High cell surface expression of Newcastle disease virus proteins via replicon vectors demonstrates syncytia forming activity of F and fusion promotion activity of HN molecules.
For functional studies, the hemagglutinin-neuraminidase (HN) and the fusion protein (F) of Newcastle disease virus (NDV) were expressed in BHK cells using two vectors which are based on the Semliki Forest virus (SFV) replicon. The first system of high protein expression works by transfection of RNA which before has been in vitro transcribed from a vector containing the gene for the SFV self-amplifying replicase (REP) and a foreign gene using the SP6 promoter. A high level of protein (HN or F) expression was detected 18-20 h after transfection. To study the host range of this expression system, a panel of different cell lines were compared for transfections with SFV RNA. A wide range of expression efficiency was observed, the highest being BHK cells. The second system is based on a DNA plasmid in which the SFV-REP and a foreign gene are expressed in cells under the transcriptional and translational control of the cytomegalovirus immediate-early enhancer T7 promoter. DNA-electroporated BHK cells expressed also high levels of the recombinant proteins but at a delayed time point (40-48 h) as compared with the corresponding RNA. Co-expression of the two NDV proteins, HN and F, via this DNA vector in the same cells led to syncytium formation in the cell monolayer, showing that both proteins expressed in this way, were functionally active. F alone, expressed via this vector, displayed residual fusion activity suggesting its proteolytic cleavage and its functional independence from HN.


Neural mechanisms of subclinical depressive symptoms in women: a pilot functional brain imaging study.
Studies of individuals who do not meet criteria for major depressive disorder (MDD) but with subclinical levels of depressive symptoms may aid in the identification of neurofunctional abnormalities that possibly precede and predict the development of MDD. The purpose of this study was to evaluate relations between subclinical levels of depressive symptoms and neural activation patterns during tasks previously shown to differentiate individuals with and without MDD. Functional magnetic resonance imaging (fMRI) was used to assess neural activations during active emotion regulation, a resting state scan, and reward processing. Participants were twelve females with a range of depressive symptoms who did not meet criteria for MDD. Increased depressive symptom severity predicted (1) decreased left midfrontal gyrus activation during reappraisal of sad stimuli; (2) increased right midfrontal gyrus activation during distraction from sad stimuli; (3) increased functional connectivity between a precuneus seed region and left orbitofrontal cortex during a resting state scan; and (4) increased paracingulate activation during non-win outcomes during a reward-processing task. These pilot data shed light on relations between subclinical levels of depressive symptoms in the absence of a formal MDD diagnosis and neural activation patterns. Future studies will be needed to test the utility of these activation patterns for predicting MDD onset in at-risk samples.


A mismatch between supply and demand of social support in dementia care: a qualitative study on the perspectives of spousal caregivers and their social network members.
ABSTRACTBackground:Access to social support contributes to feelings of independence and better social health. This qualitative study aims to investigate multi-informant perspectives on informal social support in dementia care networks. Ten spousal caregivers of people with dementia (PwD) completed an ecogram, a social network card and a semi-structured interview. The ecogram aimed to trigger subjective experiences regarding social support. Subsequently, 17 network members were interviewed. The qualitative analyses identified codes, categories, and themes. Sixth themes emerged: (1) barriers to ask for support; (2) facilitators to ask for support; (3) barriers to offer support; (4) facilitators to offer support; (5) a mismatch between supply and demand of social support; and (6) openness in communication to repair the imbalance. Integrating social network perspectives resulted in a novel model identifying a mismatch between the supply and demand of social support, strengthened by a cognitive bias: caregivers reported to think for other social network members and vice versa. Openness in communication in formal and informal care systems might repair this mismatch.


Extraocular Source of Oligodendrocytes Contribute to Retinal Myelination and Optokinetic Responses in Zebrafish.
There is no myelination in most mammalian retinas, and if it does happen, it is always accompanied by eye disease. Although lower vertebrates are born with myelin, the precise temporal dynamics of myelination in which oligodendrocytes (OLs) are involved, the origin of OLs, their behaviors in myelination, and their function in retinas have not yet been clearly elaborated. Therefore, we focus on these aspects to study the oligodendrocytes and myelin sheath in the zebrafish retina. Retinal whole mount, immunohistochemistry, and optic nerve retrograde labeling were performed to monitor the myelination. Taking advantage of whole eye eversion and transplantation techniques, we studied the retinal origin of OLs. By optic nerve transplantation, we can observe single OLs in zebrafish retina. The optokinetic reflex (OKR) behavior test and the lysophosphatidylcholine (LPC)-induced retinal demyelination model were used to test the function of the myelin. First, we demonstrated that myelination starts at 28 dpf in zebrafish retinas. Second, we directly proved that all the OLs in zebrafish retinas migrated from the optic nerve rather than from a domestic source. Third, we found that compared with adult OLs, younger OLs tend to generate longer but a fewer number of internodes. Finally, we found that the myelin in zebrafish eyes is functionally relevant to the elegant OKR. Our data suggest that the extraocular source of OLs first appeared at 28 dpf in zebrafish retina and then gradually developed with age, which contribute to optokinetic responses.


Applying nitrogen site-specifically using soil electrical conductivity maps and precision agriculture technology.
Soil texture varies significantly within many agricultural fields. The physical properties of soil, such as soil texture, have a direct effect on water holding capacity, cation exchange capacity, crop yield, production capability, and nitrogen (N) loss variations within a field. In short, mobile nutrients are used, lost, and stored differently as soil textures vary. A uniform application of N to varying soils results in a wide range of N availability to the crop. N applied in excess of crop usage results in a waste of the grower"s input expense, a potential negative effect on the environment, and in some crops a reduction of crop quality, yield, and harvestability. Inadequate N levels represent a lost opportunity for crop yield and profit. The global positioning system (GPS)-referenced mapping of bulk soil electrical conductivity (EC) has been shown to serve as an effective proxy for soil texture and other soil properties. Soils with a high clay content conduct more electricity than coarser textured soils, which results in higher EC values. This paper will describe the EC mapping process and provide case studies of site-specific N applications based on EC maps. Results of these case studies suggest that N can be managed site-specifically using a variety of management practices, including soil sampling, variable yield goals, and cropping history.


Fast fabrication of integrated surface-relief and particle-diffusing plastic diffuser by use of a hybrid extrusion roller embossing process.
Most plastic diffusers are either of surface-relief or particle-diffusing types, based on different principles and fabrication methods. This paper reports an innovative extrusion roller embossing process, which enables the fabrication of diffusers with both surface-relief and particle-diffusing functions. An extruder with die is employed to fabricate the thin film of PC/bead composite; the roller micro-embossing process is used to replicate the microstructure onto the surface of PC composite film. A metallic roller mold with microstructures is fabricated using turning process. During the extrusion rolling embossing process, the extruded film of PC with diffusion beads is immediately pressed against the surface of the roller mold. Under the proper processing parameters, the plastic diffusers integrating surface-relief and particle-diffusing functions have been successfully fabricated. The shape, uniformity, and optical properties of fabricated diffuser have been verified. This method shows the great potential for continuous fabrication of high-performance plastic diffusers integrating surface-relief and particle-diffusing functions with high throughput.


Impact of dissolved organic matter on colloid transport in the vadose zone: deterministic approximation of transport deposition coefficients from polymeric coating characteristics.
Although numerous studies have been conducted to discern colloid transport and stability processes, the mechanistic understanding of how dissolved organic matter (DOM) affects colloid fate in unsaturated soils (i.e., the vadose zone) remains unclear. This study aims to bridge the gap between the physicochemical responses of colloid complexes and porous media interfaces to solution chemistry, and the effect these changes have on colloid transport and fate. Measurements of adsorbed layer thickness, density, and charge of DOM-colloid complexes and transport experiments with tandem internal process visualization were conducted for key constituents of DOM, humic (HA) and fulvic acids (FA), at acidic, neutral and basic pH and two CaCl(2) concentrations. Polymeric characteristics reveal that, of the two tested DOM constituents, only HA electrosterically stabilizes colloids. This stabilization is highly dependent on solution pH which controls DOM polymer adsorption affinity, and on the presence of Ca(+2) which promotes charge neutralization and inter-particle bridging. Transport experiments indicate that HA improved colloid transport significantly, while FA only marginally affected transport despite having a large effect on particle charge. A transport model with deposition and pore-exclusion parameters fit experimental breakthrough curves well. Trends in deposition coefficients are correlated to the changes in colloid surface potential for bare colloids, but must include adsorbed layer thickness and density for sterically stabilized colloids. Additionally, internal process observations with bright field microscopy reveal that, under optimal conditions for retention, experiments with FA or no DOM promoted colloid retention at solid-water interfaces, while experiments with HA enhanced colloid retention at air-water interfaces, presumably due to partitioning of HA at the air-water interface and/or increased hydrophobic characteristics of HA-colloid complexes.


Regulatory role of SphK1 in TLR7/9-dependent type I interferon response and autoimmunity.
Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro-inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane-induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN-linked autoimmune disorders.


Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.
BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.


Motivations, Challenges, and Attitudes to Self-management in Kidney Transplant Recipients: A Systematic Review of Qualitative Studies.
Kidney transplantation offers better outcomes compared to dialysis, but requires patients to adhere to an ongoing and complex self-management regimen. Medication nonadherence remains a leading cause of transplant loss, and inadequate self-management undermines transplantation and other health outcomes. We aimed to describe kidney transplant recipients' motivations, challenges, and attitudes toward self-management. Systematic review and thematic synthesis of qualitative studies. Kidney transplant recipients. MEDLINE, EMBASE, PsycINFO, and CINAHL were searched to October 2014. Thematic synthesis. 50 studies involving 1,238 recipients aged 18 to 82 years across 19 countries were included. We identified 5 themes: empowerment through autonomy (achieving mastery, tracking against tangible targets, developing bodily intuition, routinizing and problem solving, and adaptive coping), prevailing fear of consequences (inescapable rejection anxiety, aversion to dialysis, minimizing future morbidity, trivialization and denial, and defining acceptable risks), burdensome treatment and responsibilities (frustrating ambiguities, inadvertent forgetfulness, intrusive side effects, reversing ingrained behaviors, and financial hardship), overmedicalizing life (dominating focus, evading patienthood, and succumbing to burnout), and social accountability and motivation (demonstrating gratitude toward medical team, indebtedness to donor, and peer learning). Non-English articles were excluded. Self-efficacy and social accountability are motivators for self-management, although adherence can be mentally and physically taxing. Multicomponent interventions incorporating personalized care planning, education, psychosocial support, decision aids, and self-monitoring tools may foster self-management capacity and improve transplantation outcomes.


Polypeptide-antibody binding mechanism: conformational adaptation investigated by equilibrium and kinetic analysis.
The mechanism of polypeptide-antibody binding was analysed by kinetic and equilibrium studies to find out whether or not the binding of an antibody to a large protein or a polypeptide antigen behaves as a one-step reaction or involves conformational adaptation. Three monoclonal antibodies recognizing 3 distinct epitopes on the C-terminal domain (F2) of Escherichia coli tryptophan synthase beta 2 subunit were used. The dissociation equilibrium constant (KD), the association rate constant (kon) and the dissociation rate constant (koff) of these antibodies for the native beta 2 subunit, its C-terminal fragment (F2) and different polypeptides obtained by chemical cleavage of the F2 fragment were measured. It was found that for some polypeptide-antibody complexes, binding could not be described as a one-step association-dissociation reaction, thus indicating the existence of conformational adaptation upon antibody-antigen complex formation. It was also shown that differences in affinities of a given antibody for its epitope carried by different polypeptides were mainly due to differences in the dissociation rate constant (koff) and not in the association rate constant (kon). Moreover, the immunoreactivity of various polypeptides obtained by cleavage of the F2 fragment enabled us to localize the 3 epitopes on the beta chain in light of the 3-dimensional structure of tryptophan synthase described recently by Hyde et al. (1988).


Evaluation of an intervention to maintain endotracheal tube cuff pressure within therapeutic range.
Endotracheal tube cuff pressure must be kept within an optimal range that ensures ventilation and prevents aspiration while maintaining tracheal perfusion. To test the effect of an intervention (adding or removing air) on the proportion of time that cuff pressure was between 20 and 30 cm H(2)O and to evaluate changes in cuff pressure over time. A repeated-measure crossover design was used to study 32 orally intubated patients receiving mechanical ventilation for two 12-hour shifts (randomized control and intervention conditions). Continuous cuff pressure monitoring was initiated, and the pressure was adjusted to a minimum of 22 cm H(2)O. Caregivers were blinded to cuff pressure data, and usual care was provided during the control condition. During the intervention condition, cuff pressure alarm or clinical triggers guided the intervention. Most patients were men (mean age, 61.6 years). During the control condition, 51.7% of cuff pressure values were out of range compared with 11.1% during the intervention condition (P < .001). During the intervention, a mean of 8 adjustments were required, mostly to add air to the endotracheal tube cuff (mean 0.28 [SD, 0.13] mL). During the control condition, cuff pressure decreased over time (P < .001). The intervention was effective in maintaining cuff pressure within an optimal range, and cuff pressure decreased over time without intervention. The effect of the intervention on outcomes such as ventilator-associated pneumonia and tracheal damage requires further study.


Sleep it off: Bullying and sleep disturbances in adolescents.
Involvement in bullying is associated with negative health outcomes for adolescents. Recent studies suggest that bullying is related to sleep disturbances. The purpose of this study was to examine differences in sleep disturbances (bedtime fears, insomnia, parasomnias) between victims, bullies, and youth not involved in bullying, as well as to explore differences across various types of bullying behavior (verbal, physical, social, cyber). High school students ages 14-17 years (mean = 16.0) in the United States (n = 885; 57.3% female; 87.5% White) completed The Children's Report of Sleep Patterns and questions about involvement in verbal, physical, social and cyberbullying. Differences in all three sleep disturbances were found across groups, with victims and bully-victims reporting more sleep disturbances than bullies and youth not involved. A similar pattern was found across all bullying types, with more sleep disturbances for victims and bullyvictims. The results of this cross-sectional study highlight the importance of screening youth for sleep disturbances that may indicate daytime issues with bullying or victimization, as well as the need for longitudinal studies to elucidate potential pathways between sleep and bullying/victimization.


Diarrheal disease incidence and morbidity among United States military personnel during short-term missions overseas.
Outpatient medical surveillance of U.S. troops was conducted during 11 different overseas missions between 1981 and 1990. In addition, at the end of each of 18 overseas missions during the same period, a sample of troops was queried regarding illnesses and exposures experienced in the preceding time overseas. Diarrhea was among the leading causes of morbidity during all of these short-term missions. Diarrhea incidence rates were found to be highest during summer months, and were higher during missions to Thailand (median = 25%, range = 20-29%), Latin America (median = 26%, range = 1-43%), and northeastern Africa and southwest Asia (median = 19%, range = < 1-52%). Rates were lowest in troops deployed to the Republic of South Korea (median = 16%, range = 8-27%). During April and May 1990, a focused surveillance and questionnaire study was conducted during a five-week, joint U.S.-Thai military training exercise in central Thailand. Among 2,600 U.S. personnel, diarrheal illness was found to be the most common medical problem for troops (estimated cumulative incidence = 29%). Travel outside of the base of operations and consumption of ice were found to be important risk factors. The 10-year database analyzed for this report is the largest, published summary showing the significant impact of diarrheal diseases on U.S. military forces during short-term deployments to less developed areas.


Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells.
Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 μM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 μM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.


Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment.
CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb led to increased activation of CD11c+ dendritic cells in the tumor draining lymph node, while sunitinib treatment reduced vessel density and decreased accumulation of CD11b+Gr1+ myeloid derived suppressor cells. The expression of ICAM-1 and VCAM-1 adhesion molecules was up-regulated on tumor endothelial cells only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced intratumoral infiltration of CD8+ cytotoxic T-cells. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exerts potent complementary antitumor effects mediated by dendritic cell activation, a reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T-cells.


2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy.
Bile duct injury (BDI) is a dangerous complication of cholecystectomy, with significant postoperative sequelae for the patient in terms of morbidity, mortality, and long-term quality of life. BDIs have an estimated incidence of 0.4-1.5%, but considering the number of cholecystectomies performed worldwide, mostly by laparoscopy, surgeons must be prepared to manage this surgical challenge. Most BDIs are recognized either during the procedure or in the immediate postoperative period. However, some BDIs may be discovered later during the postoperative period, and this may translate to delayed or inappropriate treatments. Providing a specific diagnosis and a precise description of the BDI will expedite the decision-making process and increase the chance of treatment success. Subsequently, the choice and timing of the appropriate reconstructive strategy have a critical role in long-term prognosis. Currently, a wide spectrum of multidisciplinary interventions with different degrees of invasiveness is indicated for BDI management. These World Society of Emergency Surgery (WSES) guidelines have been produced following an exhaustive review of the current literature and an international expert panel discussion with the aim of providing evidence-based recommendations to facilitate and standardize the detection and management of BDIs during cholecystectomy. In particular, the 2020 WSES guidelines cover the following key aspects: (1) strategies to minimize the risk of BDI during cholecystectomy; (2) BDI rates in general surgery units and review of surgical practice; (3) how to classify, stage, and report BDI once detected; (4) how to manage an intraoperatively detected BDI; (5) indications for antibiotic treatment; (6) indications for clinical, biochemical, and imaging investigations for suspected BDI; and (7) how to manage a postoperatively detected BDI.


"He Needs to Talk!": A Chaplain's Case Study of Nonreligious Spiritual Care.
Chaplains have always worked with nonreligious people, but it is not always clear what is distinctive about their contribution. This case describes an episode of nonreligious spiritual care in order to explore the value of chaplaincy work with people who regard themselves as nonreligious. This case reports on work with a dying man and his family-wife, daughter, sister, and son-in-law-whose religion is secularized, but whose secularism is touched by the sacred.


Nanogel hybrid assembly for exosome intracellular delivery: effects on endocytosis and fusion by exosome surface polymer engineering.
Surface polymer engineering was applied with a carrier of exosomes, namely, the amphiphilic cationic CHP (cCHP) nanogel, to improve the delivery of exosome content by forming complexes with the exosomes. Mouse macrophage cells were used to produce the exosomes, which were then mixed with the cCHP nanogel to form a hybrid. Transmission electron microscopy revealed that the surface of each exosome was coated with cCHP nanogel particles. Flow cytometry also showed a significant uptake of this exosome/nanogel hybrid by HeLa cells, with the main mechanism behind this internalization being endocytosis. A range of different molecules that inhibit different types of endocytosis were also applied to determine the particular pathway involved, with a caveolae-mediated endocytosis inhibitor being revealed to markedly affect the hybrid uptake. Next, we evaluated the fate of the internalized hybrid using fluorescent labeling, with the results suggesting fusion between endosomes and exosomes. Finally, revealing the functional efficacy of this approach, we showed that the nanogel system could successfully deliver functional exosomes into cells, as indicated by its ability to induce neuron-like differentiation in the recipient cells. Overall, our findings show the potential of using this hybrid nanocarrier system for transporting various contents in exosomes and ensuring their effective delivery in a functionally intact state.


Electronic structure and conformational conversion of calix[4]arene complexes with alkali metal ions.
The ultraviolet photodissociation (UVPD) spectra of calix[4]arene (C4A) complexes with alkali metal ions, M+·C4A (M = Na, K, Rb, and Cs), are measured in the 34 000-37 000 cm-1 region under cold (∼10 K) conditions in the gas phase. The UVPD spectra of the Na+·C4A and K+·C4A complexes show several sharp vibronic bands, while the UVPD spectra of the Rb+·C4A and Cs+·C4A complexes exhibit only broad features. The UVPD spectra are assigned with the aid of quantum chemical calculations. Most of the features in the UVPD spectra can be attributed to cone isomers, which are the most stable for all the M+·C4A complexes. In all the cone isomers, the M+ ion is encapsulated inside the cavity of C4A, and the structure is distorted to C2 symmetry from that of bare C4A (C4 symmetry). The cone isomers show a big difference in the electronic structure between the K+ and Rb+ complexes. The Rb+ and Cs+ complexes have an electronic structure similar to that of bare C4A. In the Na+ and K+ complexes, the two benzene rings facing each other in a pair have a short distance between them (<6 Å). This results in a substantial overlap of the π clouds between them, and an electronic transition is localized on this pair. Only this localized electronic transition of the Na+ and K+ complexes shows sharp band features in the UVPD spectra. In the Na+·C4A complex, the UVPD spectroscopic results suggest the coexistence of other isomers having partial-cone and 1,3-alternate forms. The energetics of the isomerization reactions of C4A and Na+·C4A is examined theoretically. The estimated potential barriers between the stable conformers are less than 75 kJ mol-1 for Na+·C4A, suggesting that conformational conversion can occur at room temperature, before the Na+·C4A complex enters the cold ion trap. The existence of multiple conformations for Na+·C4A is attributed to the higher stability of these conformers, both kinetically and thermodynamically, compared to the case of bare C4A and the other M+·C4A complexes.


Successful co-encapsulation of benzoyl peroxide and chloramphenicol in liposomes by a novel manufacturing method - dual asymmetric centrifugation.
Encapsulation of more than one active pharmaceutical ingredient into nanocarriers such as liposomes is an attractive approach to achieve a synergic drug effect and less complicated dosing schedules in multi-drug treatment regimes. Liposomal drug delivery in acne treatment may improve drug efficiency by targeted delivery to pilosebaceous units, reduce adverse effects and improve patient compliance. We therefore aimed to co-encapsulate benzoyl peroxide (BPO) and chloramphenicol (CAM) into liposomes using the novel liposome processing method - dual asymmetric centrifugation (DAC). Liposomes were formed from soybean lecithin, propylene glycol and distilled water (2:1:2w/v/v ratio), forming a viscous liposome dispersion. Liposomes containing both drugs (BPO-CAM-Lip), single drug (BPO-Lip and CAM-Lip), and empty liposomes were prepared. Drug entrapment of BPO and CAM was determined by a newly developed HPLC method for simultaneous detection and quantification of both drugs. Encapsulation of around 50% for BPO and 60% for CAM respectively was obtained in both single-drug encapsulated formulations (BPO-Lip and CAM-Lip) and co-encapsulated formulations (BPO-CAM-Lip). Liposome sizes were comparable for all liposome formulations, ranging from 130 to 150nm mean diameter, with a polydispersity index <0.2 for all formulations. CAM exhibited a sustained release from all liposomal formulations, whereas BPO appeared retained within the liposomes. BPO retention could be attributed to its poor solubility. However, HaCaT cell toxicity was found dependent on BPO released from the liposomes. In the higher concentration range (4%v/v), liposomal formulations were less cytotoxic than the corresponding drug solutions used as reference. We have demonstrated that DAC is a fast, easy, suitable method for encapsulation of more than one drug within the same liposomes.


Using personal health information: do we manage conflicting interests?
The discipline of health informatics is concerned with developing the information systems that facilitate collection, manipulation and dissemination of personal health information. It promotes the benefits of using personal health information for secondary purposes, including policy development, service planning and research. At the same time the health informatics community is a strong advocate of privacy and the need to protect individuals from negative consequences arising from unauthorised use of their personal health information. This creates a dilemma for health informatics professionals since there will be occasions when the rights and interests of individuals conflict with the rights and interests of the public, or particular sections of the public. In such instances, the community as a whole, and individual members, may be required to take a stance on whether to prioritise privacy over public needs and interests. Such instances are likely to increase in the future as demands for access to personal health information increase. This paper considers the way the health informatics community approaches the dilemma. It reports on a study which analysed various perspectives on the issue as expressed in HISA conference proceedings. The study identified six discourses, each of which focuses on different uses of personal health information. The study found that the discourses expressed strong support for expanded use of personal health information where the public interest was convincingly argued, although the interpretation of what constituted public interest varied between the discourses. The study also found that while higher level discussions highlight the potential for negative consequences arising from expanded uses of personal health information, this was not often discussed in the conference texts. It is argued that such concerns should be considered, particularly in the light of discussions around the Commonwealth government's Individual Health Identifier and Personally Controlled Electronic Health Records initiatives.


Management of cutaneous discomfort in patients with scleroderma: a clinical trial.
Systemic sclerosis (scleroderma) is a disease of unknown cause, the hallmark of which is induration of the skin. This bad condition of the skin influences negatively the quality of life of patients with scleroderma. The aim of the study was to verify the efficacy of two formulations, specifically designed to wash, moisturize and soothe the scleroderma skin. An independent, randomized, double blind, controlled trial was conducted in the Department of Rheumatology of "A. Galateo" Hospital in San Cesario di Lecce. Forty-six women affected by scleroderma, and treated with Iloprost every month, were divided into two groups: group 1 followed a specific treatment with cleansing formulation only, group 2 followed a combined treatment with the cleansing solution and the moisturizing solution. In addition, a third group was evaluated: 14 women, who did not undergo intravenous Iloprost therapy, were treated simultaneously with the cleansing formulation and the moisturizing formulation. The three treatments lasted for 4 weeks. Reduction in trans epidermal water loss (TEWL), increase in moisturization of the stratum corneum, reduction in Skin Score and improvement in quality of life were assessed. Very significant improvement in quality of life occurred in each group. Group 2 obtained very significant improvement in hydration and reduction in skin score and TEWL. The study showed that the daily use of both formulations proved to be effective in washing, hydrating and soothing the skin of patients with scleroderma, especially in association with Iloprost therapy.


Temperature regulation in emperor penguins foraging under sea ice.
Inferior vena caval (IVC) and anterior abdominal (AA) temperatures were recorded in seven emperor penguins (Aptenodytes forsteri) foraging under sea ice in order to evaluate the hypothesis that hypothermia-induced metabolic suppression might extend aerobic diving time. Diving durations ranged from 1 to 12.5 min, with 39% of dives greater than the measured aerobic dive limit of 5.6 min. Anterior abdominal temperature decreased progressively throughout dives, and partially returned to pre-dive values during surface intervals. The lowest AA temperature was 19 degrees C. However, mean AA temperatures during dives did not correlate with diving durations. In six of seven penguins, only minor fluctuations in IVC temperatures occurred during diving. These changes were often elevations in temperature. In the one exception, although IVC temperatures decreased, the reductions were less than those in the anterior abdomen and did not correlate with diving durations. Because of these findings, we consider it unlikely that regional hypothermia in emperor penguins leads to a significant reduction in oxygen consumption of the major organs within the abdominal core. Rather, temperature profiles during dives are consistent with a model of regional heterothermy with conservation of core temperature, peripheral vasoconstriction, and cooling of an outer body shell.


North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome.
Cyclic vomiting syndrome (CVS) is a disorder noted for its unique intensity of vomiting, repeated emergency department visits and hospitalizations, and reduced quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. Because no accepted approach to management has been established, the task force was charged to develop a report on diagnosis and treatment of CVS based upon a review of the medical literature and expert opinion. The key issues addressed were the diagnostic criteria, the appropriate evaluation, the prophylactic therapy, and the therapy of acute attacks. The recommended diagnostic approach is to avoid "shotgun" testing and instead to use a strategy of targeted testing that varies with the presence of 4 red flags: abdominal signs (eg, bilious vomiting, tenderness), triggering events (eg, fasting, high protein meal), abnormal neurological examination (eg, altered mental status, papilledema), and progressive worsening or a changing pattern of vomiting episodes. Therapeutic recommendations include lifestyle changes, prophylactic therapy (eg, cyproheptadine in children 5 years or younger and amitriptyline for those older than 5), and acute therapy (eg, 5-hydroxytryptamine receptor agonists, termed triptans herein, as abortive therapy, and 10% dextrose and ondansetron for those requiring intravenous hydration). This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the diagnosis and treatment of CVS in children and adolescents.


Effects of coronary sinus Reducer implantation on oxygen kinetics in patients with refractory angina.
Refractory angina is still a major public health problem. The coronary sinus Reducer (CSR) has recently been introduced as an alternative treatment to reduce symptoms in these patients. The aim of this study was to investigate objective improvements in effort tolerance and oxygen kinetics as assessed by cardiopulmonary exercise testing (CPET) in patients suffering from refractory angina undergoing CSR implantation. In this multicentre prospective study, patients with chronic refractory angina undergoing CSR implantation were scheduled for CPET before the index procedure and at six-month follow-up. The main endpoints of this analysis were improvements in VO2 max and in VO2 at the anaerobic threshold (AT). Clinical events and improvements in symptoms were also recorded. A total of 37 patients formed the study population. The CSR implantation procedure was successful and without complications in all. At follow-up CPET, significant improvement in VO2 max (+0.97 ml/kg/min [+11.3%]; 12.2±3.6 ml/kg/min at baseline vs 13.2±3.7 ml/kg/min, p=0.026), and workload (+12.9 [+34%]; 68±28 W vs 81±49 W, p=0.05) were observed, with non-significant differences in VO2 at the AT (9.84±3.4 ml/kg/min vs 10.74±3.05 ml/kg/min, p=0.06). Canadian Cardiovascular Society (CCS) grade improved from a mean of 3.2±0.5 to 1.6±0.8 (p<0.01), and significant benefits in all Seattle Angina Questionnaire variables were shown. In patients with obstructive coronary artery disease suffering from refractory angina, the implantation of a CSR was associated with objective improvement in exercise capacity and oxygen kinetics at CPET, suggesting a possible reduction of myocardial ischaemia.


Bone turnover and bone mineral density are independently related to selenium status in healthy euthyroid postmenopausal women.
Selenium status may have direct effects on bone and indirect effects through changes in thyroid hormone sensitivity. We hypothesized that variation in selenium status in healthy euthyroid postmenopausal women is associated with differences in bone turnover, bone mineral density (BMD) and fracture susceptibility. The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. The study was comprised of a population-based cohort from five European cities. A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1144. There were no interventions. We measured selenium (micrograms per liter); selenoprotein P (milligrams per liter); free T(4) (picomoles per liter); free T(3) (picomoles per liter); TSH (milliunits per liter); bone turnover markers; BMD; and vertebral, hip, and nonvertebral fractures. Higher selenium levels were associated with higher hip BMD at study entry (β = 0.072, P = 0.004) and lower levels of bone formation (osteocalcin: β = -0.101, P < 0.001; procollagen type 1 N-terminal propeptide: β = -0.074, P = 0.013) and resorption markers (C-telopeptide of type 1 collagen: β = -0.058, P = 0.050; N-telopeptide of type 1 collagen: β = -0.095, P = 0.002). Higher selenoprotein P was associated with higher hip (β = 0.113, P < 0.001) and lumbar spine BMD (β = 0.088, P = 0.003) at study entry, higher hip BMD after the 6-yr follow-up (β = 0.106, P = 0.001) and lower osteocalcin (β = -0.077, P = 0.009), C-telopeptide of type 1 collagen (β = -0.075, P = 0.012), and N-telopeptide of type 1 collagen (β = -0.110, P < 0.001). Selenium status is inversely related to bone turnover and positively correlated with BMD in healthy euthyroid postmenopausal women independent of thyroid status.


Application of CD56, P63 and CK19 immunohistochemistry in the diagnosis of papillary carcinoma of the thyroid.
Papillary carcinoma of the thyroid (PTC) is the commonest thyroid cancer. In the recent decades an obvious increase in the incidence of PTC has occurred. The pathological diagnosis of PTC is usually an easy diagnosis in the majority of cases. However since the introduction of follicular variant of PTC and the wide threshold range in interpretation of the clearly set pathological criteria for diagnosis of PTC, between pathologists including experts, the diagnosis in some cases became quite difficult. Unfortunately some cases are unjustifiably over-called as follicular variant of PTC as a result of the wide inter observable variability between pathologists, including thyroid pathologists.Ancillary studies such as immunohistochemistry may be helpful, but till now there is no 100% consistent marker(s), that distinct between PTC and other follicular thyroid lesions and tumors.We assessed expression of antibodies against CD56, CK19, P63 and E-Cadherin in PTC and other follicular thyroid lesions and neoplasms. A total of 175 cases were studied. The neoplastic cases included 75 carcinomas (72 papillary, 2 follicular, 1 Hurthle cell) and 35 adenomas (32 follicular and 3 Hurthle cell). The non-neoplastic thyroids included 65 cases, (25 nodular hyperplasia, 5 thyrotoxic hyperplasia (Grave's disease), 19 lymphocytic thyroiditis and 6 Hashimoto's thyroiditis). All cases were evaluated by immunohistochemistry for the expression of the above mentioned markers. The markers' patterns and intensities of staining were scored. Positive expression of the markers equal or >10% of the follicular epithelium within the tumor or lesional cells was considered positive. An expression of <10% was considered to be negative.Our results showed CD56 positive in all the lesions and tumors except for PTC in all cases (100%). CD56 was negative in all PTC cases (100%). CK 19 showed positive expression in PTC accounting for 85% of cases and in 26% of non PTC lesions/tumors. P63 showed selective focal positivity in PTC cases, in contrast to other non PTC lesions/tumors. P63 expression was in 70% of cases of PTC and was consistently absent in all the non PTC cases. E-Cadherin showed consistent non discriminatory expression in all cases included in the study.We concluded that a panel consisted of CD56, CK19 and P63 is of value in distinction of PTC from other thyroid follicular lesion. P63 is a specific but less sensitive marker for PTC than CK19. CD56 is more specific and sensitive marker than CK19, however it is a negative rather than a positive marker for PTC. E-Cadherin is of no value in the diagnosis of thyroid follicular lesions/tumors. We recommend application of a panel composed of CK19, P63 and CD56 by a group of expert thyroid pathologists on a large series of follicular malignant thyroid neoplasms of uncertain malignant.


Musculoskeletal manifestations of amyloidosis. A review of 83 patients on haemodialysis for at least 10 years.
Long-term regular haemodialysis for chronic renal failure is associated with amyloidosis. In this condition excess amounts of the unexcretable plasma protein beta-microglobulin are laid down in tendons, joints and bones. Amyloidosis presents with various musculoskeletal disorders only after several years of dialysis. We reviewed 83 patients who had been dialysed for at least 10 years. The commonest complaint was severe joint pain in the absence of radiological changes of arthritis (41%), the shoulders usually being the most affected (33%). Carpal tunnel syndrome had developed in 26 patients, and was bilateral in 14 of them; at operation the presence of amyloid was confirmed. Six of these patients had recurrent symptoms after a further two to three years and required another decompression. Other manifestations of amyloidosis included trigger finger, flexor tendon contracture, spontaneous tendon rupture and pathological fracture through amyloid bone cysts. The frequency of symptoms was proportional to the duration of dialysis: all 13 patients on dialysis for over 20 years were affected. Symptoms developed earlier in older patients.


Correlation lengths in hydrodynamic models of active nematics.
We examine the scaling with activity of the emergent length scales that control the nonequilibrium dynamics of an active nematic liquid crystal, using two popular hydrodynamic models that have been employed in previous studies. In both models we find that the chaotic spatio-temporal dynamics in the regime of fully developed active turbulence is controlled by a single active scale determined by the balance of active and elastic stresses, regardless of whether the active stress is extensile or contractile in nature. The observed scaling of the kinetic energy and enstrophy with activity is consistent with our single-length scale argument and simple dimensional analysis. Our results provide a unified understanding of apparent discrepancies in the previous literature and demonstrate that the essential physics is robust to the choice of model.


Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts.
The isothiocyanate sulforaphane was isolated from broccoli extracts in a bioactivity-guided fractionation as the principal and very potent inducer of cytoprotective phase 2 enzymes and subsequently shown to inhibit tumor development in animal models that involve various carcinogens and target organs. Because broccoli and broccoli sprouts are widely consumed, extracts obtained from them are viewed as convenient vehicles for sulforaphane delivery to humans. In relation to our current interest in devising strategies for protection against UV light-induced skin cancer, it was necessary to examine the safety and efficacy of topical application of sulforaphane-containing broccoli sprout extracts as single and multiple doses in both mice and humans. Topical application of an extract delivering 100 nmol sulforaphane/cm(2) increased the protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A1, and heme oxygenase 1, three representative phase 2 enzymes, in mouse skin epidermis. Quantitative assessment of the activity of NQO1 24 h after dosing showed increases of 1.5- and 2.7-fold after application of single and multiple (thrice, every 24 h) doses, respectively. A dose-escalation safety study in healthy human subjects revealed no adverse reactions when doses as high as 340 nmol of sulforaphane in the form of broccoli sprout extracts were applied topically to the center of a 1-cm-diameter circle drawn on the volar forearm. A subsequent efficacy study showed that despite the interindividual differences in basal levels, the enzyme activity of NQO1 in homogenates of 3-mm full thickness skin punch biopsies increased in a dose-dependent manner, with maximum increases of 1.5- and 4.5-fold after application of 150 nmol doses, once or three times (at 24 h-intervals), respectively, thus providing direct evidence for induction of the phase 2 response in humans.


Cognitive impairment is the major risk factor for development of geriatric syndromes during hospitalization: results from the GIFA study.
To detect the main factors associated with the occurrence of specific geriatric syndromes (namely pressure sores, fecal incontinence, urinary incontinence and falls) in elderly patients during hospitalization. Observational prospective study. Eighty-one community and university hospitals throughout Italy. 13,729 patients aged 65 years and more, consecutively admitted to medical or geriatric acute wards during 20 months in the period between 1991 and 1998. Occurrence of pressure sores, fecal incontinence, urinary incontinence and falls during the stay in hospital. Pressure sores were already present in 3% of hospitalized subjects, fecal incontinence in 7.3%, while urinary incontinence, evaluated on a subgroup of total population (4,268 subjects), had a prevalence of 22.3%. During hospitalization (mean stay of 15 days), 74 subjects developed new pressure sores, 55 became fecal and 35 urinary incontinent, and 279 subjects had at least one episode of fall. In multivariate analyses, cognitive impairment, advanced age (85+ years), length of stay (more than 3 weeks) and severe disability were the main independent predictors of development of the four geriatric syndromes, with cognitive impairment as the most significant risk factor for all the four outcomes (OR 4.9, 95% CI 2.4-9.9 for pressure sores; OR 6.3, 95% CI 3.0-13.0 for fecal incontinence; OR 5.3, 95% CI 2.3-12.0 for urinary incontinence; OR 1.6, 95% CI 1.2-2.3 for falls). Very old people have a significant increased risk of several geriatric syndromes during the stay in hospital, particularly if it is long and they are cognitively impaired. A standardized comprehensive geriatric evaluation at admission could be helpful in detecting all subjects at risk and preventing the development of hospital-acquired geriatric syndromes.


Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean.
To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3-2.8), birth weight <2.5 kg (OR = 3.1; 95% CI: 2.1-4.8), 1-min Apgar score <7 (OR = 2.5; 95% CI: 1.4-4.4), and infant infections (OR = 2.5; 95% CI: 1.5-4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common.


Functional dopamine deficits in the senile rat retina.
The activity of the endogenous retinal dopamine (DA) pathway has been examined in the pigmented rat using retinas obtained from normal adult (approximately 3 months) and senile adults (approximately 24 months) using an in vitro electrophysiological approach. By comparing the pharmacological sensitivity of the horizontal cells (HCs) to exogenous DA, a D1 receptor antagonist (SCH 23390) and a DA-transport inhibitor (nomifensine), it is suggested that there is a functional deficit in the endogenous DA activity in the senile retina. Cells recorded from retinae obtained from senile animals are more sensitive to exogenous DA, whilst the senile retina is insensitive to SCH 23390. In addition, nomifensine was effective in potentiating subthreshold DA applications, but only in the normal adult retina. The data may suggest that endogenous DA release upon the HCs and selective re-uptake are suppressed in these retinae. These functional deficits also appear to be associated with changes in the receptive fields of the HCs, suggesting there is a corresponding deficit in spatial processing at the outer plexiform layer (OPL) of the senile rat.


Pharmacological interventions for the treatment of anxiety disorders in chronic obstructive pulmonary disease.
Chronic Obstructive Pulmonary Disease (COPD) is characterised by inflammation of the airways and destruction of pulmonary tissue with post bronchodilator FEV1/FVC of <0.70 (forced expiratory volume in one second/forced vital capacity). Evidence indicates an increased prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease (COPD), as compared with the general population and persons suffering from many other chronic illnesses. Anxiety in people with COPD has been shown to increase disability and impair functional status, resulting in an overall reduction in quality of life. As such, pharmacological interventions are commonly used to treat anxiety disorders in patients with COPD. To assess the effect of pharmacological interventions on anxiety disorders in people with COPD, in terms of improvement of anxiety symptoms, quality of life, exercise tolerance, reduction in length of hospital stay and FEV1. We also evaluated adverse drug reactions. Two Cochrane Review Group Specialised Registers were searched (up to the 1st of June 2011) to identify trials for this review. Complementary searches of PsycINFO and the Cochrane Central Register of Controlled Trials (CENTRAL) were also carried out. We did not apply any language restrictions. We considered all randomised controlled trials (RCTs), cluster randomised trials and cross-over trials of pharmacological interventions for patients (age > 40 years) with COPD and co-existing anxiety disorders (as confirmed by recognised diagnostic criteria or a validated measurement scale) for the review. Two of the three review authors individually evaluated each article and extracted data. Any conflicts that arose were resolved through discussion with a third party, if necessary. Trial investigators were contacted to obtain missing/raw data. Meta-analyses of continuous outcomes were performed using the random-effect model. Four studies met all of the inclusion criteria (with a total of 40 participants). Three subclasses of anxiety medications were used including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and azapirones. Although two studies used SSRIs as the intervention (total of 21 participants), we were unable to meta-analyse the anxiety outcomes as one study had a standard deviation of zero for the control group. Included studies had relatively poor quality including small sample sizes and short follow-up periods. Due to the small number of included studies, we were unable to meta-analyse all the subclasses of medications. Due to the sub-optimal quality of the trials and statistically non-significant results, it is not possible to draw any conclusions for treatment. This review highlights the paucity of data in this area. As such, there is a need for scientifically rigorous research trials to evaluate the role of pharmacological interventions for anxiety disorders in patients with COPD, using a sample size large enough to demonstrate meaningful clinical significance.


Tissue factor in experimental acute lung injury.
Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis.


Assessment of a synthetic DNA probe for Plasmodium falciparum in African blood specimens.
Synthetic DNA oligomers homologous to 21-base long repetitive sequences of Plasmodium falciparum DNA were labeled with 32P using T4 kinase, and were hybridized with purified DNA and with processed blood samples from Africa. The sequence PFR1, its antiparallel oligomer PFR1R, and PFR1 covalently attached to biotin hybridized similarly to P. falciparum DNA. One-microliter aliquots of blood from Zaire spotted on prewet nylon filters and hybridized with PFR1 gave detectable autoradiogram signals from samples with parasitemias as low as 1,000 parasites/mm3. Blood lysis and protein digestion followed by alkylation allowed dot-blot processing of larger aliquots of blood. After hybridization with PFR 1 and autoradiography, 26 samples were scored positive visually, compared with 34 scored positive by microscopy. The effective sensitivity for processed 10-microliter samples was about 500 parasites/mm3. Signals from hybridized probes were quantitated by liquid scintillation counting and densitometry, and were proportional to the amounts of purified P. falciparum DNA applied to the filter. Autoradiogram signals also were roughly proportional (correlation coefficient, r = 0.77) to the number of parasites/mm3 of blood from field samples as determined by microscopic examination.


Degradation of cloaking by two closely neighboring cloaks.
Cloaking can prevent a scattering object from detection by electromagnetic waves as it can significantly reduce the scattering cross section of the object. In this work we show that when two cloaks are placed in close neighborhood, the interaction will greatly enhance the perturbation of near field and significantly increase the scattering cross section compared with a single cloak. This means that the cloaking functionality may strongly degrade when two or more cloaks come close to each other. This offers a route to break down electromagnetic cloaking.


Alfred Werner: Overlooked Genius of the Periodic System.
2019, which was proclaimed by the United Nations as the International Year of the Periodic Table, sees one hundred years since Alfred Werner, the first Swiss to receive a Nobel Prize in chemistry, passed away. The undoubted father of coordination chemistry, he is also well-known for influencing many other fields of chemistry, including organic, inorganic, organometallic, bioinorganic, and stereochemistry. However, one of his more rare and unique contributions to chemistry, his 1905 version of the periodic system, to this day remains overlooked. The simple and elegant idea which he used to construct his periodic table has not been communicated to the English-speaking world, because Alfred Werner published his only original paper on the periodic table in German. Werner's simple mathematical approach lead to overwhelming success with anticipating the future f-block. He managed to predict almost perfectly the number of lanthanides, which was hotly debated at that time. Werner's genius vision was considerably ahead of its time. It was not until the 1940s and the discovery of actinide series when the idea of representing the elements as a 32-column periodic table finally became justified.


Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: a clinical initiative.
The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.


Secreted expression of a hyperthermophilic α-amylase gene from Thermococcus sp. HJ21 in Bacillus subtilis.
The hyperthermophilic α-amylase from Thermococcus sp. HJ21 possesses unique traits (Ca(2+)-independent thermostability and optimal temperature of 95°C) that make it a great potential candidate for use in the food industry. However, this Archaea isolated from a deep-sea thermal vent requires strict control of culture conditions and produces only small amounts of α-amylase. To solve these problems, the α-amylase gene was cloned and expressed in Bacillus subtilis, which is an ideal food-grade host for heterologous protein expression. To express high levels of this α-amylase in B. subtilis, the promoters Pgrac, PxylA, P43, and Phag were used to construct four different expression vectors for testing. The vector containing the PxylA promoter was found to have the highest transcriptional activity and produce the highest amylase activity (19.6 U/ml). To test the secretion efficiency of signal peptides in B. subtilis, three signal peptides were cloned and fused to the α-amylase gene (lacking its native signal peptide). The optimal signal peptide was SamyQ, with a secretion efficiency of approximately 90%. These results indicate that the promoter PxylA and signal peptide SamyQ tested in this study may be useful for the expression and secretion of archaeal proteins in B. subtilis.


Açai (Euterpe oleracea Mart.) polyphenolics in their glycoside and aglycone forms induce apoptosis of HL-60 leukemia cells.
The effects of açai polyphenolics on the antiproliferation and induction of apoptosis in HL-60 human leukemia cells were investigated. Interactions between anthocyanins and non-anthocyanin-polyphenolics in both their glycosidic and their aglycone forms were also investigated to determine additive or nonadditive responses. Polyphenolic fractions at 0.17-10.7 microM were found to reduce cell proliferation from 56 to 86% likely due to caspase-3 activation (apoptosis). Anthocyanin and polyphenolic fractions were nonadditive in their contribution to the cell antiproliferation activity. At equimolar concentrations, the glycosidic forms of phenolic acids and flavonoids induced a higher magnitude of change in cell parameters (proliferation and apoptosis) than their respective aglycone forms, while the opposite trend was observed for anthocyanin aglycones. This study demonstrated that açai offers a rich source of bioactive polyphenolics and confirmed the importance of investigating whole food systems when evaluating the potential health benefits of individual phytochemical compounds.


The magnitude of abdominal adiposity and atherogenic dyslipidemia among geriatric Nigerians with arterial hypertension in a rural hospital in South-eastern Nigeria.
As the case detection rate of arterial hypertension increases daily in rural Nigeria, screening for its associated abdominal obesity and dyslipidemia is an important healthcare challenge. Of great concern in rural Nigeria is that most geriatric hypertensives with abdominal obesity and dyslipidemia are not routinely diagnosed and therefore do not receive appropriate management. This study was aimed at describing the magnitude (prevalence and pattern) of abdominal adiposity using waist circumference (WC) index and dyslipidemia among geriatric Nigerians with arterial hypertension in a rural hospital in South-eastern Nigeria. A descriptive hospital-based study was carried out from June 2008 to June 2011 on 122 consecutive geriatric patients with systemic hypertension who met the selection criteria at St. Vincent De Paul Hospital, Amurie-Omanze, a rural Mission General Hospital in Imo state. Abdominal obesity was defined as WC ≥102 cm and ≥88 cm for men and women, respectively. Dyslipidemia was defined using the third report of National Cholesterol Education Panel in adult (ATP III). The data collected included basic demographic variables, blood pressure, waist circumference, fasting lipid profile, and blood sugar. The prevalence of abdominal obesity was 50.8% and was the most common pattern of abdominal adiposity. Fifty-four (44.3%) out of 122 patients had at least one dyslipidemia with the most frequent being low high-density lipoprotein cholesterol (HDL-C, 38.5%). There was statistically significant difference between male and female gender based on abdominal adiposity (X 2 = 5.406, P value = 0.04) while their mean lipid differentials were not statistically significant. This study has shown that abdominal adiposity and dyslipidemia exist among geriatric hypertensives in the study area with abdominal obesity being the most common abdominal adiposity and low HDL-C being the most frequent lipid abnormality. This study therefore urges the necessity to consider abdominal obesity and dyslipidemia in geriatric hypertensives in rural Nigeria alongside the complex of other cardiovascular risk factors.


Proteomics for systems toxicology.
Current toxicology studies frequently lack measurements at molecular resolution to enable a more mechanism-based and predictive toxicological assessment. Recently, a systems toxicology assessment framework has been proposed, which combines conventional toxicological assessment strategies with system-wide measurement methods and computational analysis approaches from the field of systems biology. Proteomic measurements are an integral component of this integrative strategy because protein alterations closely mirror biological effects, such as biological stress responses or global tissue alterations. Here, we provide an overview of the technical foundations and highlight select applications of proteomics for systems toxicology studies. With a focus on mass spectrometry-based proteomics, we summarize the experimental methods for quantitative proteomics and describe the computational approaches used to derive biological/mechanistic insights from these datasets. To illustrate how proteomics has been successfully employed to address mechanistic questions in toxicology, we summarized several case studies. Overall, we provide the technical and conceptual foundation for the integration of proteomic measurements in a more comprehensive systems toxicology assessment framework. We conclude that, owing to the critical importance of protein-level measurements and recent technological advances, proteomics will be an integral part of integrative systems toxicology approaches in the future.


Structural Characterization of Maize SIRK1 Kinase Domain Reveals an Unusual Architecture of the Activation Segment.
Kinases are primary regulators of plant metabolism and excellent targets for plant breeding. However, most kinases, including the abundant receptor-like kinases (RLK), have no assigned role. SIRK1 is a leucine-rich repeat receptor-like kinase (LRR-RLK), the largest family of RLK. In Arabidopsis thaliana, SIRK1 (AtSIRK1) is phosphorylated after sucrose is resupplied to sucrose-starved seedlings and it modulates the sugar response by phosphorylating several substrates. In maize, the ZmSIRK1 expression is altered in response to drought stress. In neither Arabidopsis nor in maize has the function of SIRK1 been completely elucidated. As a first step toward the biochemical characterization of ZmSIRK1, we obtained its recombinant kinase domain, demonstrated that it binds AMP-PNP, a non-hydrolysable ATP-analog, and solved the structure of ZmSIRK1- AMP-PNP co-crystal. The ZmSIRK1 crystal structure revealed a unique conformation for the activation segment. In an attempt to find inhibitors for ZmSIRK1, we screened a focused small molecule library and identified six compounds that stabilized ZmSIRK1 against thermal melt. ITC analysis confirmed that three of these compounds bound to ZmSIRK1 with low micromolar affinity. Solving the 3D structure of ZmSIRK1-AMP-PNP co-crystal provided information on the molecular mechanism of ZmSIRK1 activity. Furthermore, the identification of small molecules that bind this kinase can serve as initial backbone for development of new potent and selective ZmSIRK1 antagonists.


The microbiome and innate immunity.
The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.


MRI findings in thoracic outlet syndrome.
We discuss MRI findings in patients with thoracic outlet syndrome (TOS). A total of 100 neurovascular bundles were evaluated in the interscalene triangle (IS), costoclavicular (CC), and retropectoralis minor (RPM) spaces. To exclude neurogenic abnormality, MRIs of the cervical spine and brachial plexus (BPL) were obtained in neutral. To exclude compression on neurovascular bundles, sagittal T1W images were obtained vertical to the longitudinal axis of BPL from spinal cord to the medial part of the humerus, in abduction and neutral. To exclude vascular TOS, MR angiography (MRA) and venography (MRV) of the subclavian artery (SA) and vein (SV) in abduction were obtained. If there is compression on the vessels, MRA and MRV of the subclavian vessels were repeated in neutral. Seventy-one neurovascular bundles were found to be abnormal: 16 arterial-venous-neurogenic, 20 neurogenic, 1 arterial, 15 venous, 8 arterial-venous, 3 arterial-neurogenic, and 8 venous-neurogenic TOS. Overall, neurogenic TOS was noted in 69%, venous TOS in 66%, and arterial TOS in 39%. The neurovascular bundle was most commonly compressed in the CC, mostly secondary to position, and very rarely compressed in the RPM. The cause of TOS was congenital bone variations in 36%, congenital fibromuscular anomalies in 11%, and position in 53%. In 5%, there was unilateral brachial plexitis in addition to compression of the neurovascular bundle. Severe cervical spondylosis was noted in 14%, contributing to TOS symptoms. For evaluation of patients with TOS, visualization of the brachial plexus and cervical spine and dynamic evaluation of neurovascular bundles in the cervicothoracobrachial region are mandatory.


Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.
Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.


Middle meningeal artery pseudoaneurysm and pterygoid plexus fistula following percutaneous radiofrequency rhizotomy: illustrative case.
Percutaneous treatment for trigeminal neuralgia is a safe and effective therapeutic methodology and can be accomplished in the form of balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation. These procedures are generally well tolerated and demonstrate minimal associated morbidity. Moreover, vascular complications of these procedures are exceedingly rare. We present the case of a 64-year-old female with prior microvascular decompression and balloon rhizotomy who presented after symptom recurrence and underwent a second balloon rhizotomy at our institution. Soon thereafter, she presented with pulsatile tinnitus and a right preauricular bruit on physical examination. Subsequent imaging revealed a middle meningeal artery (MMA) to pterygoid plexus fistula and an MMA pseudoaneurysm. Coil and Onxy embolization were used to manage the pseudoaneurysm and fistula. This case illustrates the potential for MMA pseudoaneurysm formation as a complication of percutaneous trigeminal balloon rhizotomy, which has not been seen in the literature. Concurrent MMA-pterygoid plexus fistula is also a rarity demonstrated in this case.


Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell-Mediated Sodium Iodide Symporter (NIS) Gene 131I Therapy.
The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter (NIS) transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of NIS-expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT. We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic NIS transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using 123I-scintigraphy followed by 131I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7). Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored in vivo by 123I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated 131I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications. MSC-based NIS-mediated 131I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive NIS expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based NIS expression within the tumor milieu.


Pharmacological screening of Coriandrum sativum Linn. for hepatoprotective activity.
Coriandrum sativum (Linn.), a glabrous, aromatic, herbaceous annual plant, is well known for its use in jaundice. Essential oil, flavonoids, fatty acids, and sterols have been isolated from different parts of C. sativum. The plant has a very effective antioxidant profile showing 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, lipoxygenase inhibition, phospholipid peroxidation inhibition, iron chelating activity, hydroxyl radical scavenging activity, superoxide dismutation, glutathione reduction and antilipid peroxidation due to its high total phenolic content with the presence of constituents like pyrogallol, caffeic acid, glycitin, etc. This study was aimed at investigating the hepatoprotective activity of C. sativum against carbon tetrachloride (CCl4), with estimation of serum serum glutamyl oxaloacetic acid transaminase (SGOT), serum glutamyl pyruvate transaminase (SGPT), alkaine phosphatase (ALP) and bilirubin, and with liver histopathology. Ethanolic extract was found to be rich in alkaloids, phenolic compounds and flavonoids, and high performance liquid chromatography (HPLC) fingerprinting showed the presence of iso-quercetin and quercetin. C. sativum signifies hepatoprotection by reducing the liver weight, activities of SGOT, SGPT, and ALP, and direct bilirubin of CCl(4) intoxicated animals. Administration of C. sativum extract at 300 mg/kg dose resulted in disappearance of fatty deposit, ballooning degeneration and necrosis, indicating antihepatotoxic activity. The results of this study have led to the conclusion that ethanolic extract of C. sativum possesses hepatoprotective activity which may be due to the antioxidant potential of phenolic compounds.


A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy.
To evaluate the efficacy and safety of weekly paclitaxel (Taxol(®)) in patients with advanced or recurrent esophageal cancer. Fifty-three patients with recurrent or advanced esophageal cancer who had previously received platinum-based chemotherapy were treated with paclitaxel 100 mg/m(2) once weekly by 1-h infusion on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Fifty-two patients were evaluable for efficacy and 53 for safety. Forty-one (77%) patients had recurrent, and 12 (23%) had advanced disease. Most patients (52/53) had squamous cell carcinoma, and one had adenocarcinoma. A median of 2 cycles was delivered (range 1-8). The overall response rate was 44.2% (23/52; 95% confidence interval (CI) 30.5, 58.7%), with 4 patients (7.7%) achieving complete response. The median duration of response was 4.8 months, and median overall survival was 10.4 months. The most common Grade 3 or 4 adverse events were neutropenia (52.8%), leukopenia (45.3%), anorexia (9.4%), and fatigue (9.4%). Adverse events resulted in treatment discontinuation in 34.0% of patients and dose reductions in 43.4%. There were no treatment-related deaths. Weekly paclitaxel demonstrated efficacy and manageable toxicity in patients with advanced or recurrent esophageal cancer and may be a treatment option for this population.


Plasma gelsolin modulates cellular response to sphingosine 1-phosphate.
Hypogelsolinemia is observed in patients with different states of acute or chronic inflammation such as sepsis, rheumatoid arthritis, and multiple sclerosis. In animal models of sepsis, repletion of plasma gelsolin reduces septic mortality. However, the functions of extracellular gelsolin and the mechanisms leading to its protective nature are poorly understood. Potential mechanisms involve gelsolin's extracellular actin scavenging function or its ability to bind bioactive lipids or proinflammatory mediators, which would limit inflammatory responses and prevent tissue damage. Here we report that human plasma gelsolin binds to sphingosine 1-phosphate (S1P), a pleiotropic cellular agonist involved in various immune responses, and to its synthetic structural analog FTY720P (Gilenya). The fluorescence intensity of a rhodamine B-labeled phosphatidylinositol 4,5-bisphosphate binding peptide derived from gelsolin and the optical density of recombinant human plasma gelsolin (rhpGSN) were found to decrease after the addition of S1P or FTY720P. Gelsolin's ability to depolymerize F-actin also decreased progressively with increasing addition of S1P. Transient increases in phosphorylation of extracellular signal-regulated kinase in bovine aortic endothelial cells (BAECs) after S1P treatment were inhibited by rhpGSN. The ability of S1P to increase F-actin content and the elastic modulus of primary astrocytes and BAECs was also prevented by rhpGSN. Evaluation of S1P and gelsolin levels in cerebrospinal fluid reveals a low concentration of gelsolin and a high concentration of S1P in samples obtained from patients suffering from lymphatic meningitis. These findings suggest that gelsolin-mediated regulation of S1P bioactivity may be important to maintain immunomodulatory balance at inflammatory sites.


Efficiency of light harvesting in a photosynthetic bacterium adapted to different levels of light.
In this study, we use the photosynthetic purple bacterium Rhodobacter sphaeroides to find out how the acclimation of photosynthetic apparatus to growth conditions influences the rates of energy migration toward the reaction center traps and the efficiency of charge separation at the reaction centers. To answer these questions we measured the spectral and picosecond kinetic fluorescence responses as a function of excitation intensity in membranes prepared from cells grown under different illumination conditions. A kinetic model analysis yielded the microscopic rate constants that characterize the energy transfer and trapping inside the photosynthetic unit as well as the dependence of exciton trapping efficiency on the ratio of the peripheral LH2 and core LH1 antenna complexes, and on the wavelength of the excitation light. A high quantum efficiency of trapping over 80% was observed in most cases, which decreased toward shorter excitation wavelengths within the near infrared absorption band. At a fixed excitation wavelength the efficiency declines with the LH2/LH1 ratio. From the perspective of the ecological habitat of the bacteria the higher population of peripheral antenna facilitates growth under dim light even though the energy trapping is slower in low light adapted membranes. The similar values for the trapping efficiencies in all samples imply a robust photosynthetic apparatus that functions effectively at a variety of light intensities.


Evolution and development of a central pattern generator for the swimming of a lamprey.
This article describes the design of neural control architectures for locomotion using an evolutionary approach. Inspired by the central pattern generators found in animals, we develop neural controllers that can produce the patterns of oscillations necessary for the swimming of a simulated lamprey. This work is inspired by Ekeberg's neuronal and mechanical model of a lamprey [11] and follows experiments in which swimming controllers were evolved using a simple encoding scheme [25, 26]. Here, controllers are developed using an evolutionary algorithm based on the SGOCE encoding [31, 32] in which a genetic programming approach is used to evolve developmental programs that encode the growing of a dynamical neural network. The developmental programs determine how neurons located on a two-dimensional substrate produce new cells through cellular division and how they form efferent or afferent interconnections. Swimming controllers are generated when the growing networks eventually create connections to the muscles located on both sides of the rectangular substrate. These muscles are part of a two-dimensional mechanical simulation of the body of the lamprey in interaction with water. The motivation of this article is to develop a method for the design of control mechanisms for animal-like locomotion. Such a locomotion is characterized by a large number of actuators, a rhythmic activity, and the fact that efficient motion is only obtained when the actuators are well coordinated. The task of the control mechanism is therefore to transform commands concerning the speed and direction of motion into the signals sent to the multiple actuators. We define a fitness function, based on several simulations of the controller with different commands settings, that rewards the capacity of modulating the speed and the direction of swimming in response to simple, varying input signals. Central pattern generators are thus evolved capable of producing the relatively complex patterns of oscillations necessary for swimming. The best solutions generate traveling waves of neural activity, and propagate, similarly to the swimming of a real lamprey, undulations of the body from head to tail propelling the lamprey forward through water. By simply varying the amplitude of two input signals, the speed and the direction of swimming can be modulated.


Evaluation of NeuroPage as a memory aid for people with multiple sclerosis: A randomised controlled trial.
Memory problems are reported in 40%-60% of people with multiple sclerosis (MS). These problems affect independence and may limit the ability to benefit from rehabilitation. Our aim was to evaluate the effectiveness of NeuroPage for people with MS living in the community. A multicentre, single-blind, randomised controlled crossover trial was conducted. The intervention comprised the NeuroPage service, which sends reminder messages to mobile phones at pre-arranged times. In the control condition participants received "non-memory texts", that is, messages not aimed at providing a reminder; for example, supplying news headlines or sport updates. Outcome measures were completed using postal questionnaires after each condition. There were 38 participants aged 28 to 72 (mean 48, SD 11) and 10 (26%) were men. There were no significant differences between NeuroPage and control conditions on the Everyday Memory Questionnaire (p = 0.41, d = 0.02). The number of daily diary items forgotten in the NeuroPage condition was significantly less than in the control (9% vs. 31%, p = 0.01, d = -0.64). Psychological distress was less in the NeuroPage condition than control (p = 0.001, d = -0.84). Further evaluation of the effect on everyday memory is required.


Zika epidemic and microcephaly in Brazil: Challenges for access to health care and promotion in three epidemic areas.
Since 2015 Brazil has experienced the social repercussions of the Zika virus epidemic, thus raising a debate about: difficulties of diagnosis; healthcare access for children with Zika Congenital Syndrome (ZCS); the search for benefits by affected families; social and gender inequalities; and a discussion on reproductive rights, among others. The objective of this article is to analyse access to specialized health services for the care of children born with ZCS in three North-eastern states of Brazil. This is an exploratory cross-sectional study which analyses recorded cases of microcephaly at the municipal level between 2015 and 2017. Most of the cases of ZCS were concentrated on the Northeast coast. Rio Grande do Norte and Paraiba had the highest incidence of microcephaly in the study period. The states of Bahia, Paraiba and Rio Grande do Norte were selected for their high incidence of microcephaly due to the Zika Virus. Socio-territorial vulnerability was stratified using access to microcephaly diagnosis and treatment indicators. The specialized care network was mapped according to State Health Secretaries Protocols. A threshold radius of 100 km was stablished as the maximum distance from municipalities centroids to specialised health care for children with microcephaly. Prenatal coverage was satisfactory in most of the study area, although availability of ultrasound equipment was uneven within states and health regions. Western Bahia had the lowest coverage of ultrasound equipment and lacked health rehabilitation services. ZCS's specialized health services were spread out over large areas, some of which were outside the affected patients' home municipalities, so displacements were expensive and very time consuming, representing an extra burden for the affected families. This study is the first to address accessibility of children with microcephaly to specialised health care services and points to the urgent need to expand coverage of these services in Brazil, especially in the northeastern states, which are most affected by the epidemic.


Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes.
Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without malignancy were analyzed by immunoaffinity enrichment of A2M protein complexes and MS identification of associated proteins. Known A2M substrates were reproducibly identified from patient serum in both cohorts, as well as proteins previously undetected in human serum. One example is heat shock protein 90 alpha (HSP90α), which was identified only in the serum of cancer patients in this study. Using an ELISA, the presence of HSP90α in human serum was validated on expanded test cohorts and found to exist in higher median serum concentrations in prostate cancer (n = 18) relative to control (n = 13) patients (median concentrations 50.7 versus 27.6 ng/mL, respectively, p = 0.001). Our results demonstrate the technical feasibility of this approach and support the analysis of A2M protein complexes for proteomic-based serum biomarker discovery.


Air pollution and detrimental effects on children's brain. The need for a multidisciplinary approach to the issue complexity and challenges.
Millions of children in polluted cities are showing brain detrimental effects. Urban children exhibit brain structural and volumetric abnormalities, systemic inflammation, olfactory, auditory, vestibular and cognitive deficits v low-pollution controls. Neuroinflammation and blood-brain-barrier (BBB) breakdown target the olfactory bulb, prefrontal cortex and brainstem, but are diffusely present throughout the brain. Urban adolescent Apolipoprotein E4 carriers significantly accelerate Alzheimer pathology. Neurocognitive effects of air pollution are substantial, apparent across all populations, and potentially clinically relevant as early evidence of evolving neurodegenerative changes. The diffuse nature of the neuroinflammation and neurodegeneration forces to employ a weight of evidence approach incorporating current clinical, cognitive, neurophysiological, radiological and epidemiological research. Pediatric air pollution research requires extensive multidisciplinary collaborations to accomplish a critical goal: to protect exposed children through multidimensional interventions having both broad impact and reach. Protecting children and teens from neural effects of air pollution should be of pressing importance for public health.


Towards a metallurgy of neutron star crusts.
In the standard picture of the crust of a neutron star, matter there is simple: a body-centered-cubic lattice of nuclei immersed in an essentially uniform electron gas. We show that, at densities above that for neutron drip (∼ 4 × 1 0(11) g cm(-3) or roughly one-thousandth of nuclear matter density), the interstitial neutrons give rise to an attractive interaction between nuclei that renders the lattice unstable. We argue that the likely equilibrium structure is similar to that in displacive ferroelectric materials such as BaTiO3. As a consequence, the properties of matter in the inner crust are expected to be much richer than previously appreciated, and we mention possible consequences for observable neutron star properties.


The synthesis of polysubstituted indoles from 3-bromo-2-indolyl phosphates.
A novel methodology for the synthesis of functionalised indoles based on the cross-coupling reactions of 3-bromo-2-indolyl phosphates is described. The preparation involves the conversion of easily available 2-oxindoles to 3,3-dibromo-2-oxindoles followed by the Perkow reaction affording 3-bromo-2-indolyl phosphates. Then bromine atom is substituted regioselectively by the Suzuki coupling reaction. We observed that aluminum chloride promoted the reaction of 3-substituted-2-indolyl phosphates with organozinc reagents furnishing 2,3-disubstituted indoles as final products. The overall diversity and efficiency of the methodology was demonstrated by the synthesis of bioactive molecule from easily available substances.