A sub-clustering algorithm based on spatial data correlation for energy conservation in wireless sensor networks.
Wireless sensor networks (WSNs) have emerged as a promising solution for various applications due to their low cost and easy deployment. Typically, their limited power capability, i.e., battery powered, make WSNs encounter the challenge of extension of network lifetime. Many hierarchical protocols show better ability of energy efficiency in the literature. Besides, data reduction based on the correlation of sensed readings can efficiently reduce the amount of required transmissions. Therefore, we use a sub-clustering procedure based on spatial data correlation to further separate the hierarchical (clustered) architecture of a WSN. The proposed algorithm (2TC-cor) is composed of two procedures: the prediction model construction procedure and the sub-clustering procedure. The energy conservation benefits by the reduced transmissions, which are dependent on the prediction model. Also, the energy can be further conserved because of the representative mechanism of sub-clustering. As presented by simulation results, it shows that 2TC-cor can effectively conserve energy and monitor accurately the environment within an acceptable level.


Field issues related to effectiveness of insecticide-treated nets in Tanzania.
Insecticide-treated nets (ITNs) impregnated with pyrethroid insecticides have become one of the most promising interventions to prevent malaria in highly endemic areas. Despite the large body of experience documenting their health impact and the best way to distribute them, some key practical issues remain unresolved. For example, the duration of effective life of a net under field conditions is unknown. The most important factor affecting net effectiveness is the issue of regular re-treatment with insecticide. Washing is also an important determinant of insecticide longevity in the field. Trials were undertaken to provide some essential field information on ITNs within the site of an extended ITN programme in the Morogoro region of Tanzania. It was found that 45% of all nets were in bad condition (defined as more than seven large holes). It is concluded that an effective 'life' for polyester nets is 2-3 years. Further, two-thirds of the 20% of nets that were reported as having been re-treated within the last 12 months had less than 5 mg/m(2) of insecticide. According to the World Health Organization this is insufficient to be effective. People reported that they washed their nets four to seven times per year, usually with soap. Observations showed that such washing does not harm the nets and that the wash-water was unlikely to have an impact on the environment. Finally, bioassays were carried out with Anopheles gambiae on polyester netting with 0.5, 2, 5, 10 and 30 mg/m(2) of deltamethrin, alphacypermethrin and lambdacyhalothrin to assess the effectiveness of pyrethroids. The results confirmed that even with low insecticide concentrations, nets can still provide partial protection.


Prognostic value of nucleated red blood cells in critically ill children.
Is there an association between the presence of nucleated red blood cells (NRBCs) in the peripheral blood and outcomes in critically ill children? Prospective observational study conducted in 2008 (January to December) in a multidisciplinary paediatric intensive care unit (PICU) of a tertiary children's hospital. We provide univariate analysis, stratified by age group (neonates and children >28 days of age), and multiple logistic regression, comparing clinically important outcomes (death, ventilation, renal replacement therapy, inotropic support) with haematological (NRBC, haemoglobin, platelets, leucocytes), illness severity (expected mortality [paediatric index of mortality, PIM2]), demographic (age, sex) and diagnostic parameters and length of stay. Haematological parameters correspond to the first 24 hours of PICU admission. Out of 670 patients, 195 (29.1%) were NRBC positive and 475 (70.9%) were NRBC negative. In the neonatal age group (n = 232), patients who died, were ventilated or received inotropic support had significantly more NRBCs than patients without these conditions (p = 0.032, 0.038 and 0.029, respectively). In the child age group (n = 438), only renal replacement therapy was significantly associated with NRBC (p <0.001). High PIM score (p <0.001) and longer length of stay (p <0.001) were independently associated with bad outcomes (composite endpoint: mortality and/or ventilation and/or renal replacement therapy and/or inotropic support); NRBC positivity was not an independent predictor of bad outcome (odds ratio 1.44, 95% confidence interval 0.62‒3.41). NRBCs are not an independent risk factor for bad outcomes in paediatric intensive care. However, NRBCs may have some prognostic value in the first month of life. In children >1 month of age, the association between NRBC and outcome is much less pronounced.


Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.
Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. To examine postulated associations of genetic alleles with HIV-1 disease progression. Meta-analysis of individual-patient data. 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. Patients with HIV-1 infection who were of European or African descent. Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.


Phase cross correlation in the coherent Raman process.
The coherent anti-Stokes Raman scattering (CARS) process with two different-color phase-fluctuating fields was studied experimentally and theoretically. It was found that the efficiency of this process depends strongly on the cross correlation between the phases of the driving fields. Depending on the detuning from Raman resonance, the CARS signal can be either enhanced or suppressed with respect to the case of uncorrelated fields.


Evolutionary history of the honey bee Apis mellifera inferred from mitochondrial DNA analysis.
Variability of mitochondrial DNA (mtDNA) of the honey bee Apis mellifera L. has been investigated by restriction and sequence analyses on a sample of 68 colonies from ten different subspecies. The 19 mtDNA types detected are clustered in three major phylogenetic lineages. These clades correspond well to three groups of populations with distinct geographical distributions: branch A for African subspecies (intermissa, monticola, scutellata, andansonii and capensis), branch C for North Mediterranean subspecies (caucasica, carnica and ligustica) and branch M for the West European populations (mellifera subspecies). These results partially confirm previous hypotheses based on morphometrical and allozymic studies, the main difference concerning North African populations, now assigned to branch A instead of branch M. The pattern of spatial structuring suggests the Middle East as the centre of dispersion of the species, in accordance with the geographic areas of the other species of the same genus. Based on a conservative 2% divergence rate per Myr, the separation of the three branches has been dated at about 1 Myr BP.


Panic attack triggering myocardial ischemia documented by myocardial perfusion imaging study. A case report.
Chest pain, a key element in the investigation of coronary artery disease is often regarded as a benign prognosis when present in panic attacks. However, panic disorder has been suggested as an independent risk factor for long-term prognosis of cardiovascular diseases and a trigger of acute myocardial infarction. Faced with the extreme importance in differentiate from ischemic to non-ischemic chest pain, we report a case of panic attack induced by inhalation of 35% carbon dioxide triggering myocardial ischemia, documented by myocardial perfusion imaging study. Panic attack is undoubtedly a strong component of mental stress. Patients with coronary artery disease may present myocardial ischemia in mental stress response by two ways: an increase in coronary vasomotor tone or a sympathetic hyperactivity leading to a rise in myocardial oxygen consumption. Coronary artery spasm was presumed to be present in cases of cardiac ischemia linked to panic disorder. Possibly the carbon dioxide challenge test could trigger myocardial ischemia by the same mechanisms. The use of mental stress has been suggested as an alternative method for myocardial ischemia investigation. Based on translational medicine objectives the use of CO2 challenge followed by Sestamibi SPECT could be a useful method to allow improved application of research-based knowledge to the medical field, specifically at the interface of PD and cardiovascular disease.


Efficacy of a Cationic Emulsion of Cyclosporine in Moderate Vernal Keratoconjunctivitis.
The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC). This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae. Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted. CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children.


Polymer-based particles against pathogenic fungi: A non-uptake delivery of compounds.
The therapy of life-threatening fungal infections is limited and needs urgent improvement. This is in part due to toxic side effects of clinically used antifungal compounds or their limited delivery to fungal structures. Until today, it is a matter of debate how drugs or drug-delivery systems can efficiently reach the intracellular lumen of fungal cells and how this can be improved. Here, we addressed both questions by applying two different polymeric particles for delivery of compounds. Their formulation was based on two biocompatible polymers, i.e., poly(lactic-co-glycolic acid)50:50 and poly(methyl methacrylate-stat-methacrylic acid)90:10 yielding particles with hydrodynamic diameters ranging from 100 to 300 nm. The polymers were covalently labeled with the fluorescent dye DY-550 to monitor the interaction between particles and fungi by confocal laser scanning microscopy. Furthermore, the fluorescent dye coumarin-6 and the antifungal drug itraconazole were successfully encapsulated in particles to study the fate of both the cargo and the particle when interacting with the clinically most important human-pathogenic fungi Aspergillus fumigatus, A. terreus, Candida albicans, and Cryptococcus neoformans. While the polymers were exclusively located on the fungal surface, the encapsulated cargo was efficiently transported into fungal hyphae, indicated by increased intracellular fluorescence signals due to coumarin-6. In accordance with this finding, compared to the pristine drug a reduced minimal inhibitory concentration for itraconazole was determined, when it was encapsulated. Together, the herein used polymeric particles were not internalized by pathogenic fungi but were able to efficiently deliver hydrophobic cargos into fungal cells.


An introduction to peptide nucleic acid.
Peptide Nucleic Acid (PNA) is a powerful new biomolecular tool with a wide range of important applications. PNA mimics the behaviour of DNA and binds complementary nucleic acid strands. The unique chemical, physical and biological properties of PNA have been exploited to produce powerful biomolecular tools, antisense and antigene agents, molecular probes and biosensors.


Involving patients in medical education: ethical issues experienced by Syrian patients.
Patients' involvement and their willingness to cooperate in clinical teaching is a vital element of medical education. Clinical teaching at the Faculty of Medicine of Damascus University relies heavily on inpatients at teaching hospitals but also on patients brought to teaching rooms. The purpose of this study was to identify patients' experiences and their attitudes toward the involvement of medical students in clinical consultations within teaching rooms conducted mainly for students' benefit. In-depth interviews were carried out by a sociologist using an interview guide with 14 patients whose clinical cases were presented to a large group of students in the teaching room at Damascus University teaching hospitals. Data analysis involved content analysis. Main themes were identified with negative ethical aspects, such as the lack of patient's involvement in decision making and approving to be part of clinical teaching. Risk and benefits were experienced by patients and identified in their experiences. Some felt that they were treated inhumanely and with a lack of dignity. Patients nevertheless felt a responsibility to be part of the teaching process. They expressed their positive attitudes towards involvement in the teaching process to serve medical students as well as the greater community. Findings provide perspectives and insights into the current clinical teaching at Damascus University Faculty of Medicine. The findings highlight the need in our institution to carry out medical education involving patients in a more ethical manner. Medical students and their teachers need more training in the ethical involvement of patients in students' learning process, as well as the need to better regulate patients' involvement in education.


Effect of polarization on symmetry of focal spot of a plasmonic lens.
When one uses a metallic nanostructure to excite surface plasmon polaritons (SPPs) for subwavelength focusing, there is the distinct shape of the light emerging from the plasmonic lens in the transverse directions due to 2D confinement of SPPs. To study the tuning of symmetry of a focal spot, we consider an annular plasmonic lens incident with a polarized plane wave having various polarization states, including circular polarization (CP), elliptical polarization (EP), and radial polarization (RP), compared to linear polarization (TM). We find that plasmonic modes are independent of the polarization approach and the different polarization states enable to tune transverse electric field. More specifically, for CP case where the phase function Re[exp(itheta)]=0, the total-electric-field intensity is distributed uniformly in the transverse plane, while for RP case where the phase function Re[exp(itheta)]=1, a significant intensity contrast is observed in the two diagonal directions. We show an agreement between the analytical description and numerical simulation.


Responsive, switchable wormlike micelles for CO2/N2 and redox dual stimuli based on selenium-containing surfactants.
A dual-stimuli responsive, wormlike micelle system was developed using a switchable selenium-containing surfactant, dihendecylcarboxylic acid sodium selenide (C11-Se-C11), and a commercially available surfactant, cetyltrimethyl ammonium bromide (CTAB). The solution showed a viscoelastic characteristic at low shear frequencies, and the synergism was significant when the concentrations of CTAB and C11-Se-C11 were 145 mM and 25 mM, respectively. Additionally, the system was fast and reversibly responded to CO2 and redox dual stimuli, and it showed a circulatory gel/sol transition, which reflected changes in the self-assembly from entangled worms to rodlike micelles. Moreover, these transitions were switchable at least three times. The dual responsiveness of the solution allowed for precise control of the wormlike micelles, and these micelles will have a wide range of applications in the development of functional materials for pharmaceutical or biomedical materials.


Head injuries among FIS World Cup alpine and freestyle skiers and snowboarders: a 7-year cohort study.
Traumatic brain injury is the leading cause of death for skiers and snowboarders. Fatal head injuries have also occurred at the International Ski Federation (FIS) World Cup (WC) level. We therefore wanted to describe the risk of head injuries across disciplines and sex among WC skiers and snowboarders. We conducted retrospective interviews with FIS WC athletes at the end of seven consecutive seasons (2006-2013) to register injuries sustained during the competitive season. Head injuries were classified as 'head/face' injuries and did not include neck or cervical spine injuries. To calculate the exposure, we extracted data from the official FIS website for all WC competitions for each of the athletes interviewed. A total of 2080 injuries were reported during seven WC seasons. Of these, 245 (11.8%) were head/face injuries. Of the 245 head/face injuries reported, nervous system injuries/concussions were the most common (81.6%) and 58 of these were severe (23.7%). The injury incidence per 1000 competition runs was higher in freestyle (1.8, 95% CI 1.2 to 2.4) than in alpine skiing (0.9, 95% CI 0.6 to 1.2; risk ratio (RR) 2.05, 95% CI 1.25 to 3.46) and snowboard (1.0, 95% CI 0.6 to 1.3; RR 1.85, 95% CI 1.15 to 2.99). Women had a higher injury incidence (5.8, 95% CI 4.8 to 6.9) versus men (3.9, 95% CI 3.2 to 4.6; RR 1.48, 95% CI 1.15 to 1.90) throughout the season (per 100 athletes). The majority of head/face injuries were nervous system injuries/concussions and one in four injuries was severe. Freestyle skiers had the highest overall head injury incidence. Across all disciplines, the injury incidence was higher in women than in men.


Mediterranean diet and risk of frailty syndrome among women with type 2 diabetes.
Previous research indicates that patients with type 2 diabetes are at higher risk of becoming frail. Emerging evidence also indicates that the Mediterranean diet may prevent frailty in the older population. The aim of this study was to assess whether a Mediterranean-style diet pattern was associated with lower risk of frailty among older women with diabetes. This was a prospective cohort study in 8970 women aged ≥60 y with type 2 diabetes from the Nurses' Health Study. Adherence to the alternate Mediterranean diet (aMED) score was first measured in 1990 and repeated every 4 y until 2010. Frailty occurrence was ascertained up to 2012 and was defined as having ≥3 of the following 5 criteria from the fatigue, resistance, aerobic, illnesses, loss of weight (FRAIL) scale: Fatigue, low Resistance, low Aerobic capacity, having ≥5 Illnesses, and weight Loss of ≥5%. Those with frailty at baseline were excluded. During follow-up, we identified 569 incident cases of frailty. After adjustment for lifestyle factors and medication use, the HR (95% CI) of frailty was 1 for the lowest quartile of the aMED score, 0.88 (0.71, 1.10) for the second quartile, 0.69 (0.53, 0.88) for the third quartile, and 0.54 (0.42, 0.71) for the highest quartile (P-trend < 0.001). A 2-point (∼1 SD) increase in the aMED score was associated with a 28% (95% CI: 19%, 36%) reduced risk of frailty. The largest reduction in the risk was observed for a higher consumption of vegetables and fruit, as well as for alcohol intake. A Mediterranean-style diet pattern was associated with reduced risk of frailty syndrome in older women with type 2 diabetes.


Not All DDRs Are Created Equal: Non-Canonical DNA Damage Responses.
It is commonly assumed that there is a single canonical DNA damage response (DDR) that protects cells from various types of double-strand breaks and that its activation occurs via recognition of DNA ends by the DDR machinery. Recent work suggests that both assumptions may be oversimplifications. Here, we discuss several variations of the DDR in which the pathway is activated by diverse cellular events and/or generates distinct signaling outcomes. The existence of multiple non-canonical DDRs provides insights into how DNA damage is sensed and suggests a highly modular organization of the DDR.


Biological responses to cationically charged phosphorylcholine-based materials in vitro.
Phosphorylcholine (PC)-based polymers have been used in a variety of medical device applications to improve biocompatibility. The use of PC-based materials for biomaterials is associated with low protein adsorption, reduced complement activation, low inflammatory response and cell adhesion. For some medical device applications however, materials that support cell adhesion are also beneficial, allowing host interaction and encouraging full incorporation within the body. As previous studies have suggested that cell adhesion to materials is enhanced by the addition of charge, PC-based polymers have therefore been modified to incorporate various concentrations of cationic charge. In this study, the affect of cationic charge on a range of biological responses was investigated. In vitro assays have been used to assess the adsorption of protein onto the materials surface, the adhesion of mouse fibroblasts and rabbit corneal epithelial cells and the adhesion of human mononuclear cells and granulocytes. The results corroborate previous work showing that PC without charge significantly reduces protein adsorption, cell adhesion and inflammatory cell activation. The addition of cationic charge to PC polymers however, resulted in an increase in all of the above responses. This increase did not however, increase linearly with cationic monomer concentration. The differences in cell adhesion are discussed in terms of differences in protein adsorption, cytotoxicity and/or stability of the different cationic polymer coatings.


Power scaling of a picosecond vortex laser based on a stressed Yb-doped fiber amplifier.
Power scaling of a picosecond vortex laser based on a stressed Yb-doped fiber amplifier is analyzed. An output power of 25 W was obtained for 53 W of pumping, with a peak power of 37 kW. Frequency doubling of the vortex output was demonstrated using a nonlinear PPSLT crystal. A second-harmonic output power of up to 1.5 W was measured at a fundamental power of 11.2 W.


Fast diffusion-limited lyotropic phase transitions studied in situ using continuous flow microfluidics/microfocus-SAXS.
Fast concentration-induced diffusion-limited lyotropic phase transitions can be studied in situ with millisecond time resolution using continuous flow microfluidics in combination with microfocus small-angle X-ray scattering. The method was applied to follow a classical self-assembly sequence where amphiphiles assemble into micelles, which subsequently assemble into an ordered lattice via a disorder/order transition. As a model system we selected the self-assembly of an amphiphilic block copolymer induced by the addition of a nonsolvent. Using microchannel hydrodynamic flow-focusing, large concentration gradients can be generated, leading to a deep quench from the miscible to the microphase-separated state. Within milliseconds the block copolymers assembly via a spinodal microphase separation into micelles, followed by a disorder/order transition into an FCC liquid-crystalline phase with late-stage domain growth and shear-induced domain orientation into a mesocrystal. A comparison with a slow macroscopic near-equilibrium kinetic experiment shows that the fast structural transitions follow a direct pathway to the equilibrium structure without the trapping of metastable states.


Fresh stored allografts for the treatment of osteochondral defects of the knee.
Osteochondral allograft reconstruction of articular cartilage defects is a well-established cartilage repair strategy. Currently, fresh osteochondral allograft tissue is commercially available to clinicians approximately thirty days following graft harvest. Little clinical information is available on the outcome of patients who have been treated with fresh allografts stored for several weeks or more. The purpose of this study was to prospectively analyze the clinical outcome and graft morphology of patients who received fresh, hypothermically stored, allograft tissue for the treatment of symptomatic chondral and osteochondral defects of the knee. Nineteen patients with symptomatic chondral and osteochondral lesions of the knee who were treated with fresh osteochondral allografts between 1999 and 2002 were prospectively followed. The mean age at the time of surgery was thirty-four years. Validated outcomes instruments (the Activities of Daily Living Scale and the Short Form-36) were used; all patients must have had a baseline functional score prior to surgery and a minimum two-year follow-up evaluation. All grafts were obtained from commercial vendors; the mean preimplantation storage time of the graft was thirty days (range, seventeen to forty-two days). The mean lesion size was 602 mm(2). Magnetic resonance imaging was used to evaluate the morphologic characteristics of the implanted grafts. The mean duration of clinical follow-up was forty-eight months (range, twenty-one to sixty-eight months). The mean score (and standard deviation) on the Activities of Daily Living Scale increased from a baseline of 56 +/- 24 to 70 +/- 22 at the time of the final follow-up (p < 0.05). The mean Short Form-36 score increased from a baseline of 51 +/- 23 to 66 +/- 24 at the time of final follow-up (p < 0.005). With the numbers studied, we could not correlate graft storage time, body mass index, lesion size, lesion location, or patient age with the functional outcome scores. At a mean follow-up interval of twenty-five months, cartilage-sensitive magnetic resonance imaging demonstrated that the normal articular cartilage thickness was preserved in eighteen implanted grafts, and allograft cartilage signal properties were isointense relative to normal articular cartilage in eight of the eighteen grafts. Osseous trabecular incorporation of the allograft was complete or partial in fourteen patients and poor in four patients. Complete or partial trabecular incorporation positively correlated with Short Form-36 scores at the time of follow-up (r = 0.487, p < 0.05). Fresh osteochondral allografts that were hypothermically stored between seventeen and forty-two days were effective in the short term both structurally and functionally in reconstructing symptomatic chondral and osteochondral lesions of the knee. Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.


On a regulatory gene controlling the expression of the murine lambda1 light chain.
We describe here two alleles, an allele of the lambda1 locus present in the SJL strain (rlambda1lo) and an allele of the lambda1 locus present in the BALB/c strain (rlambda1 +), of a regulatory gene locus which specifically influences the expression of the mouse lambda1 light chain structural gene. The rlambda1 regulatory gene is not linked to either the major histocompatibility complex or to the heavy-chain allogroup but appears to be linked to the lambda1 structural gene locus. In the homozygous state, the present of the rlambda1lo allele results in a 50-fold reduction in the number of lambda1 antigen-sensitive, bone-marrow derived lymphocytes (ASCs) compared to the presence of the rlambda1 + allele. However, those few lambda1ASCs present in rlambda1lo homozygotes can be induced normally to produce lambda1 light chains indistinguishable from those found in rlambda1 + homozygotes. The reduction in lambda1ASC's due to the rlambda1lo allele results both in a reduction in the amount of lambda1 Ig in the serum and also in a large variation in the magnitude of the lambda1 antibody response to alpha(1,3) dextran by individual animals. This variation permits the estimate that, on the average, 50 B cells of anti-alpha(1,3) specificity must be present per animal to permit a measurable response. Surprisingly, the expression of a gene locus regulating lambda1 light chain expression (rlambda1 locus) shows a clear gene dosage effect with rlambda1lo/rlambda1 + heterozygotes having 1/2 the number of lambda1ASCs and 1/2 the amount of serum lambda1 Ig as rlambda1 +/rlambda1 + homozygotes. This fact permits an analysis of the relationship between germ-line v-genes and their individual expression in serum Ig. The rlambda1 locus controls specifically a DNA-level event which occurs in stem cells as they become committed to lambda1 light chain expression. We postulate that the rlambda1 locus represents one of the DNA level recognition sites involved in the translocation event which places the vlambda1 and clambda1 structural genes in a transcriptional unit.


Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.
Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function. We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b(+)CCR8(+) cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b(+)CCR8(+) cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. This study provides the first evidence that CCR8(+) myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers.


[Effect of different doses of diphtheria exotoxin on the properties of L929 and HeLa cells].
Various forms of interaction between diphtheria exotoxin and the continuous L and HeLa cell lines were revealed, depending on its doses: toxic, subtoxic and small (following the subtoxic dose). Cells of the same origin, treated with these doses, develop similar changes in some of their properties, differing only in their "survival" time, the period of adaptation and the time of entering the phase of active proliferation. the systems of cells, having simultaneously low susceptibility to infection with some RNA-containing viruses (L cells with low susceptibility to vesicular stomatitis virus and HeLa cells with low susceptibility to Coxsackie B5 virus) and high susceptibility to repeated treatment with diphtheria exotoxin, have been obtained.


Molecular abnormalities associated with secretory carcinomas of the breast.
Secretory carcinomas (SCAs) represent a unique histological variant of invasive breast carcinomas, occurring predominantly in patients younger than 30 years of age. Data from limited series have shown SCAs to have a favorable prognosis in patients younger than 20 years of age, whereas the clinical course tends to parallel the more common in filtrating ductal carcinomas (IDCs) in patients older than 20 years. There are no reports on the molecular abnormalities associated with this unusual tumor. Microdissected archival formalin-fixed tissue from 10 SCAs collected from 2 institutions were used to determine the frequencies of allelic loss at 13 chromosomal regions with 19 microsatellite markers, using multiplex polymerase chain reaction (PCR)-based techniques. The results of loss of heterozygosity (LOH) and microsatellite alterations (MAs) analyses were compared with 20 cases of IDCs. P53 gene mutation analysis was also performed on the 10 SCAs using single-strand conformation polymorphism (SSCP) analysis, followed by sequencing of abnormal bands. LOH at multiple regions of chromosome 3p were the most common abnormality in both SCAs (55%) and IDCs (50%), followed by LOH at 17q21 (BRCA1 locus), 13q14 (retinoblastoma gene locus), and 8p21-23. No significant differences were seen in the frequencies of LOH at any chromosomal region except for 17p13 (p53 gene locus), where allelic losses were absent in SCAs, but evident in 46% of IDCs (P < .05). The 2 histological entities were similar in the fractional regional loss (FRL) index (0.26 v 0.24), fractional allelic loss (FAL) index (0.23 v 0.27), as well as in the frequency of MAs (0.015 v 0.005), P > .05. P53 gene missense mutation (G:C::A:T) was detected in 1 of 10(10%) SCAs. Based on the considerable similarities in the molecular abnormalities associated with both tumors, the formation of secondary lumina in both the in situ and the invasive components, as well as suggestions from limited series that the clinical behavior in adult patients parallels that of IDCs, SCA most likely reflects a secretory variant of IDCs.


Symptom Burden: Experiences of Puerto Rican Men With Prostate Cancer Prior to External Beam Radiation Therapy.
Prostate cancer is the most frequently diagnosed cancer in men in Puerto Rico, and external beam radiation therapy (EBRT) is a popular treatment. Although symptom management is a clinical priority of comprehensive oncology care, symptom assessment at the time of primary or adjuvant EBRT has received limited attention. This article examines the prevalence and severity of symptoms experienced by 54 Puerto Rican men prior to EBRT. Participants completed a demographic form and the MD Anderson Symptom Inventory. Descriptive statistics were generated. Most participants had received hormonal treatment, and about a third had received no treatment prior to EBRT. About a third of those who received hormonal treatment reported experiencing side effects before EBRT, and disturbed sleep, numbness and tingling, fatigue, and dry mouth were the most severe. Puerto Rican men with prostate cancer who receive hormonal treatment are at increased risk for experiencing symptom burden prior to EBRT. Greater need for symptom surveillance, treatment, and control may be needed among this population.


The genetic basis of color-related local adaptation in a ring-like colonization around the Mediterranean.
Uncovering the genetic basis of phenotypic variation and the population history under which it established is key to understand the trajectories along which local adaptation evolves. Here, we investigated the genetic basis and evolutionary history of a clinal plumage color polymorphism in European barn owls (Tyto alba). Our results suggest that barn owls colonized the Western Palearctic in a ring-like manner around the Mediterranean and meet in secondary contact in Greece. Rufous coloration appears to be linked to a recently evolved nonsynonymous-derived variant of the melanocortin 1 receptor (MC1R) gene, which according to quantitative genetic analyses evolved under local adaptation during or following the colonization of Central Europe. Admixture patterns and linkage disequilibrium between the neutral genetic background and color found exclusively within the secondary contact zone suggest limited introgression at secondary contact. These results from a system reminiscent of ring species provide a striking example of how local adaptation can evolve from derived genetic variation.


CD247, a novel T cell-derived diagnostic and prognostic biomarker for detecting disease progression and severity in patients with type 2 diabetes.
We have previously shown that chronic inflammation results in immunosuppression associated with CD247 downregulation in T lymphocytes. Type 2 diabetes mellitus (T2DM) is known to be associated with chronic inflammation. We therefore sought to examine CD247 expression levels in patients with T2DM and to assess whether it can serve as a diagnostic and prognostic biomarker for disease complications and outcomes. Peripheral blood samples from 75 T2DM patients and 40 healthy control subjects were collected and analyzed for the expression level of CD247 in T lymphocytes. Subjects with T2DM underwent a medical interview with physical examination and were followed for an additional average of 19.2 ± 0.9 months to determine the occurrence of major adverse disease end points. The relationship between the level of CD247 expression and disease status at the time of blood draw and the ability of the marker to identify future complications was evaluated. We observed a significant reduction in CD247 expression levels in T lymphocytes of T2DM patients when compared with healthy volunteers. CD247 downregulation was associated with disease severity, complications, and the occurrence of future cardiovascular events, suggesting its potential use not only as a diagnostic but also as a prognostic biomarker. Our results suggest the use of CD247 as a biomarker in diabetic patients for evaluating the state of chronic inflammation that contributes to morbidity and mortality in this disease and for the prediction of future cardiovascular events.


Obesity enhances nongenomic estrogen receptor crosstalk with the PI3K/Akt and MAPK pathways to promote in vitro measures of breast cancer progression.
Epidemiological and clinical studies indicate that obesity is associated with a worse postmenopausal breast cancer prognosis and an increased risk of endocrine therapy resistance. However, the mechanisms mediating these effects remain poorly understood. Here we investigate the molecular pathways by which obesity-associated circulating factors in the blood enhance estrogen receptor alpha (ERα) positive breast cancer cell viability and growth. Blood serum was collected from postmenopausal breast cancer patients and pooled by body mass index (BMI) category (Control: 18.5 to 24.9 kg/m²; Obese: ≥30.0 kg/m²). The effects of patient sera on MCF-7 and T47D breast cancer cell viability and growth were examined by MTT and colony formation assays, respectively. Insulin-like growth factor receptor 1(IGF-1R), Akt, and ERK1/2 activation and genomic ERα activity were assessed to determine their possible contribution to obese patient sera-induced cell viability and growth. To further define the relative contribution of these signaling pathways, cells grown in patient sera were treated with various combinations of ERα, PI3K/Akt and MAPK targeted therapies. Comparisons between cells exposed to different experimental conditions were made using one-way analysis of variance (ANOVA) and Student's t test. Cells grown in media supplemented with obese patient sera displayed greater cell viability and growth as well as IGF-1R, Akt and ERK1/2 activation relative to control sera. Despite the lack of a significant difference in genomic ERα activity following growth in obese versus control patient sera, we observed a dramatic reduction in cell viability and growth after concurrent inhibition of the ERα and PI3K/Akt signaling pathways. Further, we demonstrated that ERα inhibition was sufficient to attenuate obese serum-induced Akt and ERK1/2 activation. Together, these data suggest that obesity promotes greater ERα positive breast cancer cell viability and growth through enhanced crosstalk between nongenomic ERα signaling and the PI3K/Akt and MAPK pathways. Circulating factors in the serum of obese postmenopausal women stimulate ERα positive breast cancer cell viability and growth by facilitating non-genomic ERα crosstalk with the PI3K/Akt and MAPK signaling pathways. These findings provide valuable insight into one mechanism by which obesity may promote ERα positive postmenopausal breast cancer progression and endocrine therapy resistance.


Cochlear implantation in patients with neurofibromatosis type 2 and bilateral vestibular schwannoma.
To investigate the results of cochlear implantation in patients with neurofibromatosis Type 2 (NF2) and bilateral vestibular schwannoma. Retrospective case review. Three academic tertiary referral centers. Seven patients with NF2 and bilateral vestibular schwannoma who lost hearing in at least one ear after treatment of their tumor (surgery or radiation therapy). Cochlear implantation after treatment of their vestibular schwannoma. Postimplantation audiometric scores (pure-tone average thresholds, consonant-nucleus-consonant (CNC) words/phonemes, Central Institute for the Deaf (CID) sentences, Hearing in Noise Test (HINT) quiet/noise, and Monosyllable, Trochee, Spondee (MTS) recognition/category tests), patient satisfaction, and device use patterns. The average age at implantation was 40 years (range, 16-57 yr). Follow-up ranged from 6 to 88 months after implantation. Three patients were implanted with residual useful hearing in the contralateral ear, whereas four patients had no hearing in the contralateral ear. Hearing loss was due to surgical excision of tumor (n=5) or gamma-knife radiotherapy (n=2). Postactivation pure-tone average thresholds in the implanted ear ranged from 30 to 55 dB (average, 32.5 dB), although speech reception testing varied considerably among subjects. Despite this variability, all patients continue to use the device on a daily basis. In selected cases of deafness in patients with NF2 where there has been anatomic preservation of the auditory nerve after acoustic neuroma resection or radiation therapy, cochlear implantation may offer some improvement in communication skills, including the possibility of open-set speech communication in some patients. These results compare favorably to the auditory brainstem implant offering an alternative for hearing rehabilitation in patients with NF2.


Potentially highly potent drugs for 2019-nCoV.
The World Health Organization (WHO) has declared the 2019 novel coronavirus (2019-nCoV) infection outbreak a global health emergency. Currently, there is no effective anti-2019-nCoV medication. The sequence identity of the 3CL proteases of 2019-nCoV and SARS is 96%, which provides a sound foundation for structural-based drug repositioning (SBDR). Based on a SARS 3CL protease X-ray crystal structure, we construct a 3D homology structure of 2019-nCoV 3CL protease. Based on this structure and existing experimental datasets for SARS 3CL protease inhibitors, we develop an SBDR model based on machine learning and mathematics to screen 1465 drugs in the DrugBank that have been approved by the U.S. Food and Drug Administration (FDA). We found that many FDA approved drugs are potentially highly potent to 2019-nCoV.


Is bruxism a risk factor for dental implants? A systematic review of the literature.
To systematically review the literature on the role of bruxism as a risk factor for the different complications on dental implant-supported rehabilitations. A systematic search in the National Library of Medicine's Medline Database was performed to identify all peer-reviewed papers in the English literature assessing the role of bruxism, as diagnosed with any other diagnostic approach (i.e., clinical assessment, questionnaires, interviews, polysomnography, and electromyography), as a risk factor for biological (i.e., implant failure, implant mobility, and marginal bone loss) or mechanical (i.e., complications or failures of either prefabricated components or laboratory-fabricated suprastructures) complications on dental implant-supported rehabilitations. The selected articles were reviewed according to a structured summary of the articles in relation to four main issues, viz., "P" - patients/problem/population, "I" - intervention, "C" - comparison, and "O" - outcome. A total of 21 papers were included in the review and split into those assessing biological complications (n = 14) and those reporting mechanical complications (n = 7). In general, the specificity of the literature for bruxism diagnosis and for the study of the bruxism's effects on dental implants was low. From a biological viewpoint, bruxism was not related with implant failures in six papers, while results from the remaining eight studies did not allow drawing conclusions. As for mechanical complications, four of the seven studies yielded a positive relationship with bruxism. Bruxism is unlikely to be a risk factor for biological complications around dental implants, while there are some suggestions that it may be a risk factor for mechanical complications.


Two distinct promoter architectures centered on dynamic nucleosomes control ribosomal protein gene transcription.
In yeast, ribosome production is controlled transcriptionally by tight coregulation of the 138 ribosomal protein genes (RPGs). RPG promoters display limited sequence homology, and the molecular basis for their coregulation remains largely unknown. Here we identify two prevalent RPG promoter types, both characterized by upstream binding of the general transcription factor (TF) Rap1 followed by the RPG-specific Fhl1/Ifh1 pair, with one type also binding the HMG-B protein Hmo1. We show that the regulatory properties of the two promoter types are remarkably similar, suggesting that they are determined to a large extent by Rap1 and the Fhl1/Ifh1 pair. Rapid depletion experiments allowed us to define a hierarchy of TF binding in which Rap1 acts as a pioneer factor required for binding of all other TFs. We also uncovered unexpected features underlying recruitment of Fhl1, whose forkhead DNA-binding domain is not required for binding at most promoters, and Hmo1, whose binding is supported by repeated motifs. Finally, we describe unusually micrococcal nuclease (MNase)-sensitive nucleosomes at all RPG promoters, located between the canonical +1 and -1 nucleosomes, which coincide with sites of Fhl1/Ifh1 and Hmo1 binding. We speculate that these "fragile" nucleosomes play an important role in regulating RPG transcriptional output.


Neuropeptides modulate immune deviation induced via the anterior chamber of the eye.
Ag presentation via the anterior chamber of the eye results in a form of immune deviation termed anterior chamber-associated immune deviation (ACAID). The hallmarks of this response are the suppression of delayed-type hypersensitivity with simultaneous induction of Ab production. In this study, we examined the role of the neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) and found that the levels of these two peptides are controlled by neurogenic stimulation of the eye by light, and that these molecules determine the outcome of Ag presentation in the eye. Mice reared under diurnal conditions had VIP in the iris and ciliary body (not free in aqueous humor) and low levels of SP. Mice that were reared in the dark (or dark-adapted) did not contain detectable levels of VIP but had high levels of SP. The adaptation of diurnal mice to the dark eliminated VIP and increased SP, while adapting dark-reared mice to the diurnal cycle increased VIP and reduced SP. We then tested the hypothesis that immune reactions resulting from Ag presentation in the eye were linked to SP and VIP. We found that a VIP receptor antagonist, when injected into the eye with Ag, reversed ACAID in diurnal mice, while a SP receptor antagonist restored ACAID to dark-adapted mice. We further determined that injection of Ag or TNF-alpha induced VIP release, while SP was liberated into the aqueous humor following reexposure of dark-reared mice to light. Our results demonstrate a close linkage of intraocular immune reactions to neuropeptide levels in the eye.


Neuromuscular electrical and thermal-tactile stimulation for dysphagia caused by stroke: a randomized controlled trial.
The aim of this study was to assess the effectiveness of neuromuscular electrical stimulation in patients with dysphagia caused by stroke. Thirty-six subjects were randomized into experimental and control groups. The control group was given thermal-tactile stimulation treatment only, while in the experimental group neuromuscular electrical stimulation and thermal-tactile stimulation treatments were applied simultaneously. Swallowing function was assessed before and 4 weeks after treatment, and evaluated via the swallow function scoring system, penetration-aspiration scale, and pharyngeal transit time. In addition, the discomfort score during the treatments and the satisfaction score 4 weeks after the treatments were measured. Twenty-eight persons with dysphagia completed the study, 16 in the experimental group and 12 in the control group. Both groups showed improvement, but the experimental group showed more significant improvement in the swallow function scoring system, penetration-aspiration scale and pharyngeal transit time than the control group. The patient's discomfort score did not show statistically significant differences in either group, but the satisfactory score was higher in the experimental group. The results suggest that neuromuscular electrical stimulation combined with thermal-tactile stimulation is a better treatment for patients with swallowing disorders after stroke than thermal-tactile stimulation alone.


Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals.
Gut homing CD4+ T cells expressing the integrin α4β7 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-α4β7 monoclonal antibodies have shown promise in preventing or attenuating the disease course of simian immunodeficiency virus in nonhuman primate studies, the mechanisms of drug action remain elusive. We present a cohort of individuals with mild inflammatory bowel disease and concomitant HIV-1 infection receiving anti-α4β7 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-α4β7 therapy in HIV-1 infection.


Time-course investigation of infection with a low virulent Pasteurella multocida strain in normal and immune-suppressed 12-week-old free-range chickens.
Twelve-week-old indigenous chickens, either immune-suppressed using dexamethasone (IS) or non-immune-suppressed (NIS), were challenged with a low virulent strain, Pasteurella multocida strain NCTC 10322(T), and developed clinical signs and pathological lesions typical of chronic fowl cholera. NIS birds demonstrated much more severe signs of fowl cholera than IS birds. With few exceptions, signs recorded in IS and NIS birds were of the same types, but significantly milder in the IS birds, indicating that immune suppression does not change the course of infection but rather the severity of signs in fowl cholera. P. multocida signals by fluorescent in situ hybridization (FISH) were observed between 1 h and 14 days in the lungs, trachea, air sacs, liver, spleen, bursa of Fabricius and caecal tonsils, while signals from other organs mostly were observed after 24 h. More organs had FISH signals in NIS birds than in IS birds and at higher frequency per organ. Many organs were positive by FISH even 14 days post infection, and it is suggested that these organs may be likely places for long-term carriage of P. multocida following infection. The present study has demonstrated the spread of P. multocida in different tissues in chickens and distribution of lesions associated with chronic fowl cholera, and pointed to a decrease of pathology in IS birds. Since dexamethasone mostly affects heterophils, the study suggests that these cells play a role in the development of lesions associated with chronic fowl cholera in chickens.


First percutaneous transcatheter aortic valve-in-valve implant with three year follow-up.
This study was conducted to report the clinical, hemodynamic, and iconographic outcomes of the longest survivor of the global CoreValve experience. Early results of percutaneous heart valve (PHV) implantation for severe symptomatic aortic stenosis (AS) have been encouraging, with mid term survival up to 2 years; however longer durability term is unknown. Although a PHV has been implanted in a degenerated surgical bioprosthesis, the feasibility of a PHV-in-PHV has not been demonstrated. A patient with severe refractory heart failure due to severe aortic regurgitation (AR) and moderate AS, underwent CoreValve prosthesis implantation. The PHV was deployed too proximal into the left ventricular outflow tract, resulting in severe AR through the frame struts. Using the first PHV as a landmark, a second CoreValve was then deployed slightly distal to the first, with trivial residual paravalvular leak. The second CoreValve expanded well with proper function. Transvalvular gradient was 8 mmHg. Both coronary ostia were patent. New mild to moderate mitral regurgitation occurred due to impingement of the anterior mitral leaflet by the first PHV. NYHA functional class improved from IV to II, maintained over the past 3 years. Echocardiography at 3 years showed normal functioning CoreValve-in-CoreValve prostheses, without AR or paravalvular leaks. Transvalvular gradient was 10 mmHg. Cardiac CT showed stable valve-in-valve protheses with no migration. The CoreValve prosthesis has maintained proper function up to 3 years, with no structural deterioration or migration. Treating mixed aortic valve disease with predominant AR is feasible. The concept as well as durability of the first PHV-in-PHV has also been demonstrated.


Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.
As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.


The Creation and Management of Innovations in Healthcare and ICT: The European and African Experience.
The purpose of the study was to gain new insights into innovation systems by comparing state-of-the-art of existing approaches of innovation creation and innovation management in healthcare and ICT. It is unique, in that it compares countries in Africa with countries in Europe in order to identify similarities and differences regarding the creation and management of innovations. The main similarity is that early dialogue between different stakeholders was underrepresented during the whole innovation process in all countries. Our results also indicated that the various stakeholders often work in silos. The main difference was that the countries face problems at different stages of the innovation process. Whereas European countries face more problems in the innovation creation process, African countries experience difficulty sustaining and managing innovation. To overcome barriers, we suggest the application of systematic early dialogue between all key stakeholders.


MeetingVis: Visual Narratives to Assist in Recalling Meeting Context and Content.
In team-based workplaces, reviewing and reflecting on the content from a previously held meeting can lead to better planning and preparation. However, ineffective meeting summaries can impair this process, especially when participants have difficulty remembering what was said and what its context was. To assist with this process, we introduce MeetingVis, a visual narrative-based approach to meeting summarization. MeetingVis is composed of two primary components: (1) a data pipeline that processes the spoken audio from a group discussion, and (2) a visual-based interface that efficiently displays the summarized content. To design MeetingVis, we create a taxonomy of relevant meeting data points, identifying salient elements to promote recall and reflection. These are mapped to an augmented storyline visualization, which combines the display of participant activities, topic evolutions, and task assignments. For evaluation, we conduct a qualitative user study with five groups. Feedback from the study indicates that MeetingVis effectively triggers the recall of subtle details from prior meetings: all study participants were able to remember new details, points, and tasks compared to an unaided, memory-only baseline. This visual-based approaches can also potentially enhance the productivity of both individuals and the whole team.


Modulation of NF-κB and FOXOs by baicalein attenuates the radiation-induced inflammatory process in mouse kidney.
The bioactive flavonoid baicalein has been shown to have radioprotective activity, although the molecular mechanism is poorly understood in vivo. C57BL/6 mice were irradiated with X-rays (15 Gy) with and without baicalein treatment (5 mg/kg/day). Irradiation groups showed an increase of NF-κB-mediated inflammatory factors with oxidative damage and showed inactivation of FOXO and its target genes, catalase and SOD. However, baicalein suppressed radiation-induced inflammatory response by negatively regulating NF-κB and up-regulating FOXO activation and catalase and SOD activities. Furthermore, baicalein inhibited radiation-induced phosphorylation of MAPKs and Akt, which are the upstream kinases of NF-κB and FOXOs. Based on these findings, it is concluded that baicalein has a radioprotective effect against NF-κB-mediated inflammatory response through MAPKs and the Akt pathway, which is accompanied by the protective effects on FOXO and its target genes, catalase and SOD. Thus, these findings provide new insights into the molecular mechanism underlying the radioprotective role of baicalein in mice.


The Effects of Hyperbaric Oxygen Therapy on Pelvic Radiation Induced Gastrointestinal Complications (Rectal Bleeding, Diarrhea, and Pain): A Meta-Analysis.
Background: Radiotherapy is a routine treatment for pelvic cancer patients. While it had been proven effective, gastrointestinal side effects remain a concern, impairing the quality of life. A few studies focused on the effects of hyperbaric oxygen (HBO) treatment to alleviate radiation-induced gastrointestinal complications. This meta-analysis aimed to critically review and summarize existing literature, assessing the effectiveness of HBO therapy for the treatment of radiation-induced gastrointestinal side effects. Methods: Medical literature search was performed with PubMed, Cochrane Library, and EMBASE up to March 14, 2019. Literatures about HBO treatment upon patients undergoing pelvic cancer (endometrial, cervix, rectum, or prostate cancers) radiotherapy were collected, and the effects of HBO treatment on radiotherapy-induced gastrointestinal complications were evaluated. A random-effects model was used to calculate the pooled effect size. Subgroup analyses were performed to search for sources of heterogeneity. Publication bias was detected with Funnel plots and Egger's test. Results: Three different radiotherapy-related gastrointestinal complications, including rectal bleeding, diarrhea, and pain, were analyzed after screening. It was revealed that the improvement rates were considerable in rectal bleeding (0.81, 95% CI: 0.74-0.89) and diarrhea (0.75, 95% CI: 0.61-0.90) and slightly in pain (0.58, 95% CI: 0.38-0.79). Subgroup analysis revealed factors that significantly influenced the heterogeneity of rectal bleeding, diarrhea, and pain (evaluation criteria, follow-up time, and scoring system, respectively). No significant publication bias was detected. Conclusion: HBO treatment might have the potential to alleviate radiotherapy-related gastrointestinal complications, including rectal bleeding, diarrhea, and pain, but more data are needed for further conclusions. Other symptoms were not further analyzed, as the number of studies was insufficient. More large-scale and prospective studies are needed for better evaluation of HBO's therapeutic values.


Major signal increase in fluorescence microscopy through dark-state relaxation.
We report a substantial signal gain in fluorescence microscopy by ensuring that transient molecular dark states with lifetimes >1 micros, such as the triplet state relax between two molecular absorption events. For GFP and Rhodamine dye Atto532, we observed a 5-25-fold increase in total fluorescence yield before molecular bleaching when strong continuous-wave or high-repetition-rate pulsed illumination was replaced with pulses featuring temporal pulse separation >1 micros. The signal gain was observed both for one- and two-photon excitation. Obeying dark or triplet state relaxation in the illumination process signifies a major step toward imaging with low photobleaching and strong fluorescence fluxes.


The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction.
The prevalence of acute myocardial infarction (AMI) has increased due to the recent definitions, but the magnitude of this effect using contemporary highly sensitive troponin assays is unclear. The objective of this study is to compare the diagnosis of AMI using a contemporary troponin I (cTnI) biomarker and the 2003 American Heart Association (AHA) case definition with diagnoses made using the 1994 World Health Organization MONICA definition. Contemporary troponin I measurements were performed with the Beckman Coulter AccuTnI assay (Chaska, MN) on plasma specimens originally assayed in 1996 for creatine kinase (CK)-MB mass from 486 emergency department patients presenting within 24 hours of onset of symptoms suggestive of cardiac ischemia. In a subgroup of 258 patients with 2 specimens drawn at least 6 hours apart (the AHA "adequate set of biomarkers"), AMI prevalence using CK-MB was 19.4% (95% CI 15.0-24.7) based on MONICA and 19.8% (15.4-25.1) based on the AHA case definition using the criterion for change of > or = 20% between specimens. Using cTnI as the biomarker of choice, under the AHA definition, the prevalence increased to as high as 35.7% (30.1-41.7, a relative increase of 84%, P < .001) using the 99th percentile cutoff. In 121 patients with a lower index of suspicion and without the requisite 6-hour interval between measurements, positivity increased from 5% with CK-MB by MONICA up to 12% to 16% with cTnI by AHA. A highly sensitive contemporary cTnI assay used with the AHA case definition results in a 62% to 84% increase in the frequency of AMI diagnosis compared with MONICA criteria.


Development of a data registry to evaluate the quality and safety of nursing practice.
To describe the development, testing, and implementation of a data registry of nursing-sensitive indicators for measuring the quality and safety of nursing practice. Recent research has established causal links between nurse staffing and patient outcomes. Unit level data is necessary for implementation of evidence-based strategies on nurse staffing and nursing care processes. Multi-site, cross-sectional design. Retrospective data were collected from administrative data sets on nurse staffing, patient flow, and adverse events in three hospitals in 2016. Periodic observational surveys on pressure injury prevalence, hand hygiene practices, and documentation of processes of care were also conducted. Prospective data were collected from patients at time of discharge using the Caring Assessment Tool. Nurses' perceptions of their practice environment were assessed using the Nursing Work Index - Revised: Australian. Data from annual Press Ganey® surveys on patient satisfaction/experience were obtained. The Australian Nursing Outcomes Collaborative (AUSNOC) data registry was developed in three phases. Phase 1 involved development of a data codebook; phase 2 involved development and testing of data collection methods; and phase 3 involved development of data reports and data dissemination strategies. This paper gives an overview of these phases and includes a summary of the descriptive statistics from the indicator set. Unit level data is pivotal for measuring the quality and safety of nursing care. Data from the Australian Nursing Outcomes Collaborative (AUSNOC) can be feasibly collected and used to benchmark nursing performance, evaluate patient outcomes, and identify areas for practice improvement.


Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10-15 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant HTT with zinc finger proteins (ZFPs) in an HD model. We tested a "molecular tape measure" approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse HTT genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6/2 mice was efficient and revealed dose-dependent repression of mutant HTT in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.


Robust Fusion of c-VEP and Gaze.
Brain computer interfaces (BCIs) are one of the developing technologies, serving as a communication interface for people with neuromuscular disorders. Electroencephalography (EEG) and gaze signals are among the commonly used inputs for the user intent classification problem arising in BCIs. Fusing different types of input modalities, i.e. EEG and gaze, is an obvious but effective solution for achieving high performance on this problem. Even though there are some simplistic approaches for fusing these two evidences, a more effective method is required for classification performances and speeds suitable for real-life scenarios. One of the main problems that is left unrecognized is highly noisy real-life data. In the context of the BCI framework utilized in this work, noisy data stem from user error in the form of tracking a nontarget stimuli, which in turn results in misleading EEG and gaze signals. We propose a method for fusing aforementioned evidences in a probabilistic manner that is highly robust against noisy data. We show the performance of the proposed method on real EEG and gaze data for different configurations of noise control variables. Compared to the regular fusion method, robust method achieves up to 15% higher classification accuracy.


Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism.
Ultrasound has received widespread attention as an emerging technology for targeted, non-invasive neuromodulation based on its ability to evoke electrophysiological and motor responses in animals. However, little is known about the spatiotemporal pattern of ultrasound-induced brain activity that could drive these responses. Here, we address this question by combining focused ultrasound with wide-field optical imaging of calcium signals in transgenic mice. Surprisingly, we find cortical activity patterns consistent with indirect activation of auditory pathways rather than direct neuromodulation at the ultrasound focus. Ultrasound-induced activity is similar to that evoked by audible sound. Furthermore, both ultrasound and audible sound elicit motor responses consistent with a startle reflex, with both responses reduced by chemical deafening. These findings reveal an indirect auditory mechanism for ultrasound-induced cortical activity and movement requiring careful consideration in future development of ultrasonic neuromodulation as a tool in neuroscience research.


A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation.
Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories. 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.0 single nucleotide polymorphism (SNP) array. Analyses of 695,193 SNPs were conducted using UNPHASED, which combines information across families and unrelated individuals. We attempted to replicate signals found in 23 genomic regions using existing data on nonoverlapping samples from the Psychiatric GWAS Consortium and Schizophrenia-GENE-plus cohorts (10,352 schizophrenia patients and 24,474 controls). No individual SNP showed compelling evidence for association with psychosis in our data. However, we observed a trend for association with same risk alleles at loci previously associated with schizophrenia (one-sided p = .003). A polygenic score analysis found that the Psychiatric GWAS Consortium's panel of SNPs associated with schizophrenia significantly predicted disease status in our sample (p = 5 × 10(-14)) and explained approximately 2% of the phenotypic variance. Although narrowly defined phenotypes have their advantages, we believe new loci may also be discovered through meta-analysis across broad phenotypes. The novel statistical methodology we introduced to model effect size heterogeneity between studies should help future GWAS that combine association evidence from related phenotypes. Applying these approaches, we highlight three loci that warrant further investigation. We found that SNPs conveying risk for schizophrenia are also predictive of disease status in our data.


Amino-PAHs activated Nrf2/ARE anti-oxidative defense system and promoted inflammatory responses: the regulation of PI3K/Akt pathway.
The amino polycyclic aromatic hydrocarbons (amino-PAHs) were frequently detected in PM2.5, and it was suggested that they contributed to the harmful health effects associated with PM2.5. However, the process through which amino-PAHs induce oxidative stress responses as well as the pro-inflammatory processes along with the associated mechanisms is still not well-known. In this study, oxidative stress level, Nrf2/ARE anti-oxidative defense responses, oxidative damages and cytokine expressions were investigated in the A549 cell line after it was treated with typical airborne amino-PAHs including 1-aminopyrene (1-AP) and 3-aminofluoranthene (3-AF). The possibility of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway participating in the regulation of cytokine gene expression was also considered, and the study was conducted accordingly. The results showed that 1-AP and 3-AF in a dose-dependent manner could cause extensive damages including cell apoptosis, cell cycle arrests, and DNA damages and could up-regulate the TNF-α gene expression. In addition, the Nr2/ARE defense system was activated, as evidenced by the increased protein expression levels and nuclear translocation of Nrf2. The Nrf2/ARE binding activity was elevated and was measured with the EMSA method. Also, the protein of heme oxygenase-1 (HO-1) was up-regulated. Finally, an increase in the protein expressions of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylation levels of Akt was observed, indicating that the PI3K/Akt pathway was activated. Furthermore, both LY294002 (an inhibitor of PI3K) and MK-2206 (an inhibitor of Akt) could significantly decrease the elevated TNF-α gene expressions, suggesting that the PI3K/Akt pathway was involved in the regulation of TNF-α expressions induced by 1-AP and 3-AF. Our results further confirmed that amino-PAHs could be a particularly important PAH derivatives contributing to the health risks caused by PM2.5.


Growth hormone does not stimulate early healing in rat tendons.
Growth Hormone stimulates bone growth and fracture repair. It acts mainly by increasing the systemic levels of IGF-1. Local treatment with IGF-1 appears to stimulate tendon healing. We therefore hypothesized that systemic treatment with Growth Hormone would also stimulate tendon healing. Rat Achilles tendons were transected and left to heal. 4 groups were studied. Intramuscular injections of botulinum toxin A (Botox) were used to reduce loading in 2 groups. The animals were randomized to twice daily injections of Growth Hormone (n=2×10) or saline (n=2×10), and killed after 10 days. Healing was assessed by mechanical testing. Muscle paralysis induced by Botox reduced the strength of the healing tendon by two thirds. Growth Hormone increased femoral and tibial length in the unloaded, and femoral and tibial weight in the loaded group. Body weight and muscle weight were increased in both. In contrast, there was no increase in the strength of the healing tendons, regardless of mechanical loading status. An increase in peak force of the loaded healing tendons by more than 5% could be excluded with 95% confidence. In spite of its stimulatory effects on other tissues, Growth Hormone did not appear to stimulate tendon or tendon repair.


Discussion effects on racial attitudes.
We predicted that discussion would enhance dominant group values, leading to increased polarization between homogeneously composed groups of high-, medium-, and low-prejudice high school subjects. In an experimental condition, group members made individual attitude judgments, discussed them, and remade judgments. Control groups discussed irrelevant materials before responding again to the attitude items. As predicted, discussion of the racial attitude items with others having similar attitudes significantly increased the gap between high- and low-prejudice groups.


Uncooled CMOS terahertz imager using a metamaterial absorber and pn diode.
We demonstrate a low-cost uncooled terahertz (THz) imager fabricated in a standard 180 nm CMOS process. The imager is composed of a broadband THz metamaterial absorber coupled with a diode microbolometer sensor where the pn junction is used as a temperature sensitive device. The metamaterial absorber array is integrated in the top metallic layers of a six metal layer process allowing for complete monolithic integration of the metamaterial absorber and sensor. We demonstrate the capability of the detector for stand-off imaging applications by using it to form transmission and reflection images of a metallic object hidden in a manila envelope.


Presentation and task effects on migration errors in attentional dyslexia.
We report a case study of a patient, FL, who shows symptoms of attentional dyslexia. He performs better at reading aloud single words than pairs of words, where he tends to make letter migration errors. These letter migrations are particularly prevalent from the word presented on the right into FL's response to the word presented on the left. Performance on the word pair reading task is improved if the two words are presented in different cases or the space between them is increased. Further, FL performs better at reading a target word if he is only required to name the initial letter of a distractor word rather than read the whole word. However, single letter distractors then produce more interference than whole words. These findings are consistent with FL having poor letter location coding when attention is diffuse [Cognitive Neuropsychol. 18 (2001) 551; Cognitive Neuropsychol. 13 (1996) 205]. In addition, representations on the left side of his attentional space are particularly weak, and so vulnerable to stimuli on the right when FL adopts a wide spatial window for the task. The data point to a pre-categorical deficit in reading in this case.


Defect-Tolerant Bioinspired Hierarchical Composites: Simulation and Experiment.
Defect tolerance, the capacity of a material to maintain strength even under the presence of cracks or flaws, is one of the essential demands in the design of composite materials, as manufacturing induced defects, or those generated during operation, can lead to catastrophic failure and dramatically reduce the mechanical performance. In this paper, we combine computational modeling and advanced multimaterial 3D printing to examine the mechanics of several different classes of defect-tolerant bioinspired hierarchical composites, built from two base materials with contrasting mechanical properties (stiff and soft). We find that in contrast to the brittle base constituents of the composites, the existence of a hierarchical architecture leads to superior defect-tolerant properties. We show that composites with more hierarchical levels dramatically improve the defect tolerance of the material. We also examine the effect of adding both self-similar and dissimilar hierarchical levels to the materials architecture, and show that the geometries with multiple hierarchical levels can retain a significant portion of their fracture strength in the presence of either large edge cracklike flaws or multiple small distributed defects in the material. We compare the stress distributions in materials with different numbers of hierarchies in both simulation and experiment and find a more uniform stress distribution in the uncracked region of materials with higher hierarchy levels. These results provide micromechanical insights into the origin of the higher defect tolerance observed in simulation and experiment.


Belantamab Mafodotin: First Approval.
Belantamab mafodotin (BLENREP™; belantamab mafodotin-blmf) is a first-in-class monoclonal antibody-drug conjugate (ADC) that has been developed for the treatment of multiple myeloma by GlaxoSmithKline. The ADC comprises an antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin F (MMAF). The antibody moiety binds to BCMA on the tumour cell surface, delivering the cytotoxic microtubule inhibitor MMAF to the therapeutic target. Based on preliminary results from the multinational DREAMM-2 trial, belantamab mafodotin was approved in early August 2020 in the USA for the treatment of relapsed or refractory multiple myeloma in adult patients who have received at least four prior therapies, including an anti CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The ADC was also approved in the EU for this indication in late August 2020. This article summarizes the milestones in the development of belantamab mafodotin leading to this first approval.


Validation of the assessment of risk tool: patient prioritisation technology for clinical pharmacist interventions.
Adverse drug events (ADEs) pose a heavy burden on health systems worldwide. The assessment of risk tool (ART) was developed to help prioritise hospitalised patients for interventions such as medication reconciliation (MR) and review, and to reduce potential ADEs from unintentional medication discrepancies and prescribing errors. To validate ART, and to determine which of the selected 25 flags were significantly associated with risk of unintentional medication discrepancies and prescribing errors. This was a prospective observational study of 247 admissions to two medical teams in a New Zealand hospital. Study pharmacists undertook MR and review for all eligible admissions over 5 months. A Kruskal-Wallis test was used to determine differences in numbers of unintentional medication discrepancies and prescribing errors, followed by generalised linear modelling, to find the estimated ratio of the mean number of unintentional medication discrepancies between the three ART groups. In part 2 of the study, using multivariable logistic regression, combinations of flags significantly associated with risk were identified. Significant differences in the number of unintentional medication discrepancieswere found between the ART risk groups (p<0.0001, Kruskal-Wallis test). Patients in the high-risk group had a significantly greater number of unintentional medication discrepancies than those in the medium- and low-risk groups. There were no significant differences in prescribing errors between the ART risk groups (p=0.08, Kruskal-Wallis test). Flags significantly associated with risk, included 'more than eight admission medications', OR=3.7 (95% CI 2.2 to 6.4) and 'readmission within 30 days', OR=6.8 (95% CI 3.0 to 15.2), p<0.0001. ART was effective for prioritising patients for interventions such as MR.


Dynamic Refraction Stereo.
In this paper we consider the problem of reconstructing the 3D position and surface normal of points on an unknown, arbitrarily-shaped refractive surface. We show that two viewpoints are sufficient to solve this problem in the general case, even if the refractive index is unknown. The key requirements are 1) knowledge of a function that maps each point on the two image planes to a known 3D point that refracts to it, and 2) light is refracted only once. We apply this result to the problem of reconstructing the time-varying surface of a liquid from patterns placed below it. To do this, we introduce a novel "stereo matching" criterion called refractive disparity, appropriate for refractive scenes, and develop an optimization-based algorithm for individually reconstructing the position and normal of each point projecting to a pixel in the input views. Results on reconstructing a variety of complex, deforming liquid surfaces suggest that our technique can yield detailed reconstructions that capture the dynamic behavior of free-flowing liquids.


A systematic review of the health economic consequences of quadrivalent influenza vaccination.
Quadrivalent influenza vaccines (QIVs) contain antigens derived from an additional influenza type B virus as compared with currently used trivalent influenza vaccines (TIVs). This should overcome a potential reduced vaccine protection due to mismatches between TIV and circulating B viruses. In this study, we systematically reviewed the available literature on health economic evaluations of switching from TIV to QIV. Areas covered: The databases of Medline and Embase were searched systematically to identify health economic evaluations of QIV versus TIV published before September 2016.A total of sixteen studies were included, thirteen cost-effectiveness analyses and three cost-comparisons. Expert commentary: Published evidence on the cost-effectiveness of QIV suggests that switching from TIV to QIV would be a valuable intervention from both the public health and economic viewpoint. However, more research seems mandatory. Our main recommendations for future research include: 1) more extensive use of dynamic models in order to estimate the full impact of QIV on influenza transmission including indirect effects, 2) improved availability of data on disease outcomes and costs related to influenza type B viruses, and 3) more research on immunogenicity of natural influenza infection and vaccination, with emphasis on cross-reactivity between different influenza B viruses and duration of protection.


The effects of a responsive parenting intervention on parent-child interactions during shared book reading.
This study examined mother-child shared book reading behaviors before and after participation in a random-assignment responsive parenting intervention called Play and Learning Strategies (PALS) that occurred during infancy (PALS I), the toddler-preschool (PALS II) period, or both as compared with a developmental assessment (DAS) intervention (DAS I and/or II). The efficacy of PALS was previously demonstrated for improving mother and child behaviors within play contexts, everyday activities, and standardized measures of child language. We hypothesized that PALS effects would generalize to influence maternal and child behaviors during a shared reading task even though this situation was not a specific focus of the intervention and that this would be similar for children who varied in biological risk. Participation in at least PALS II was expected to have a positive effect due to children's increased capacity to engage in book reading at this age. Four groups of randomized mothers and their children (PALS I-II, PALS I-DAS II, DAS I-PALS II, DAS I-II) were observed in shared reading interactions during the toddler-preschool period and coded for (a) mother's affective and cognitive-linguistic supports and (b) child's responses to maternal requests and initiations. Support was found for significant changes in observed maternal and child behaviors, and evidence of mediation was found for the intervention to affect children's behaviors through change in maternal responsiveness behaviors. These results add to other studies supporting the importance of targeting a broad range of responsive behaviors across theoretical frameworks in interventions to facilitate children's development.


Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma and End-stage Renal Disease at 2 Centers.
There is scarce information regarding nivolumab treatment for metastatic renal cell carcinoma (mRCC) in patients with end-stage renal disease (ESRD). This study investigated the safety and efficacy of nivolumab in patients with mRCC and ESRD. This 2-center retrospective study evaluated 62 patients who were administered nivolumab for mRCC between June 2013 and August 2018. The ESRD group (n = 7) and non-ESRD group (n = 55) were compared in terms of their immune-related adverse events (irAEs), objective response rate, progression-free survival, and overall survival. All 7 patients with ESRD were male (median age, 67 years; range, 52-73 years), and their median duration of nivolumab use was 6.0 months (range, 1.8-8.2 months). One patient experienced a partial response, and 4 patients had stable disease. The objective response rate was lower in the ESRD group than in the non-ESRD group (16.7% vs. 37.5%; P = .25). Relative to the non-ESRD group, the ESRD group had slightly lower rates of all irAEs (42.9% vs. 58.7%) and grade 3 or higher irAEs (14.3% vs. 21.7%). The irAEs in the ESRD group were skin rash (grade 1), diarrhea (grade 1), and severe fatigue (grade 3) after the first nivolumab infusion, which required treatment discontinuation. The Kapan-Meier curves revealed no significant differences between the ESRD and non-ESRD groups in terms of progression-free (P = .63) and overall survival (P = .62). It may be possible to safely and effectively use nivolumab for select patients with mRCC and ESRD.


Fluorescent indomethacin-dansyl conjugates utilize the membrane-binding domain of cyclooxygenase-2 to block the opening to the active site.
Many indomethacin amides and esters are cyclooxygenase-2 (COX-2)-selective inhibitors, providing a framework for the design of COX-2-targeted imaging and cancer chemotherapeutic agents. Although previous studies have suggested that the amide or ester moiety of these inhibitors binds in the lobby region, a spacious alcove within the enzyme's membrane-binding domain, structural details have been lacking. Here, we present observations on the crystal complexes of COX-2 with two indomethacin-dansyl conjugates (compounds 1 and 2) at 2.22-Å resolution. Both compounds are COX-2-selective inhibitors with IC50 values of 0.76 and 0.17 μm, respectively. Our results confirmed that the dansyl moiety is localized in and establishes hydrophobic interactions and several hydrogen bonds with the lobby of the membrane-binding domain. We noted that in both crystal structures, the linker tethering indomethacin to the dansyl moiety passes through the constriction at the mouth of the COX-2 active site, resulting in displacement and disorder of Arg-120, located at the opening to the active site. Both compounds exhibited higher inhibitory potency against a COX-2 R120A variant than against the WT enzyme. Inhibition kinetics of compound 2 were similar to those of the indomethacin parent compound against WT COX-2, and the R120A substitution reduced the time dependence of COX inhibition. These results provide a structural basis for the further design and optimization of conjugated COX reagents for imaging of malignant or inflammatory tissues containing high COX-2 levels.


Ice nucleation and phase behavior on oligo(ethylene glycol) and hydroxyl self-assembled monolayers: simulations and experiments.
The nucleation and phase behavior of ultrathin D2O-ice overlayers have been studied on oligo(ethylene glycol) (OEG)-terminated and hydroxyl self-assembled monolayers (SAMs) at low temperatures in ultrahigh vacuum. Infrared reflection-absorption spectroscopy (IRAS) is used to characterize the ice overlayers, the SAMs, and the interactions occurring between the ice and the SAM surfaces. Spectral simulations, based on optical models in conjunction with Maxwell Garnett effective medium theory, point out the importance of including voids in the modeling of the ice structures, with void fractions reaching 60% in some overlayers. The kinetics of the phase transition from amorphous-like to crystalline-like ice upon isothermal annealing at 140 K is found to depend on the conformational state of the supporting OEG SAM surface. The rate is fast on the helical OEG SAMs and slow on the corresponding all-trans SAMs. This difference in kinetics is most likely due to a pronounced D2O interpenetration and binding to the all-trans segments of the ethylene glycol portion of the SAM. No such penetration and binding was observed on the helical OEG SAM.


Introgression patterns in the mosaic hybrid zone between Mytilus edulis and M. galloprovincialis.
Hybrid zones are fascinating systems to investigate the structure of genetic barriers. Marine hybrid zones deserve more investigation because of the generally high dispersion potential of planktonic larvae which allows migration on scales unrivalled by terrestrial species. Here we analyse the genetic structure of the mosaic hybrid zone between the marine mussels Mytilus edulis and M. galloprovincialis, using three length-polymorphic PCR loci as neutral and diagnostic markers on 32 samples along the Atlantic coast of Europe. Instead of a single genetic gradient from M. galloprovincialis on the Iberian Peninsula to M. edulis populations in the North Sea, three successive transitions were observed in France. From South to North, the frequency of alleles typical of M. galloprovincialis first decreases in the southern Bay of Biscay, remains low in Charente, then increases in South Brittany, remains high in most of Brittany, and finally decreases again in South Normandy. The two enclosed patches observed in the midst of the mosaic hybrid zone in Charente and Brittany, although predominantly M. edulis-like and M. galloprovincialis-like, respectively, are genetically original in two respects. First, considering only the various alleles typical of one species, the patches show differentiated frequencies compared to the reference external populations. Second, each patch is partly introgressed by alleles of the other species. When introgression is taken into account, linkage disequilibria appear close to their maximum possible values, indicating a strong genetic barrier within all transition zones. Some pre- or postzygotic isolation mechanisms (habitat specialization, spawning asynchrony, assortative fertilization and hybrid depression) have been documented in previous studies, although their relative importance remains to be evaluated. We also provided evidence for a recent migratory 'short-cut' connecting M. edulis-like populations of the Charente patch to an external M. edulis population in Normandy and thought to reflect artificial transfer of spat for aquaculture.


The Internet and the future of psychiatry.
The Internet is a rapidly growing communications resource that is beginning to have an impact on medicine, and it is anticipated that the Internet will soon have a major effect on psychiatry. It is essential for psychiatrists to have a conceptual framework for understanding the many aspects of the Internet. Using a four-layer model, the authors describe the components of the Internet and how these work together to establish communication. They discuss some of the practical implications of the model, potential future applications of the Internet, and some of the challenges its use will create. In the Internet model described, the bottom three layers involve hardware and modes of information transmission; the fourth layer is human interaction. The Internet has great potential in psychiatric education, clinical care, research, and administration, but major adjustments in individual and organizational expectations and responses will be needed. These changes relate to the speed, dispersion, volume, privacy, and permanence of communication. The growth of the Internet and related information technologies is inevitable and has diverse technical and social implications. As psychiatrists, we must remain effective communicators of information and adjust to a changing world with new roles and skills that will permit us to best serve our professional mission.


Mortality in epilepsy.
Both community-based studies and reports from more selected epilepsy populations consistently reveal persons with epilepsy to have a mortality rate two to three times that of the general population. This increased rate is most pronounced in patients with remote symptomatic epilepsy, although many studies also report a significant excess mortality also among those with idiopathic epilepsy. The highest standardized mortality ratios (SMR) are seen in young age groups, mainly due to the low expected mortality in children, and during the first 5-10 years after diagnosis. Many of these observations suggest that the higher mortality is partly related to the underlying disorder causing epilepsy rather than a direct consequence of the seizures. For example, mortality in cerebrovascular diseases is increased, with SMRs ranging from 1.8 to 5.3 in the various studies. Deaths due to neoplasms, and in particular brain tumors, is also increased among patients with epilepsy. Accidents, status epilepticus, and sudden unexpected death (SUD) are more directly seizure-related causes of death. The incidence of such deaths vary considerably depending on the population being studied. While rare among patients with new-onset epilepsy, seizure-related deaths may account for up to 40% of all deaths in patients with chronic epilepsy. SUD is probably the most frequent seizure-related cause of death among young adults with epilepsy, with an SMR more than 20 compared with the general population. Seizure-induced autonomic cardiorespiratory effects have been suggested, but the mechanisms behind SUD are far from fully understood. It appears, however, that the risk of SUD is closely related to seizure frequency, being 40 times higher in patients who continue to have seizures than in those who are seizure-free.