain GP participants. Nonetheless, we experienced attrition due to GPs' competing demands, eligibility, personnel issues and the perceived impact of the study on patients. A summary of effective and ineffective methods for recruitment and retention is provided.


Core-shell designs of photoluminescent nanodiamonds with porous silica coatings for bioimaging and drug delivery II: application.
Recent advances within materials science and its interdisciplinary applications in biomedicine have emphasized the potential of using a single multifunctional composite material for concurrent drug delivery and biomedical imaging. Here we present a novel composite material consisting of a photoluminescent nanodiamond (ND) core with a porous silica (SiO2) shell. This novel multifunctional probe serves as an alternative nanomaterial to address the existing problems with delivery and subsequent tracing of the particles. Whereas the unique optical properties of ND allows for long-term live cell imaging and tracking of cellular processes, mesoporous silica nanoparticles (MSNs) have proven to be efficient drug carriers. The advantages of both ND and MSNs were hereby integrated in the new composite material, ND@MSN. The optical properties provided by the ND core rendered the nanocomposite suitable for microscopy imaging in fluorescence and reflectance mode, as well as super-resolution microscopy as a STED label; whereas the porous silica coating provided efficient intracellular delivery capacity, especially in surface-functionalized form. This study serves as a demonstration how this novel nanomaterial can be exploited for both bioimaging and drug delivery for future theranostic applications.


Spatial primes produce dissociated inhibitory effects on saccadic latencies and trajectories.
In masked priming, a briefly presented prime can facilitate or inhibit responses to a subsequent target. In most instances, targets with an associated response that is congruent with the prime direction speed up reaction times to the target (a positive compatibility effect; PCE). However, under certain circumstances, slower responses for compatible primes are obtained (a negative compatibility effect; NCE). NCEs can be found when a long pre-target delay is used. During the delay, inhibition is assumed to take place, and therefore an effect on saccade trajectories may also be expected. In a previous study, we found the effects of inhibition on response times and trajectories to be dissociated, but this experiment varied the timing of several aspects of the stimulus sequence and it is therefore unclear what caused the dissociation. In the present study, we varied only one aspect of the timing, but replicated the dissociation. By varying just the pre-target delay, we found a PCE for a short delay, and an NCE for a long delay, but saccade trajectories deviated away from prime directions in both conditions. This suggests dissociated inhibitory effects of primes on response times and saccade trajectories.


Complex interactions between spatial pattern of resident species and invasiveness of newly arriving species affect invasibility.
Understanding the factors that affect establishment success of new species in established communities requires the study of both the ability of new species to establish and community resistance. Spatial pattern of species within a community can affect plant performance by changing the outcome of inter-specific competition, and consequently community invasibility. We studied the effects of spatial pattern of resident plant communities on fitness of genotypes from the native and introduced ranges of two worldwide invasive species, Centaurea stoebe and Senecio inaequidens, during their establishment stage. We experimentally established artificial plant mixtures with 4 or 8 resident species in intra-specifically aggregated or random spatial patterns, and added seedlings of genotypes from the native and introduced ranges of the two target species. Early growth of both S. inaequidens and C. stoebe was higher in aggregated than randomly assembled mixtures. However, a species-specific interaction between invasiveness and invasibility highlighted more complex patterns. Genotypes from native and introduced ranges of S. inaequidens showed the same responses to spatial pattern. By contrast, genotypes from the introduced range of C. stoebe did not respond to spatial pattern whereas native ones did. Based on phenotypic plasticity, we argue that the two target species adopted different strategies to deal with the spatial pattern of the resident plant community. We show that effects of spatial pattern of the resident community on the fitness of establishing species may depend on the diversity of the recipient community. Our results highlight the need to consider the interaction between invasiveness and invasibility in order to increase our understanding of invasion success.


Carboxyl-terminal truncations alter the activity of the human α-galactosidase A.
Fabry disease is an X-linked inborn error of glycolipid metabolism caused by deficiency of the human lysosomal enzyme, α-galactosidase A (αGal), leading to strokes, myocardial infarctions, and terminal renal failure, often leading to death in the fourth or fifth decade of life. The enzyme is responsible for the hydrolysis of terminal α-galactoside linkages in various glycolipids. Enzyme replacement therapy (ERT) has been approved for the treatment of Fabry disease, but adverse reactions, including immune reactions, make it desirable to generate improved methods for ERT. One approach to circumvent these adverse reactions is the development of derivatives of the enzyme with more activity per mg. It was previously reported that carboxyl-terminal deletions of 2 to 10 amino acids led to increased activity of about 2 to 6-fold. However, this data was qualitative or semi-quantitative and relied on comparison of the amounts of mRNA present in Northern blots with αGal enzyme activity using a transient expression system in COS-1 cells. Here we follow up on this report by constructing and purifying mutant enzymes with deletions of 2, 4, 6, 8, and 10 C-terminal amino acids (Δ2, Δ4, Δ6, Δ8, Δ10) for unambiguous quantitative enzyme assays. The results reported here show that the kcat/Km approximately doubles with deletions of 2, 4, 6 and 10 amino acids (0.8 to 1.7-fold effect) while a deletion of 8 amino acids decreases the kcat/Km (7.2-fold effect). These results indicate that the mutated enzymes with increased activity constructed here would be expected to have a greater therapeutic effect on a per mg basis, and could therefore reduce the likelihood of adverse infusion related reactions in Fabry patients receiving ERT treatment. These results also illustrate the principle that in vitro mutagenesis can be used to generate αGal derivatives with improved enzyme activity.


Mathematical model of pulsed immunotherapy for superficial bladder cancer.
We present a theoretical study of superficial bladder cancer growth and its treatment via pulsed immunotherapy with Bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis. BCG pulsed immunotherapy is a clinically established procedure for the treatment of superficial bladder cancer. In this paper, periodic BCG instillations are modeled using impulsive differential equations, which are studied using a combination of analytical and numerical techniques. In this way, we determine critical threshold values of the BCG instillation dose and rate of pulsing for successful treatment. We also identify treatment regimes in which tumor destruction occurs, but undesirable side effects are maintained at low levels by the immune system.


Dissection of thousands of cell type-specific enhancers identifies dinucleotide repeat motifs as general enhancer features.
Gene expression is determined by genomic elements called enhancers, which contain short motifs bound by different transcription factors (TFs). However, how enhancer sequences and TF motifs relate to enhancer activity is unknown, and general sequence requirements for enhancers or comprehensive sets of important enhancer sequence elements have remained elusive. Here, we computationally dissect thousands of functional enhancer sequences from three different Drosophila cell lines. We find that the enhancers display distinct cis-regulatory sequence signatures, which are predictive of the enhancers' cell type-specific or broad activities. These signatures contain transcription factor motifs and a novel class of enhancer sequence elements, dinucleotide repeat motifs (DRMs). DRMs are highly enriched in enhancers, particularly in enhancers that are broadly active across different cell types. We experimentally validate the importance of the identified TF motifs and DRMs for enhancer function and show that they can be sufficient to create an active enhancer de novo from a nonfunctional sequence. The function of DRMs as a novel class of general enhancer features that are also enriched in human regulatory regions might explain their implication in several diseases and provides important insights into gene regulation.


The Effects of Compensatory Scanning Training on Mobility in Patients with Homonymous Visual Field Defects: A Randomized Controlled Trial.
Homonymous visual field defects (HVFD) are a common consequence of postchiasmatic acquired brain injury and often lead to mobility-related difficulties. Different types of compensatory scanning training have been developed, aimed at decreasing consequences of the HVFD by changing visual scanning. The aim of the present study is to examine the effects of a compensatory scanning training program using horizontal scanning on mobility-related activities and participation in daily life. The main interest of this study is to assess the effectiveness of training on mobility-related activities and participation in daily life. Visual scanning tests, such as dot counting and visual search, and control measures for visual functions and reading have been included as well. First, it is examined how performance on scanning and mobility-related measures is affected in patients with HVFD by comparing scores with scores of a healthy control group (n = 25). Second, the effect of training is assessed using an RCT design, in which performance of 26 patients before and after training is compared to performance of 23 patients in a waiting list control group. Self-reported improvements after training were found, accompanied by improvements in detecting peripheral stimuli and avoiding obstacles during walking, especially in dual task situations in which a second task limits the attentional capacity available for compensatory scanning. Training only improved mobility-related activities in which detection of peripheral stimuli is important, while no improvement was found on tests that require other visual skills, such as reading, visual counting and visual search. This is the first RCT to evaluate the effects of a compensatory scanning training that is based on a systematic horizontal scanning rhythm. This training improved mobility-related activities. The results suggest that different types of compensatory scanning strategies are appropriate for different types of activities. ISRCTN Registry ISRCTN16833414.


Unacceptably high mortality related to measles epidemics in Niger, Nigeria, and Chad.
Despite the comprehensive World Health Organization (WHO)/United Nations Children's Fund (UNICEF) measles mortality-reduction strategy and the Measles Initiative, a partnership of international organizations supporting measles mortality reduction in Africa, certain high-burden countries continue to face recurrent epidemics. To our knowledge, few recent studies have documented measles mortality in sub-Saharan Africa. The objective of our study was to investigate measles mortality in three recent epidemics in Niamey (Niger), N'Djamena (Chad), and Adamawa State (Nigeria). We conducted three exhaustive household retrospective mortality surveys in one neighbourhood of each of the three affected areas: Boukoki, Niamey, Niger (April 2004, n = 26,795); Moursal, N'Djamena, Chad (June 2005, n = 21,812); and Dong District, Adamawa State, Nigeria (April 2005, n = 16,249), where n is the total surveyed population in each of the respective areas. Study populations included all persons resident for at least 2 wk prior to the study, a duration encompassing the measles incubation period. Heads of households provided information on measles cases, clinical outcomes up to 30 d after rash onset, and health-seeking behaviour during the epidemic. Measles cases and deaths were ascertained using standard WHO surveillance-case definitions. Our main outcome measures were measles attack rates (ARs) and case fatality ratios (CFRs) by age group, and descriptions of measles complications and health-seeking behaviour. Measles ARs were the highest in children under 5 y old (under 5 y): 17.1% in Boukoki, 17.2% in Moursal, and 24.3% in Dong District. CFRs in under 5-y-olds were 4.6%, 4.0%, and 10.8% in Boukoki, Moursal, and Dong District, respectively. In all sites, more than half of measles cases in children aged under 5 y experienced acute respiratory infection and/or diarrhoea in the 30 d following rash onset. Of measles cases, it was reported that 85.7% (979/1,142) of patients visited a health-care facility within 30 d after rash onset in Boukoki, 73.5% (519/706) in Moursal, and 52.8% (603/1,142) in Dong District. Children in these countries still face unacceptably high mortality from a completely preventable disease. While the successes of measles mortality-reduction strategies and progress observed in measles control in other countries of the region are laudable and evident, they should not overshadow the need for intensive efforts in countries that have just begun implementation of the WHO/UNICEF comprehensive strategy.


The Use of Sleep Medication in Youth Residential Care.
Objectives: To investigate the use of sleep medication and concomitant psychotropic medication in children and adolescents placed under residential care (RC). Methods: Participants were youth 0-20 years of age placed in RC institutions at least once during 2016. Data on filled prescriptions were taken from the Norwegian Prescription Database to compare the use of sleep medication in RC with the general child population (GenPop) and how it covaried with gender, age, reasons for RC placement, and concomitant use of other psychotropic medications (antidepressants, anxiolytics, antipsychotics, and psychostimulants). Results: A total of 2171 youths were identified in RC at mean age 14 years (82% ≥ 13 years). Seventeen percent (371/2171) used sleep medications (melatonin 11%, alimemazine 7%, and benzodiazepines/z-hypnotics 2%) significantly more than the 2.3% who used in GenPop. The girl/boy ratio for medication use in RC was 1.8 (95% confidence interval [CI] = 1.5-2.2), not significantly different from the corresponding ratio in GenPop (1.4; 95% CI = 1.3-1.5). The use of sleep medication increased with age. When comparing reasons for placement in RC, medication use was particularly low among unaccompanied minor asylum seekers (2%). About half of the youths used concomitant psychotropic medication, with clear gender differences; girls used about twice as much antidepressants, anxiolytics, and antipsychotics, whereas boys used 1.3 times more psychostimulants. Conclusion: Youths in RC used more sleep medication and concomitant psychotropic medication than the GenPop, most likely reflecting the increased psychosocial strain and mental disorders reported in this population. Further studies of prevalence, assessment, and treatment of sleep problems in RC populations are warranted.


In situ speciation measurements of trace metals in headwater streams.
Concentrations of Al, Fe, Mn, Ni, Cu, Cd, Pb, and Zn were measured using DGT (diffusive gradients in thin-films) devices deployed in situ in 34 headwater streams in Northern England. Mean values of filtered samples analyzed by ICP-MS (inductively coupled plasma mass spectrometry) were used, along with DOC (dissolved organic carbon), pH and major ions, to calculate the distribution of metal species using the speciation code WHAM. DGT-measured concentrations, [Me]DGT, of Zn and Cd were generally similar to concentrations in filtered samples, [Me]filt. For the other metals, [Me]DGT was similar to or lower than [Me]filt. Calculation of the maximum dynamic metal from the speciation predicted using WHAM showed that most of the lower values of [Cu]DGT could be attributed to the dominance of Cu-fulvic acid complexes, which diffuse more slowly than simple inorganic species. Similar calculations for Al, Pb, and Mn were consistent with appreciable proportions of these metals being present as colloids that are not simple complexes with humic substances. Differences between WHAM predictions and the measured [Ni]DGT indicated that WHAM used with the default binding parameters underestimates Ni binding to natural organic matter. Plots of [Me]DGT versus the ratio of bound metal to DOC provided slight evidence of heterogeneous binding of Pb and Cu, while results for Mn, Cd, and Zn were consistent with weak binding and complete lability.


An artificial receptor fabricated by target recognition determinant imprinting for selective capture of α-amanitin.
This is the first reported work of artificial α-amanitin receptors which are prepared using the design and synthesis of a template molecule based on an α-amanitin recognition determinant imprinting strategy. The resultant molecularly imprinted polymers (MIPs) are evaluated using high performance liquid chromatography (HPLC), binding experiment, nitrogen adsorption measurement, and solid-phase extraction. Experiment clearly demonstrates that the MIPs as the HPLC stationary phase can specifically recognize α-amanitin from analogues. The MIPs also successfully adsorb trace amounts of α-amanitin in spiked serum samples selectively pretreated and enriched through molecularly imprinted solid phase extraction. The limit of detection and recovery is 3.0 ng mL(-1) and 88.5-95.9%, respectively, for α-amanitin in serum samples. The high specific adsorption and excellent selectivity of the MIPs arises from imprinting effects related to the imprinting cavity of the polymeric matrix, the metal-coordination bond, and the hydrogen bond between the receptor and ligand.


Oxidative stress, DNA damage, and inflammation induced by ambient air and wood smoke particulate matter in human A549 and THP-1 cell lines.
Combustion of biomass and wood for residential heating and/or cooking contributes substantially to both ambient air and indoor levels of particulate matter (PM). Toxicological characterization of ambient air PM, especially related to traffic, is well advanced, whereas the toxicology of wood smoke PM (WSPM) is poorly assessed. We assessed a wide spectrum of toxicity end points in human A549 lung epithelial and THP-1 monocytic cell lines comparing WSPM from high or low oxygen combustion and ambient PM collected in a village with many operating wood stoves and from a rural background area. In both cell types, all extensively characterized PM samples (1.25-100 μg/mL) induced dose-dependent formation of reactive oxygen species and DNA damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sites assessed by the comet assay with WSPM being most potent. The WSPM contained more polycyclic aromatic hydrocarbons (PAH), less soluble metals, and expectedly also had a smaller particle size than PM collected from ambient air. All four types of PM combined increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine dose-dependently in A549 cells, whereas there was no change in the levels of etheno-adducts or bulky DNA adducts. Furthermore, mRNA expression of the proinflammatory genes monocyte chemoattractant protein-1, interleukin-8, and tumor necrosis factor-α as well as the oxidative stress gene heme oxygenase-1 was upregulated in the THP-1 cells especially by WSPM and ambient PM sampled from the wood stove area. Expression of oxoguanine glycosylase 1, lymphocyte function-associated antigen-1, and interleukin-6 did not change. We conclude that WSPM has small particle size, high level of PAH, low level of water-soluble metals, and produces high levels of free radicals, DNA damage as well as inflammatory and oxidative stress response gene expression in cultured human cells.


The Perception of Spontaneous and Volitional Laughter Across 21 Societies.
Laughter is a nonverbal vocalization occurring in every known culture, ubiquitous across all forms of human social interaction. Here, we examined whether listeners around the world, irrespective of their own native language and culture, can distinguish between spontaneous laughter and volitional laughter-laugh types likely generated by different vocal-production systems. Using a set of 36 recorded laughs produced by female English speakers in tests involving 884 participants from 21 societies across six regions of the world, we asked listeners to determine whether each laugh was real or fake, and listeners differentiated between the two laugh types with an accuracy of 56% to 69%. Acoustic analysis revealed that sound features associated with arousal in vocal production predicted listeners' judgments fairly uniformly across societies. These results demonstrate high consistency across cultures in laughter judgments, underscoring the potential importance of nonverbal vocal communicative phenomena in human affiliation and cooperation.


The interaction of cephalosporin antibiotics with renal cortex of rats: accumulation to cortical slices and binding to purified plasma membranes.
The interaction of cephalosporin antibiotics with renal cortex of rats has been examined in vitro by means of cortical slice uptake and binding assay to plasma membranes and other subcellular fractions, including the comparative study with p-aminohippurate. The uptakes of cephalexin and cephaloridine by cortical slices were concentrative, and were strongly inhibited in the presence of 2,4-dinitrophenol, ouabain, nitrogen gas and probenecid. In the case of cefazolin, the degree of concentrative uptake and influence of inhibitors were low. Cephalexin, cephaloridine and p-aminohippurate specifically bound to the basolateral membranes, compared to brush border membranes and other subcellular fractions. Cefazolin binding to basolateral membranes was relatively small. These results suggest that the specificity of cephalexin and cephaloridine bindings to the basolateral membranes could be related to the interaction with the organic acid transport system at the antiluminal side. Thus, an examination of cephalosporin interaction with plasma membranes from renal cortex could offer an appropriate in vitro model system to study the renal transport of these antibiotics.


Oxygen delivery through nasal cannulae to preterm infants: can practice be improved?
Oxygen delivery through nasal cannulae to convalescent preterm infants is a common but largely unstudied practice. To learn more about current nasal cannula oxygen delivery practices, we examined the variations in oxygen delivery through nasal cannulae among the centers of the Neonatal Research Network, the frequency of prescription of low levels of oxygen, and the success of weaning to room air. We hypothesized that some infants treated with oxygen through nasal cannulae were receiving oxygen levels equivalent to those of room air. This was a descriptive, nested, cohort study of nasal cannula oxygen prescription among 187 infants with birth weights of <1250 g. All infants were studied at a postmenstrual age of 36 weeks, with a timed oxygen reduction challenge to establish their ability to be weaned to room air. The results of this challenge were compared with the fraction of inspired oxygen (FIO2) delivered, calculated as effective FIO2. Infants who maintained oxygen saturation values of > or =90% during oxygen weaning and during a 30-minute period in room air were defined as passing the challenge. Fifty-two infants (27.8%) were receiving oxygen concentrations and flow rates through nasal cannulae that delivered an effective FIO2 of <0.23, of whom 16 were receiving oxygen concentrations and flow rates that delivered an effective FIO2 of 0.21. In addition, 22 infants (11.8%) were prescribed room air through nasal cannulae intentionally. Seventy-two percent of those prescribed an effective FIO2 of <0.23 passed the room air challenge. Prescription of oxygen with combinations of flow rates and oxygen concentrations that delivered a low effective FIO2 was common. We speculate that some of this, including the inadvertent prescription of an effective FIO2 equivalent to that of room air, is related to lack of knowledge of the effective FIO2. Routine calculation of effective FIO2 values may prompt earlier trials of room air and thus reduce unnecessary days of oxygen therapy.


The host defense of Drosophila melanogaster.
To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them.


Prosthodontic approach to treat obstructive sleep apnea.
Sleep disordered breathing represents a continuum, ranging from simple snoring sans sleepiness, upper-airway resistance syndrome, obstructive sleep apnea (OSA) syndrome, to hypercapnic respiratory failure. Fifty seven articles formed the initial database and a final total of 50 articles were selected to form this review report. Four months were spent on the collection and retrieval of the articles. Articles were selected based on accuracy and evidence in the scientific literature. Oral appliances (OAs) are indicated for use in patients with mild to moderate OSA who prefer them to continuous positive airway pressure (CPAP) therapy, or for those who do not respond to, are not appropriate candidates for, or for those who have failed treatment attempts with CPAP. OAs protrude the mandible and hold it in a forward and downward position. As a consequence, the upper airway enlarges antero-posteriorly and laterally, improving its stability. Although OA are effective in some patients with OSA, they are not universally suitable. Compliance with OAs depends mainly on the balance between the perception of benefit and the side effects. In conclusion, marked variability is illustrated in the individual response to OA therapy and hence the treatment outcome is subjective.


A Minimum Free Energy Model of Motor Learning.
Even highly trained behaviors demonstrate variability, which is correlated with performance on current and future tasks. An objective of motor learning that is general enough to explain these phenomena has not been precisely formulated. In this six-week longitudinal learning study, participants practiced a set of motor sequences each day, and neuroimaging data were collected on days 1, 14, 28, and 42 to capture the neural correlates of the learning process. In our analysis, we first modeled the underlying neural and behavioral dynamics during learning. Our results demonstrate that the densities of whole-brain response, task-active regional response, and behavioral performance evolve according to a Fokker-Planck equation during the acquisition of a motor skill. We show that this implies that the brain concurrently optimizes the entropy of a joint density over neural response and behavior (as measured by sampling over multiple trials and subjects) and the expected performance under this density; we call this formulation of learning minimum free energy learning (MFEL). This model provides an explanation as to how behavioral variability can be tuned while simultaneously improving performance during learning. We then develop a novel variant of inverse reinforcement learning to retrieve the cost function optimized by the brain during the learning process, as well as the parameter used to tune variability. We show that this population-level analysis can be used to derive a learning objective that each subject optimizes during his or her study. In this way, MFEL effectively acts as a unifying principle, allowing users to precisely formulate learning objectives and infer their structure.


Methodologic principles of cost analyses in the nursing, medical, and health services literature, 1990-1996.
Cost analyses are needed to inform resource decisions. Oftentimes, however cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), cost-minimization analysis (CMA), and cost-utility analysis (CUA) are performed using untested techniques and adhering to a variety of questionable principles. To analyze, compare, and present a set of useful principles for the main types and methods of cost analyses through a synthesis of current information in the published literature. The area of interest included all reports of cost research published as full articles in professional journals from January 1990 to August 1996 in the nursing, medical, and health services fields. In all, 88 sampled articles met the criteria for inclusion. A four-page data collection guide with 28 items grouped as demographics, cost-analysis types, methods, and principles was designed for the review. Incremental testing for interrater reliability using the kappa statistic for two raters was performed. Sampling, process-oriented, construct, and correlational validity were assessed. The 88 articles included 4 from nursing, 59 from medical, and 25 from health services journals. Of these articles, 45 (51%) reported CBA, 36 (41%) CEA, 2 CMA, 4 CUA, and 1 both CBA and CEA. Three nursing studies were authored only by nurses. Three fourths of the medical and four fifths of the health services publications had interdisciplinary authorship. Existing databases were the primary source of data in 61 (69%) publications. Adherence to six main methodologic principles was apparent in 19 (22%) articles. None of the nursing studies adhered to all six principles, whereas 16% of the health services and 25% of the medical studies did. Funded cost analyses of nursing interventions that adhere to the six known methodologic principles are needed to inform policy-level health care decisions. Because of the complexity of cost analysis methodology, including sensitivity analysis, future interdisciplinary efforts using existing databases may prove most effective. The six methodologic principles presented in this article can be useful for future nursing education and cost-analysis research designed to control cost and increase the quality of health care.


Predictors of breast cancer development in women with atypical ductal hyperplasia and atypical lobular hyperplasia.
Atypical ductal hyperplasia and atypical lobular neoplasia are common benign breast diseases that increase breast cancer risk. We performed a cohort analysis that compared atypia patients for additional risk factors to asses the effect on breast cancer risk by atypia status. This longitudinal cohort study used data from the Women At Risk High-Risk Registry at Columbia University Medical Center, New York. Women with atypia were compared to women without atypia across known risk factors to determine the combined effect on breast cancer development. Odds ratios (ORs) stratified by atypia status were calculated for each risk factor of interest with 95% confidence intervals (95% CIs). P values were calculated to determine statistical significance. The study population included 1598 high-risk women, 921 (57.6%) of whom had a history of biopsy-proven atypia. The remaining 677 high-risk women (42.4%) did not have atypia. Fifty women (3.1%) developed breast cancer. Alcohol was significantly associated with the development of breast cancer (P = 0.02) and increased breast cancer risk among women with atypia (OR, 2.13; 95% CI, 0.95-4.81) compared to women without atypia (OR, 1.71). The odds of breast cancer were higher for atypia patients with first-degree relatives (OR, 1.48; 95% CI, 0.64-3.35) compared to women with a relative and no atypia diagnosis (OR, 0.98; 95% CI, 0.41-2.63). The other risk factors of interest did not differ significantly by atypia status. Atypia patients who drank alcohol and had a first-degree relative with breast cancer have an increased risk of breast cancer compared to those without atypia. Continued understanding of the high-risk population will lead to more individualized protocols for risk reduction and prevention.


HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress.
Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC. HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase. HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.


Occupation and the risk of lung cancer in Uruguay.
The purpose of this study was to provide more information regarding the risk of lung cancer associated with asbestos, and other exposures in the Uruguayan work force. This multisite case-referent study was part of a large project designed for evaluating the role of occupational exposures in cancer risk in Uruguay. According to the design employed, cases were a subset of the data base corresponding to a particular site (in this instance lung cancer), and they were compared with all other sites combined (referents). Significant increases in risk associated with workers in the construction industry were mainly observed for squamous-cell carcinoma. Asbestos, silica dust, and DDT (dichlorodiphenyltrichloroethane) exposure were also associated with increases in the risk of lung cancer. Pipefitters, bakers, and textile workers were also at increased risk of developing lung cancer. Workers employed in the construction industry, as well as those exposed to DDT may have an excess risk of lung cancer. These findings are particularly important in showing that developing countries like Uruguay display risk patterns of similar magnitude as those observed in developed communities.


A Long π-Conjugated Poly(para-Phenylene)-Based Polymeric Segment of Single-Walled Carbon Nanotubes.
Conjugated polymers have attracted much attention for many years and have applications in various organic devices. Carbon nanotubes can be considered as all-carbon tube-shaped conjugated polymers containing only sp2-bonded atoms, which play an important role in nanotechnology and nanoelectronics. So far, no study has reported the realization of long π-conjugated polymers as diameter-specified carbon nanotube segments. Herein, we report the first synthesis of a π-conjugated polymeric segment (PS1) of armchair single-walled carbon nanotubes (SWCNTs). PS1 is achieved by a rationally designed synthesis of a bifunctionalized cyclo-para-phenylene monomer, followed by inserting these ring-shaped units into the conjugated poly(para-phenylene) backbone. PS1 was fully characterized by gel permeation chromatography (GPC) combined with NMR, FTIR, and Raman spectra. Possessing unique structural and physical properties, this long π-extended polymer PS1 can provide new insight for the development of bottom-up syntheses of uniform carbon nanotube segments and potential applications in electron- and hole-transport devices.


Simulation training for pediatric residents on central venous catheter placement: a pilot study.
To assess the effect of simulation training on pediatric residents' acquisition and retention of central venous catheter insertion skills. A secondary objective was to assess the effect of simulation training on self-confidence to perform the procedure. Prospective observational pilot study. Single university clinical simulation center. Pediatric residents, postgraduate years 1-3. Residents participated in a 60- to 90-minute ultrasound-guided central venous catheter simulation training session. Video recordings of residents performing simulated femoral central venous catheter insertions were made before (baseline), after, and at 3-month following training. Three blinded expert raters independently scored the performances using a 24-item checklist and 100-mm global rating scale. At each time point, residents rated their confidence to perform the procedure on a 100-mm scale. Twenty-six residents completed the study. Compared with baseline, immediately following training, median checklist score (54.2% [interquartile range, 40.8-68.8%] vs 83.3% [interquartile range, 70.0-91.7%]), global rating score (8.0 mm [interquartile range, 0.0-64.3 mm] vs 79.5 mm [interquartile range, 16.3-91.7 mm]), success rate (38.5% vs 80.8%), and self-confidence (8.0 mm [interquartile range, 3.8-19.0 mm] vs 52.0 mm [interquartile range, 43.5-66.5 mm]) all improved (p < 0.05 for all variables). Compared with baseline, median checklist score (54.2% [interquartile range, 40.8-68.8%] vs 54.2% [interquartile range, 45.8-80.4%], p = 0.47), global rating score (8.0 mm [interquartile range, 0.0-64.3 mm] vs 35.5 mm [interquartile range, 5.3-77.0], p = 0.62), and success rate (38.5% vs 65.4%, p = 0.35) were similar at 3-month follow-up. Self-confidence, however, remained above baseline at 3-month follow-up (8.0 mm [interquartile range, 3.8-19.0 mm] vs 61.0 mm [interquartile range, 31.5-71.8 mm], p < 0.01). Simulation training improved pediatric residents' central venous catheter insertion procedural skills. Decay in skills was found at 3-month follow-up. This suggests that simulation training for this procedure should occur in close temporal proximity to times when these skills would most likely be used clinically and that frequent refresher training might be beneficial to prevent skills decay.


The effect of glazing on the biaxial flexural strength of different zirconia core materials.
The aim of this study was to evaluate the effect of glazing on biaxial flexural strength of different zirconia core materials. Disc-shaped zirconia (ZirkonZahn, Cercon, Ceramill) specimens (15 mm x 1.15+/-0.02 mm) were prepared according to manufacturers' instructions. The specimens from each system were divided into 2 groups (N= 10): unglazed and glazed. Glaze liquid was applied on the entire surface of the specimens of the glazed group and fired according to manufacturers' instructions. Flexural strength test was performed in a universal testing machine (crosshead speed: 1 mm/min). Data were statistically analyzed using two-way ANOVA and Tukey's test (p= 0.05). The mean flexural strength values for unglazed ZirkonZahn specimens (1388+132 MPa) were significantly higher than those of unglazed Cercon (1104+124 MPa) and unglazed Ceramill (1172+127 MPa) specimens. The mean flexural strength of glazed specimens did not show any statistically significant difference. Glazing decreased the flexural strength results significantly for all systems (p< 0.05). Glazing decreased the flexural strength values for ZirkonZahn, Cercon and Ceramill specimens. Unglazed ZirkonZahn specimens revealed significantly higher mean flexural strength values than that ofunglazed and glazed zirconia materials tested in this study.


Do clinical pathways enhance access to evidence-based acute myocardial infarction treatment in rural emergency departments?
The objective of this study is to measure the impact of a five-step implementation process for an acute myocardial infarction (AMI) clinical pathway (CPW) on thrombolytic administration in rural emergency departments. Cluster randomised controlled trial. Six rural Victorian emergency departments participated. The five-step CPW implementation process comprised (i) engaging clinicians; (ii) CPW development; (iii) reminders; (iv) education; and (v) audit and feedback. The impact of the intervention was assessed by measuring the proportion of eligible AMI patients receiving a thrombolytic and time to thrombolysis and electrocardiogram. Nine hundred and fifteen medical records were audited, producing a final sample of 108 patients eligible for thrombolysis. There was no significant difference between intervention and control groups for median door-to-needle time (29 mins versus 29 mins; P = 0.632), proportion of those eligible receiving a thrombolytic (78% versus 84%; P = 0.739), median time to electrocardiogram (7 mins versus 6 mins; P = 0.669) and other outcome measures. Results showed superior outcome measures than other published studies. The lack of impact of the implementation process for a chest pain CPW on thrombolytic delivery or time to electrocardiogram in these rural hospitals can be explained by a ceiling effect in outcome measures but was also compromised by the small sample. Results suggest that quality of AMI treatment in rural emergency departments (EDs) is high and does not contribute to the worse mortality rate reported for AMIs in rural areas.


Mouse colorectal cancer an early detection approach using nonlinear microscopy.
Murine induced colon cancer has been used to demonstrate that Second Harmonic Generation (SHG) microscopy images, combined with Two-Photon Excitation Fluorescence (TPEF) and specific quantization scoring methods allow distinguishing early alterations in colon mucosa. TPEF was used only to identified crypts and submucosa regions, whereas the image analysis was used to get quantitative data (Integrated Intensity and Aspect Ratio scoring) of different cancer stages. The submucosa amount of collagen fibers was significant and their orientation suffering proportional changes with the development of the pathological processes. Both after the fourth and eighth weeks after colon cancer induction, integrated intensity and aspect ratio values have shown significant statistical differences compared with control samples. Thus, SHG microscopy has proved to be a useful quantitative tool to highlight early changes of submucosa and the progression of these through the cancer development.


Primary cryotherapy for localised or locally advanced prostate cancer.
Traditionally, radical prostatectomy and radiotherapy with or without androgen deprivation therapy have been the main treatment options to attempt to cure men with localised or locally advanced prostate cancer. Cryotherapy is an alternative option for treatment of prostate cancer that involves freezing of the whole prostate (whole gland therapy) or only the cancer (focal therapy), but it is unclear how effective this is in comparison to other treatments. To assess the effects of cryotherapy (whole gland or focal) compared with other interventions for primary treatment of clinically localised (cT1-T2) or locally-advanced (cT3) non-metastatic prostate cancer. We updated a previously published Cochrane Review by performing a comprehensive search of multiple databases (CENTRAL, MEDLINE, EMBASE), clinical trial registries (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform) and a grey literature repository (Grey Literature Report) up to 6 March 2018. We also searched the reference lists of other relevant publications and conference proceedings. We applied no language restrictions. We included randomised or quasi-randomised trials comparing cryotherapy to other interventions for the primary treatment of prostate cancer. Two independent reviewers screened the literature, extracted data, and assessed risk of bias. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence (QoE) according to the GRADE approach. We included only one comparison of whole gland cryotherapy versus external beam radiotherapy, which was informed by two trials with a total of 307 randomised participants. The median age of the included studies was around 70 years. The median follow-up of included studies ranged from 100 to 105 months.Primary outcomes: we are uncertain about the effect of whole gland cryotherapy compared to radiation therapy on time to death from prostate cancer; hazard ratio (HR) of 1.00 (95% confidence interval (CI) 0.11 to 9.45; 2 trials, 293 participants; very low QoE); this would correspond to zero fewer death from prostate cancer per 1000 men (95% CI 85 fewer to 520 more). We are equally uncertain about the effect of quality of life-related urinary function and bowel function (QoL) at 36 months using the UCLA-Prostate Cancer Index score for which higher values (range: 0 to 100) reflect better quality of life using minimal clinically important differences (MCID) of 8 and 7 points, respectively; mean difference (MD) of 4.4 (95% CI -6.5 to 15.3) and 4.0 (95% CI -73.96 to 81.96), respectively (1 trial, 195 participants; very low QoE). We are also uncertain about sexual function-related QoL using a MCID of 8 points; MD of -20.7 (95% CI -36.29 to -5.11; 1 trial, 195 participants; very low QoE). Lastly, we are uncertain of the risk for major adverse events; risk ratio (RR): 0.91 (95% CI 0.47 to 1.78; 2 trials, 293 participants; very low QoE); this corresponds to 10 fewer major adverse events per 1000 men (95% CI 58 fewer to 86 more). we are very uncertain about the effects of cryotherapy on time to death from any cause (HR 0.99, 95% CI 0.05 to 18.79; 2 trials, 293 participants; very low QoE), and time to biochemical failure (HR 2.15, 95% CI 0.07 to 62.12; 2 trials, 293 participants; very low QoE). Rates of secondary interventions for treatment failure and minor adverse events were either not reported in the trials, or the data could not be used for analyses.We found no trials that compared whole gland cryotherapy or focal cryotherapy to other treatment forms such as radical surgery, active surveillance, watchful waiting or other forms of radiotherapy. Based on very low quality evidence, primary whole gland cryotherapy has uncertain effects on oncologic outcomes, QoL, and major adverse events compared to external beam radiotherapy. Reasons for downgrading the QoE included serious study limitations, indirectness due to the use of lower doses of radiation in the comparison group than currently recommended, and serious or very serious imprecision.


Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes.
The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.


Substance use related behavior of the members of Narcotics Anonymous and Alcoholics Anonymous in Greece.
The aim of this research project is to provide basic information regarding the use of substances and its behavioral consequences such as health problems and criminal offences. It is the first survey in Greece in the field of self-help groups. The main research instrument was a 55-item questionnaire that was administered to members of NA and AA in the Greek cities of Athens, Thessaloniki, Serres, Nafplio, Iraklio, and Katerini. This article presents an analysis of the answers given by the respondents to 12 of the 55 items of the questionnaire. It also includes a comparison of the relevant findings with data provided by the central organizations of AA and NA as well as by official therapeutic programs in Greece and by other researchers who have studied the same subject. More specifically, this article presents, examines and analyzes data which focuses on: (a) the age at which a substance was first used, (b) the time it took the individual respondents to acknowledge such use as a problem, (c) the main substance abused at the onset, (d) the main substance in use when the individuals approached the self-help group, (e) the existence or not of another individual with a substance abuse disorder in the immediate family, (f) possible health problems and (g) the entanglement or not with the penal justice system.


The alpha(2A)-adrenergic agonist guanfacine improves visuomotor associative learning in monkeys.
Two monkeys were trained on two-problem visuomotor associations: if the cue was a circle pattern, move a handle to the left ('go-left'), and if it was a triangle pattern, move the handle to the right ('go-right'). These two visuomotor associations were unchanged throughout all the experiments and therefore were very familiar to the monkeys. For learning of new visuomotor associations, each monkey was presented with a new set of four novel patterns in each and every daily session, two of which instructed 'go-left' response and the other two 'go-right' response. Systemically administered guanfacine, a selective alpha(2A)-adrenergic agonist, improved the monkeys' learning ability: trials and errors to the learning criterion of 90% correct decreased significantly. The monkeys showed an enhanced capability of using at least three response strategies: win-stay on 'repeat trial', change-stay and change-shift on 'change trial'. The beneficial effect could be reversed by the coadministered idaxozan, an alpha(2)-adrenergic antagonist, which had no effect when administered alone. Similar treatment with guanfacine had no beneficial effect on visual discriminative learning, a task that involves the inferotemporal cortex. The present results indicate that stimulation by guanfacine of alpha(2A)-adrenoceptors improves visuomotor associative learning, probably through actions at alpha(2A)-adrenoceptors in the prefrontal cortex.


The Effects of a Lateral Wedge Insole on Knee and Ankle Joints During Slope Walking.
The purpose of this study was to determine whether a lateral wedge insole reduces the external knee adduction moment during slope walking. Twenty young, healthy subjects participated in this study. Subjects walked up and down a slope using 2 different insoles: a control flat insole and a 7° lateral wedge insole. A three-dimensional motion analysis system and force plate were used to examine the knee adduction moment, the ankle valgus moment, and the moment arm of the ground reaction force to the knee joint center in the frontal plane. The lateral wedge insole significantly decreased the moment arm of the ground reaction force, resulting in a reduction of the knee adduction moment during slope walking, similar to level walking. The reduction ratio of knee adduction moment by the lateral wedge insole during the early stance of up-slope walking was larger than that of level walking. Conversely, the lateral wedge insole increased the ankle valgus moment during slope walking, especially during the early stance phase of up-slope walking. Clinicians should examine the utilization of a lateral wedge insole for knee osteoarthritis patients who perform inclined walking during daily activity, in consideration of the load on the ankle joint.


Combining Anisotropic Etching and PDMS Casting for Three-Dimensional Analysis of Laser Ablation Processes.
State-of-the-art laser ablation (LA) depth-profiling techniques (e.g. LA-ICP-MS, LIBS, and LIMS) allow for chemical composition analysis of solid materials with high spatial resolution at micro- and nanometer levels. Accurate determination of LA-volume is essential to correlate the recorded chemical information to the specific location inside the sample. In this contribution, we demonstrate two novel approaches towards a better quantitative analysis of LA craters with dimensions at micrometer level formed by femtosecond-LA processes on single-crystalline Si(100) and polycrystalline Cu model substrates. For our parametric crater evolution studies, both the number of applied laser shots and the pulse energy were systematically varied, thus yielding 2D matrices of LA craters which vary in depth, diameter, and crater volume. To access the 3D structure of LA craters formed on Si(100), we applied a combination of standard lithographic and deep reactive-ion etching (DRIE) techniques followed by a HR-SEM inspection of the previously formed crater cross sections. As DRIE is not applicable for other material classes such as metals, an alternative and more versatile preparation technique was developed and applied to the LA craters formed on the Cu substrate. After the initial LA treatment, the Cu surface was subjected to a polydimethylsiloxane (PDMS) casting process yielding a mold being a full 3D replica of the LA craters, which was then analyzed by HR-SEM. Both approaches revealed cone-like shaped craters with depths ranging between 1 and 70 μm and showed a larger ablation depth of Cu that exceed the one of Si by a factor of about 3.