Baseline GABA concentration and fMRI response.
Coordination between glutamatergic excitatory neurons and gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons is fundamental to the regulation of neuronal firing rates and is believed to have relevance to functional magnetic resonance imaging (fMRI) contrast. While much is known regarding the molecular behavior of excitatory and inhibitory processes, comparatively less is known regarding the role of such processes in explaining variations in fMRI and related hemodynamic imaging metrics. The relationship between baseline GABA levels, as measured by MR spectroscopy, and hemodynamic contrasts from four sequences in human visual cortex are investigated (n=12; field strength=3.0 T): blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF)-weighted arterial spin labelling (ASL), cerebral blood volume (CBV)-weighted vascular-space-occupancy (VASO), and arterial CBV (aCBV)-weighted inflow VASO (iVASO). Results indicate that baseline GABA levels (GABA+ macromolecules normalized to creatine) inversely correlate with BOLD reactivity (R=-0.70; P=0.01) and magnitude CBV-weighted VASO reactivity (R=-0.71; P=0.01). A trend for significance was found between baseline aCBV-weighted iVASO (R=-0.50; P=0.10) and baseline GABA. A positive correlation was found between baseline CBF-weighted ASL signal and GABA (R=0.65; P=0.02) and ASL time-to-peak and baseline GABA (R=0.58; P=0.05). These findings demonstrate that both the dominant BOLD fMRI contrast, as well as other emerging MR hemodynamic contrasts, have signal variations that are linked to baseline GABA levels.


Targeted interventions for patellofemoral pain syndrome (TIPPS): classification of clinical subgroups.
Patellofemoral pain (PFP) can cause significant pain leading to limitations in societal participation and physical activity. An international expert group has highlighted the need for a classification system to allow targeted intervention for patients with PFP; we have developed a work programme systematically investigating this. We have proposed six potential subgroups: hip abductor weakness, quadriceps weakness, patellar hypermobility, patellar hypomobility, pronated foot posture and lower limb biarticular muscle tightness. We could not uncover any evidence of the relative frequency with which patients with PFP fell into these subgroups or whether these subgroups were mutually exclusive. The aim of this study is to provide information on the clinical utility of our classification system. 150 participants will be recruited over 18 months in four National Health Services (NHS) physiotherapy departments in England. adults 18-40 years with PFP for longer than 3 months, PFP in at least two predesignated functional activities and PFP elicited by clinical examination. prior or forthcoming lower limb surgery; comorbid illness or health condition; and lower limb training or pregnancy. We will record medical history, demographic details, pain, quality of life, psychomotor movement awareness and knee temperature. We will assess hip abductor and quadriceps weakness, patellar hypermobility and hypomobility, foot posture and lower limb biarticular muscle tightness. The primary analytic approach will be descriptive. We shall present numbers and percentages of participants who meet the criteria for membership of (1) each of the subgroups, (2) none of the subgroups and (3) multiple subgroups. Exact (binomial) 95% CIs for these percentages will also be presented. This study has been approved by National Research Ethics Service (NRES) Committee North West-Greater Manchester North (11/NW/0814) and University of Central Lancashire (UCLan) Built, Sport, Health (BuSH) Ethics Committee (BuSH 025). An abstract has been accepted for the third International Patellofemoral Pain Research Retreat, Vancouver, September 2013.


72-hour discharge after cesarean delivery: results in a selected Medicaid population.
The purpose of this study was to determine the safety and cost savings of discharging low income patients at 72 hours following cesarean delivery. Predetermined criteria were used to allow discharge. Selection criteria were no medical problems, an afebrile postoperative course, documented bowel function, to have tolerated at least one regular meal, and to have reached 72 hours postdelivery by 6 o'clock PM at discharge. Each patient returned to clinic 2-3 days postdischarge for staple removal. Physicians also discharged some low income patients home at 72 hours even though strict eligibility criteria were not met. Maternal outcome and financial data were compared between patients discharged after meeting eligibility criteria versus those who did not. Of 1,299 cesareans performed from July 1, 1993-July 31, 1995, 906 (70%) were performed in low income patients and 399 (44%) of these women were discharged at 72 hours. Twenty-seven women were lost to follow-up and 286 (77%; Group A) met the eligibility criteria for 72-hour discharge. Eighty-six women (23%; Group B) who did not meet criteria were also discharged at 72 hours. When maternal outcome data from the two groups were compared, Group B patients (did not meet criteria) were more likely to have been readmitted at < or = 30 days (7 of 86; 8% vs. 8 of 286; 3%; P = 0.05) and had longer hospital stays (27 days vs. 22 days) than Group A patients (met criteria). Net cost savings in 2 years was $448 per discharge for Group A, but only $333 per discharge for Group B. In our selective 72-hour discharge program, failure to abide by predetermined guidelines established to select only low risk, afebrile patients for 72-hour discharge resulted in more hospital readmissions, and longer stays and thus was not as cost effective.


The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.
Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures.


Stories from Lake Volta: the lived experiences of trafficked children in Ghana.
Child trafficking is one of the worst forms of child maltreatment and is often difficult to recognize when it happens intra-country. This paper presents the narratives of children on their experiences as victims of trafficking in fishing communities along the Volta Lake in the Volta region of Ghana. The narratives were co-constructed with the children through child-friendly participatory approaches which involved drawings, writing, and in-depth interviews. The stories reflect the magnitude of maltreatment trafficked children suffer, which ranges from physical to psychological and emotional. The authors recommend commitment by the government to the implementation of the Human Trafficking Act to deter child traffickers. Further studies on the living conditions of rescued children and the need to implement strategies to prevent re-trafficking are suggested.


Clinical practice guidelines for oral management of Sjögren disease: Dental caries prevention.
Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. Final recommendations for patients with Sjögren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). The incidence of caries in patients with Sjögren disease can be reduced with the use of topical fluoride and other preventive strategies.


Hypoactive sexual desire disorder in menopausal women: a survey of Western European women.
The prevalence of hypoactive sexual desire disorder (HSDD) in menopausal women and the frequency of sexual activity, sexual behavior, and relationship or sexual satisfaction associated with HSDD have not been studied using validated instruments to identify women with HSDD. To determine: (i) the prevalence of HSDD among women who have undergone hysterectomy and bilateral oophorectomy (surgical menopause) with that of premenopausal or naturally menopausal women; (ii) the relationship between low sexual desire and sexual activity and behavior; and (iii) the relationship between low sexual desire and sexual or partner relationship satisfaction. Cross-sectional survey of 2,467 European women aged 20-70 years, resident in France, Germany, Italy, and the United Kingdom. Measures were the Profile of Female Sexual Function (PFSF), Personal Distress Scale (PDS), and a sexual activities measure. Clinically derived cutoff scores for the desire domain of the PFSF and the PDS were used, sequentially, to classify women as having low sexual desire and to further classify these women with low desire as distressed or nondistressed. Thus, women with HSDD had low sexual desire and were distressed by their low desire. The analysis population included 1,356 women who had current sexual partners and were surgically menopausal, regularly menstruating, or naturally postmenopausal. A greater proportion of surgically menopausal women had low sexual desire compared with premenopausal or naturally menopausal women (odds ratio [OR] = 1.4; confidence interval [CI] = 1.1, 1.9; P = 0.02). Surgically menopausal women were more likely to have HSDD than premenopausal or naturally menopausal women (OR = 2.1; CI = 1.4, 3.4; P = 0.001). Sexual desire scores and sexual arousal, orgasm, and sexual pleasure were highly correlated (P < 0.001), demonstrating that low sexual desire is frequently associated with decreased functioning in other aspects of sexual response. Women with low sexual desire were less likely to engage in sexual activity and more likely to be dissatisfied with their sex life and partner relationship than women with normal desire (P < 0.001). Surgically menopausal women are at increased risk for HSDD. HSDD is associated with diminished sexual and partner relationship satisfaction and negative emotional states.


Cruising on the Internet highway.
This study evaluated differences in sexual behavior and risk for sexually transmitted diseases (STDs) among men who have sex with men (MSM) who met their partners on-line and those who did not. A self-administered questionnaire on sexual behavior was offered to a convenience sample of patients seeking public STD services. Thirty-two percent of MSM patients reported meeting a sexual partner over the Internet in the past year. MSM with on-line partners were younger, more likely to report sex with an HIV-positive person in the last year, and more likely to report casual partners in the last year compared with MSM with only off-line partners. HIV-negative MSM with on-line partners were more likely than HIV-negative MSM with only off-line partners to have received money or drugs for sex in the past year and to report sex with an HIV-positive partner in the past year. Although meeting partners on the Internet was common and associated with increased risk for STDs in MSM, it also presents new untapped opportunities for on-line health promotion and disease prevention.


Strong contributors to network persistence are the most vulnerable to extinction.
The architecture of mutualistic networks facilitates coexistence of individual participants by minimizing competition relative to facilitation. However, it is not known whether this benefit is received by each participant node in proportion to its overall contribution to network persistence. This issue is critical to understanding the trade-offs faced by individual nodes in a network. We address this question by applying a suite of structural and dynamic methods to an ensemble of flowering plant/insect pollinator networks. Here we report two main results. First, nodes contribute heterogeneously to the overall nested architecture of the network. From simulations, we confirm that the removal of a strong contributor tends to decrease overall network persistence more than the removal of a weak contributor. Second, strong contributors to collective persistence do not gain individual survival benefits but are in fact the nodes most vulnerable to extinction. We explore the generality of these results to other cooperative networks by analysing a 15-year time series of the interactions between designer and contractor firms in the New York City garment industry. As with the ecological networks, a firm's survival probability decreases as its individual nestedness contribution increases. Our results, therefore, introduce a new paradox into the study of the persistence of cooperative networks, and potentially address questions about the impact of invasive species in ecological systems and new competitors in economic systems.


Investigating the role for adaptation of the microbial community to transform trace organic chemicals during managed aquifer recharge.
This study was undertaken to investigate whether adaptation by pre-exposure to trace organic chemicals (TOrCs) was necessary for microbial transformation during managed aquifer recharge (MAR). Two pairs of laboratory-scale soil columns, each receiving a different primary substrate, were utilized to simulate the dominant bulk organic carbon present in MAR systems receiving wastewater effluent of varying quality and having undergone different degrees of pre-treatment, as well as organic carbon prevalent at different stages of subsurface travel. Each pair of columns consisted of duplicate set-ups receiving the same feed solution with only one pre-exposed to a suite of eight TOrCs for approximately ten months. Following the pre-exposure period, a spiking experiment was conducted in which the non-exposed columns also received the same suite of TOrCs. TOrC attenuation was quantified for the pre- and non-exposed columns of each pair during the spiking experiment. The microbial community structure and function of these systems were characterized by pyrosequencing of 16S rRNA gene and metagenomics, respectively. Biotransformation rather than sorption was identified as the dominant removal mechanism for almost all the TOrCs (except triclocarban). Similar removal efficiencies were observed between pre-exposed and non-exposed columns for most TOrCs. No obvious differences in microbial community structure were revealed between pre- and non-exposed columns. Using metagenomics, biotransformation capacity potentials of the microbial community present were also similar between pre- and non-exposed columns of each pair. Overall, the pre-exposure of MAR systems to TOrCs at ng/L levels did not affect their attenuation and had no obvious influence on the resulting microbial community structure and function. Thus, other factors such as bioavailability of the primary substrate play a greater role regarding biotransformation of TOrCs. These results indicate that MAR systems adapted to a primary substrate are capable of degrading TOrC without necessarily being pre-exposed to them, making MAR a robust treatment barrier for biodegradable TOrCs.


Internet Addiction Through the Phase of Adolescence: A Questionnaire Study.
Adolescents increasingly use the Internet for communication, education, entertainment, and other purposes in varying degrees. Given their vulnerable age, they may be prone to Internet addiction. Our aim was to identify possible differences in the purpose of Internet use among adolescents with respect to age subgroup, country of residence, and gender and the distribution of Internet addiction across age subgroups. Another aim was to determine if there is a correlation between the purpose of Internet use and age and if this interaction influences the level of addiction to the Internet. The study included a simple random sample of 1078 adolescents-534 boys and 525 girls-aged 11-18 years attending elementary and grammar schools in Croatia, Finland, and Poland. Adolescents were asked to complete an anonymous questionnaire and provide data on age, gender, country of residence, and purpose of Internet use (ie, school/work or entertainment). Collected data were analyzed with the chi-square test for correlations. Adolescents mostly used the Internet for entertainment (905/1078, 84.00%). More female than male adolescents used it for school/work (105/525, 20.0% vs 64/534, 12.0%, respectively). Internet for the purpose of school/work was mostly used by Polish adolescents (71/296, 24.0%), followed by Croatian (78/486, 16.0%) and Finnish (24/296, 8.0%) adolescents. The level of Internet addiction was the highest among the 15-16-year-old age subgroup and was lowest in the 11-12-year-old age subgroup. There was a weak but positive correlation between Internet addiction and age subgroup (P=.004). Male adolescents mostly contributed to the correlation between the age subgroup and level of addiction to the Internet (P=.001). Adolescents aged 15-16 years, especially male adolescents, are the most prone to the development of Internet addiction, whereas adolescents aged 11-12 years show the lowest level of Internet addiction.


17O NMR and computational study of a tetrasiliconiobate ion, [H(2+x)Si4Nb16O56](14-x)-.
Rates of oxygen-isotope exchange were measured in the tetrasiliconiobate ion [H(2+x)Si(4)Nb(16)O(56)]((14-x)-) to better understand how large oxide ions interact with water. The molecule has 19 nonequivalent oxygen sites and is sufficiently complex to evaluate hypotheses derived from our previous work on smaller clusters. We want to examine the extent to which individual oxygen atoms react independently with particular attention given to the order of protonation of the various oxygen sites as the pH decreases from 13 to 6. As in our previous work, we find that the set of oxygen sites reacts at rates that vary over approximately 10(4) across the molecule at 6<pH<13 but with similar pH dependencies. There is NMR evidence of an intra- or intermolecular reaction at pH∼7, where new peaks began to slowly form without losing the (17)O isotopic tag, and at pH ≤ 6 these new peaks formed rapidly. The oxygen atoms bonded to silicon atoms began to isotopically exchange at pH 9 and below. The (17)O NMR peak positions also vary considerably with pH for some, but not all, nonequivalent oxygen sites. This variation could be only partly accounted by electronic calculations, which indicate that oxygen atoms should shift similarly upon protonation. Instead, we see that some sites change enormously with pH, whereas other, similarly coordinated oxygen atoms are less affected, suggesting that either some protons are exchanging so rapidly that the oxygen sites are seeing an averaged charge, or that counterions are modulating the effect of the coordinated protons.


Superaerophilic copper nanowires for efficient and switchable CO2 electroreduction.
Copper is one of the most efficient electrocatalysts for switchable carbon dioxide conversion, but the design of an advanced Cu-based catalyst with high selectivity while suppressing hydrogen evolution remains a great challenge. Herein, we use Cu nanowires (Cu NWs) as the starting materials and polytetrafluoroethylene (PTFE) as the surface modifier to make a superaerophilic electrode using a wettability control strategy. This strategy allows tuning of the selectivity of the CO2 reduction reaction (CO2RR) and a decrease of the hydrogen evolution rate simultaneously by facilitating the supply of CO2 reactants and inhibiting the adsorption of water (protons). The transferring point from a pinning to bursting state turned out to be the optimized condition leading to the highest CO2RR faradaic efficiency without significant interference of current density. The optimized superaerophilic Cu NW catalyst showed CO-selectivity with a Faraday efficiency of 71% at -0.4 V vs. RHE and HCOOH-selectivity with a Faraday efficiency of 68% at -0.6 V vs. RHE. Moreover, the accelerated gas and ion diffusion and homogenized reactions also avoided accumulative damage on the surface of the Cu NWs and enhanced the stability of the Cu catalyst. This wettability tuning strategy provides a facile and efficient way to optimize the gas and ion diffusion layers, therefore promoting the performance of the CO2RR. This strategy potentially can be extended to the design of other gas consumption electrocatalysts.


Differential regulation of C5a receptor 1 in innate immune cells during the allergic asthma effector phase.
C5a drives airway constriction and inflammation during the effector phase of allergic asthma, mainly through the activation of C5a receptor 1 (C5aR1). Yet, C5aR1 expression on myeloid and lymphoid cells during the allergic effector phase is ill-defined. Recently, we generated and characterized a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we used this reporter strain to monitor C5aR1 expression in airway, pulmonary and lymph node cells during the effector phase of OVA-driven allergic asthma. C5aR1 reporter and wildtype mice developed a similar allergic phenotype with comparable airway resistance, mucus production, eosinophilic/neutrophilic airway inflammation and Th2/Th17 cytokine production. During the allergic effector phase, C5aR1 expression increased in lung tissue eosinophils but decreased in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs). Surprisingly, expression in neutrophils was not affected. Of note, moDCs but not CD11b+ cDCs from mediastinal lymph nodes (mLN) expressed less C5aR1 than DCs residing in the lung after OVA challenge. Finally, neither CD103+ cDCs nor cells of the lymphoid lineage such as Th2 or Th17-differentiated CD4+ T cells, B cells or type 2 innate lymphoid cells (ILC2) expressed C5aR1 under allergic conditions. Our findings demonstrate a complex regulation pattern of C5aR1 in the airways, lung tissue and mLN of mice, suggesting that the C5a/C5aR1 axis controls airway constriction and inflammation through activation of myeloid cells in all three compartments in an experimental model of allergic asthma.


Blockade of nitric oxide overproduction and oxidative stress by Nigella sativa oil attenuates morphine-induced tolerance and dependence in mice.
The effects of Nigella sativa oil on morphine-induced tolerance and dependence in mice and possible mechanism(s) of these effects were investigated, for the first time, in this study. Repeated administration of Nigella sativa oil (4 ml/kg, p.o.) along with morphine (5 mg/kg, s.c.) attenuated the development of tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone (5 mg/kg, i.p.)-precipitated withdrawal manifestations. Concomitantly, nitric oxide overproduction and increase in brain malondialdehyde level induced by repeated administration of morphine to mice or by administration of naloxone to morphine-dependent mice were inhibited by co-administration of the oil. Also, the decrease in brain intracellular reduced glutathione level and glutathione peroxidase activity induced by both treatments were inhibited by co-administration of the oil. The increase in brain glutamate level induced by both treatments was not inhibited by concurrent administration of the oil. The inhibitory effect of the oil on morphine-induced tolerance and dependence and on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine (0.25 mg/kg). Similarly, concurrent i.p. administration of the NO synthase inhibitors; L-N (G)-nitroarginine methyl ester (10 mg/kg), aminoguanidine (20 mg/kg) and 7-nitroindazole (25 mg/kg) or the antioxidant, N-acetylcysteine (50 mg/kg) enhanced this inhibitory effect of the oil. On the other hand, this effect was antagonized by concurrent i.p. administration of the nitric oxide precursor, L-arginine (300 mg/kg). These results provide evidence that Nigella sativa oil, through inhibition of morphine-induced NO overproduction and oxidative stress, appears to have a therapeutic potential in opioid tolerance and dependence.


Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain.
Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system. Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency. Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5. Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.


Chemotactic role of neurotropin 3 in the embryonic testis that facilitates male sex determination.
The first morphological event after initiation of male sex determination is seminiferous cord formation in the embryonic testis. Cord formation requires migration of pre-peritubular myoid cells from the adjacent mesonephros. The embryonic Sertoli cells are the first testicular cells to differentiate and have been shown to express neurotropin-3 (NT3), which can act on high-affinity trkC receptors expressed on migrating mesonephros cells. NT3 expression is elevated in the embryonic testis during the time of seminiferous cord formation. A trkC receptor tyrophostin inhibitor, AG879, was found to inhibit seminiferous cord formation and mesonephros cell migration. Beads containing NT3 were found to directly promote mesonephros cell migration into the gonad. Beads containing other growth factors such as epidermal growth factor (EGF) did not influence cell migration. At male sex determination the SRY gene promotes testis development and the expression of downstream sex differentiation genes such as SOX-9. Inhibition of NT3 actions caused a reduction in the expression of SOX-9. Combined observations suggest that when male sex determination is initiated, the developing Sertoli cells express NT3 as a chemotactic agent for migrating mesonephros cells, which are essential to promote embryonic testis cord formation and influence downstream male sex differentiation.


Universal Dermal Microbiome in Human Skin.
Human skin microbiota has been described as a "microbial fingerprint" due to observed differences between individuals. Current understanding of the cutaneous microbiota is based on sampling the outermost layers of the epidermis, while the microbiota in the remaining skin layers has not yet been fully characterized. Environmental conditions can vary drastically between the cutaneous compartments and give rise to unique communities. We demonstrate that the dermal microbiota is surprisingly similar among individuals and contains a specific subset of the epidermal microbiota. Variability in bacterial community composition decreased significantly from the epidermal to the dermal compartment but was similar among anatomic locations (hip and knee). The composition of the epidermal microbiota was more strongly affected by environmental factors than that of the dermal community. These results indicate a well-conserved dermal community that is functionally distinct from the epidermal community, challenging the current dogma. Future studies in cutaneous disorders and chronic infections may benefit by focusing on the dermal microbiota as a persistent microbial community.IMPORTANCE Human skin microbiota is thought to be unique according to the individual's lifestyle and genetic predisposition. This is true for the epidermal microbiota, while our findings demonstrate that the dermal microbiota is universal between healthy individuals. The preserved dermal microbial community is compositionally unique and functionally distinct to the specific environment in the depth of human skin. It is expected to have direct contact with the immune response of the human host, and research in the communication between host and microbiota should be targeted to this cutaneous compartment. This novel insight into specific microbial adaptation can be used advantageously in the research of chronic disorders and infections of the skin. It can enlighten the alteration between health and disease to the benefit of patients suffering from long-lasting socioeconomic illnesses.


Disruption of the blood-brain barrier in 22q11.2 deletion syndrome.
Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.


Bioimpedance monitoring of 3D cell culturing--complementary electrode configurations for enhanced spatial sensitivity.
A bioimpedance platform is presented as a promising tool for non-invasive real-time monitoring of the entire process of three-dimensional (3D) cell culturing in a hydrogel scaffold. In this study, the dynamics involved in the whole process of 3D cell culturing, starting from polymerisation of a bare 3D gelatin scaffold, to human mesenchymal stem cell (MSC) encapsulation and proliferation, was monitored over time. The platform consists of a large rectangular culture chamber with four embedded vertical gold plate electrodes that were exploited in two- and three terminal (2T and 3T) measurement configurations. By switching between the different combinations of electrode couples, it was possible to generate a multiplexing-like approach, which allowed for collecting spatially distributed information within the 3D space. Computational finite element (FE) analysis and electrochemical impedance spectroscopic (EIS) characterisation were used to determine the configurations' sensitivity field localisation. The 2T setup gives insight into the interfacial phenomena at both electrode surfaces and covers the central part of the 3D cell culture volume, while the four 3T modes provide focus on the dynamics at the corners of the 3D culture chamber. By combining a number of electrode configurations, complementary spatially distributed information on a large 3D cell culture can be obtained with maximised sensitivity in the entire 3D space. The experimental results show that cell proliferation can be monitored within the tested biomimetic environment, paving the way to further developments in bioimpedance tracking of 3D cell cultures and tissue engineering.


Predictive models of forest dynamics.
Dynamic global vegetation models (DGVMs) have shown that forest dynamics could dramatically alter the response of the global climate system to increased atmospheric carbon dioxide over the next century. But there is little agreement between different DGVMs, making forest dynamics one of the greatest sources of uncertainty in predicting future climate. DGVM predictions could be strengthened by integrating the ecological realities of biodiversity and height-structured competition for light, facilitated by recent advances in the mathematics of forest modeling, ecological understanding of diverse forest communities, and the availability of forest inventory data.


Nematic liquid crystal dynamics under applied electric fields.
In this paper we investigate the coarsening dynamics of liquid crystal textures in a two-dimensional nematic under applied electric fields, using numerical simulations performed using a publicly available liquid crystal algorithm developed by the authors. We consider both positive and negative dielectric anisotropies and two different possibilities for the orientation of the electric field (parallel and perpendicular to the two-dimensional lattice). We determine the effect of an applied electric field pulse on the evolution of the characteristic length scale and other properties of the liquid crystal texture network. In particular, we show that different types of defects are produced after the electric field is switched on, depending on the orientation of the electric field and the sign of the dielectric anisotropy.


Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders.
The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17-26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular.


Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction.
A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. In the test cohort, CDKN1C was lower in patients with a reduced EF (<40%) compared to patients with preserved EF (≥50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CDKN1C is a novel female-specific biomarker of LV function after AMI.


The effect of a connexin43-based Peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial.
The gap junction protein, connexin43 (Cx43), has critical roles in the inflammatory, edematous, and fibrotic processes following dermal injury and during wound healing, and is abnormally upregulated at the epidermal wound margins of venous leg ulcers (VLUs). Targeting Cx43 with ACT1, a peptide mimetic of the carboxyl-terminus of Cx43, accelerates fibroblast migration and proliferation, and wound reepithelialization. In a prospective, multicenter clinical trial conducted in India, adults with chronic VLUs were randomized to treatment with an ACT1 gel formulation plus conventional standard-of-care (SOC) protocols, involving maintaining wound moisture and four-layer compression bandage therapy, or SOC protocols alone. The primary end point was mean percent ulcer reepithelialization from baseline to 12 weeks. A significantly greater reduction in mean percent ulcer area from baseline to 12 weeks was associated with the incorporation of ACT1 therapy (79% (SD 50.4)) as compared with compression bandage therapy alone (36% (SD 179.8); P=0.02). Evaluation of secondary efficacy end points indicated a reduced median time to 50 and 100% ulcer reepithelialization for ACT1-treated ulcers. Incorporation of ACT1 in SOC protocols may represent a well-tolerated, highly effective therapeutic strategy that expedites chronic venous ulcer healing by treating the underlying ulcer pathophysiology through Cx43-mediated pathways.


Mechanism of action of recombinant acc-royalisin from royal jelly of Asian honeybee against gram-positive bacteria.
The antibacterial activity of royalisin, an antimicrobial peptide from the royal jelly produced by honeybees, has been addressed extensively. However, its mechanism of action remains unclear. In this study, a recombinant royalisin, RAcc-royalisin from the royal jelly of Asian honeybee Apis cerana cerana, was expressed by fusing with glutathione S-transferase (GST) in Escherichia coli BL21, isolated and purified. The agar dilution assays with inhibition zone showed that RAcc-royalisin, similar to nisin, inhibits the growth of Gram-positive bacteria. The antibacterial activity of RAcc-royalisin was associated with its concentration, and was weakened by heat treatment ranging from 55°C to 85°C for 15 min. Both RAcc-royalisin and nisin exhibited the minimum inhibitory concentrations (MIC) of 62.5 µg/ml, 125 µg/ml, and 250 µg/ml against Gram-positive bacterial strains, Bacillus subtilis and Micrococcus flavus and Staphyloccocus aureus in the microplate assay, respectively. However, RAcc-royalisin did not show antimicrobial activity against tested Gram-negative bacterial and fungal strains. The antibacterial activity of RAcc-royalisin agrees well with the decrease in bacterial cell hydrophobicity, the leakage of 260-nm absorbing materials, and the observation by transmission electron microscopy, all indicating that RAcc-royalisin induced the disruption and dysfunction of cell walls and membranes. This is the first report detailing the antibacterial mechanism of royalisin against Gram-positive bacteria, and provides insight into the application of recombinant royalisin in food and pharmaceutical industries as an antimicrobial agent.


Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation.
The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC). A retrospective longitudinal chart review was performed, selecting patients who received multiple neuropsychological assessments. Intellectual/Developmental Quotients, Adaptive Behavior Composite scores, and clinical data were collected. On available EEGs, interictal epileptiform discharges were counted. Sixty-six (18%) patients with TSC received multiple cognitive and adaptive development assessments. The mean intelligence of this study group remained relatively stable, albeit variable. Significant decline in adaptive functioning was observed, associated with lower age at seizure onset. Patients who underwent neurosurgery prior to baseline testing showed cognitive improvement. Developmental declines were significantly associated with increased numbers of antiepileptic drugs, with a trend toward association with mutation type and interictal epileptiform discharges. This study suggests that the developmental course of patients with TSC may be altered by epilepsy comorbidity and neurosurgery, underlining the need for early and effective interventions in this population.


Impact of Ivabradine on Health-Related Quality of Life of Patients with Ischaemic Chronic Heart Failure.
Chronic heart failure (CHF) remains a major health problem, with high levels of morbidity and mortality and a low health-related quality of life (HRQoL). We assessed the impact on HRQoL of adding the If channel blocker, ivabradine, to a standard treatment regimen of patients with ischaemic CHF (I-CHF) and heart rate (HR) ≥70 beats/min (bpm). A randomized prospective study of 100 consecutive patients presenting with stable I-CHF, left ventricular ejection fraction (LVEF) <40% and a sinus HR ≥70 bpm. New York Heart Association (NYHA) class, overall summary score (OSS) and clinical summary score (CSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) were used to assess HRQoL. The patients were randomized into 2 groups: carvedilol only (group I (n=50)) and carvedilol + ivabradine (group II (n=50)). The patients were followed up for 12 weeks and their HRQoL scores were monitored and compared. The overall mean age of the cohort was 63±10 years with 70% (n=70) males. HRQoL scores had significantly improved in group II after 12 weeks of follow-up. The net proportion of patients with a 5-point improvement in CSS was 30% higher in group II (p=0.002), whereas that for the OSS, it was 24% (p=0.001), when compared with group I. These improvements were accompanied by a significant HR reduction (69 vs 78 bpm; p=0.002). Adding ivabradine to the standard drug regimen, currently advocated by guidelines for CHF with a heart rate ≥70 bpm, resulted in a significant improvement in HRQoL.


Proteomic analysis of mammalian sperm cells identifies new components of the centrosome.
Centrioles are evolutionarily conserved microtubule-based structures at the core of the animal centrosome that are essential for nucleating the axoneme of cilia. We hypothesized that centriole proteins have been under-represented in proteomic studies of the centrosome, because of the larger amount of pericentriolar material making up the centrosome. In this study, we have overcome this problem by determining the centriolar proteome of mammalian sperm cells, which have a pair of centrioles but little pericentriolar material. Mass spectrometry of sperm centrioles identifies known components of centrioles and many previously uncharacterized candidate centriole proteins. Assessment of localization of a subset of these candidates in cultured cells identified CCDC113, CCDC96, C4orf47, CCDC38, C7orf31, CCDC146, CCDC81 and CCDC116 as centrosome-associated proteins. We examined the highly conserved protein CCDC113 further and found that it is a component of centriolar satellites, is in a complex with the satellite proteins HAP1 and PCM1, and functions in primary cilium formation.


Optical properties of the mouse eye.
The Shack-Hartmann wavefront sensor (SHWS) spots upon which ocular aberration measurements depend have poor quality in mice due to light reflected from multiple retinal layers. We have designed and implemented a SHWS that can favor light from a specific retinal layer and measured monochromatic aberrations in 20 eyes from 10 anesthetized C57BL/6J mice. Using this instrument, we show that mice are myopic, not hyperopic as is frequently reported. We have also measured longitudinal chromatic aberration (LCA) of the mouse eye and found that it follows predictions of the water-filled schematic mouse eye. Results indicate that the optical quality of the mouse eye assessed by measurement of its aberrations is remarkably good, better for retinal imaging than the human eye. The dilated mouse eye has a much larger numerical aperture (NA) than that of the dilated human eye (0.5 NA vs. 0.2 NA), but it has a similar amount of root mean square (RMS) higher order aberrations compared to the dilated human eye. These measurements predict that adaptive optics based on this method of wavefront sensing will provide improvements in retinal image quality and potentially two times higher lateral resolution than that in the human eye.


The effect of domestication on post-conflict management: wolves reconcile while dogs avoid each other.
Highly cooperative social species are expected to engage in frequent reconciliation following conflicts in order to maintain pack cohesiveness and preserve future cooperation. By contrast, in social species with low reliance on cooperation, reconciliation is expected to be less frequent. Here, we investigate the pattern of reconciliation in four captive wolf packs and four captive dog packs. We provide evidence for reconciliation in captive wolves, which are highly dependent on cooperation between pack members, while domestic dogs, which rely on conspecific cooperation less than wolves, avoided interacting with their partners after conflicts. Occurrence, intensity, latency, duration and initiation of wolf reconciliations appeared to vary as a consequence of a compromise between the costs (e.g. risk of further aggression) and the benefits (e.g. restoring relationship with opponents) of such interactions. Our results are in line with previous findings on various wolf packs living under different social and ecological conditions, suggesting that reconciliation is an important strategy for maintaining functional relationships and pack cohesiveness. However, current results on dogs are in contrast to the only other study showing that reconciliation can occur also in this species. Therefore, the occurrence of reconciliation in dogs may be influenced by social and environmental conditions more than in wolves. Which factors promote and modulate reconciliation in dogs needs to be further investigated.


Distinct combinatorial effects of the plant polyphenols curcumin, carnosic acid, and silibinin on proliferation and apoptosis in acute myeloid leukemia cells.
Acute myeloid leukemia (AML) is a malignancy without effective treatment for most patients. Here we demonstrate that combinations of the dietary plant polyphenols--curcumin and carnosic acid--at noncytotoxic concentrations of each agent, produced a synergistic antiproliferative effect and a massive apoptotic cell death in HL-60 and KG-1a human AML cells. In contrast, combinations of curcumin and another plant polyphenol silibinin had a predominantly additive cytostatic effect, without pronounced cytotoxicity. Neither polyphenol combination affected viability of normal human fibroblasts or proliferating and nonproliferating blood cells. Early stage of curcumin/carnosic acid-induced apoptosis was associated with cleavage (activation) of caspase-8, caspase-9, and caspase-3 and the proapoptotic protein Bid, but not with oxidative stress or altered levels of other Bcl-2 family proteins (Bcl-2, Bcl-xl, Mcl-1, Bax, and Bak). Inhibitors of caspase-8 and caspase-9 markedly attenuated apoptosis, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by curcumin + carnosic acid. Collectively, these results suggest a mechanistic basis for the potential use of dietary plant polyphenol combinations in the treatment and prevention of AML.


Pollinators underestimated: a molecular phylogeny reveals widespread floral convergence in oil-secreting orchids (sub-tribe Coryciinae) of the Cape of South Africa.
The oil-secreting orchids of southern Africa belong to the sub-tribe Coryciinae within Diseae. A phylogeny of Diseae is inferred using sequence data from all genera in the tribe, with an emphasis on resolving generic classifications within Coryciinae. Nuclear (ITS) and plastid (trnLF and matK) gene region sequences were analysed for 79 ingroup taxa and three outgroup taxa. Coryciinae is confirmed to be diphyletic, with Disperis and Coryciinae sensu stricto (s.s.) forming separate monophyletic clades. The current genera Corycium and Pterygodium are not monophyletic according to our analysis and we propose a subdivision of Coryciinae s.s. into 10 monophyletic clades including three monotypic groups. Previous generic classifications of Coryciinae s.s. have been hampered by convergent evolution of floral parts, a consequence of few pollinator species and limited pollinia attachment sites in the oil-bee pollination system common to this group.


An animal model to train Lichtenstein inguinal hernia repair.
Inguinal hernia repair is a common surgical procedure, and the majority of operations worldwide are performed ad modum Lichtenstein (open tension-free mesh repair). Until now, no suitable surgical training model has been available for this procedure. We propose an experimental surgical training model for Lichtenstein's procedure on the male and female pig. In the pig, an incision is made 1 cm cranially to the inguinal sulcus where a string of subcutaneous lymph nodes is located and extends toward the pubic tubercle. The spermatic cord is located in a narrow sulcus in the pig, thus complicating the procedure if operation should be done in the inguinal canal. The chain of lymph nodes resembles the human spermatic cord and can be used to perform Lichtenstein's hernia repair. This experimental surgical model has been tested on two adult male pigs and three adult female pigs, and a total of 55 surgeons have been educated to perform Lichtenstein's hernia repair in these animals. This new experimental surgical model for training Lichtenstein's hernia repair mimics the human inguinal anatomy enough to make it suitable as a training model. The operation facilitates the training in the positioning and fixation of the mesh and can be performed numerous times on the same pig. It is therefore a useful training method for inexperienced surgeons to obtain experience in aspects of the Lichtenstein procedure.


Forelimb myology of the pygmy hippopotamus (Choeropsis liberiensis).
Based on morphological analyses, hippos have traditionally been classified as Suiformes, along with pigs and peccaries. However, molecular data indicate hippos and cetaceans are sister taxa (see review in Uhen, 2007, this issue). This study analyzes soft tissue characters of the pygmy hippo forelimb to elucidate the functional anatomy and evolutionary relationships of hippos within Artiodactyla. Two specimens from the National Zoological Park in Washington, D.C. were dissected, revealing several adaptations to an aquatic lifestyle. However, these adaptations differ functionally from most aquatic mammals as hippos walk along river or lake bottoms, rather than swim. Several findings highlight a robust mechanism for propelling the trunk forward through the water. For example, mm. pectoralis superficialis and profundus demonstrate broad sites of origin, while the long flexor tendons serve each of the digits, reflecting the fact that all toes are weight-bearing. Pygmy hippos also have eight mm. interossei and a well-developed m. lumbricalis IV. Retention of intrinsic adductors functions to prevent splaying of the toes, an advantageous arrangement in an animal walking on muddy substrates. Published descriptions indicate common hippos share all of these features. Hippo and ruminant forelimbs share several traits; however, hippos are unique among artiodactyls in retaining several primitive muscles (e.g., mm. palmaris longus and flexor digitorum brevis). These findings are consistent with the hypothesis that hippos diverged from other Artiodactyla early in the history of this group. Additional analyses of hindlimb and axial muscles may help determine whether this trajectory was closely allied to that of Cetacea.


Noise-induced synchronization, desynchronization, and clustering in globally coupled nonidentical oscillators.
We study ensembles of globally coupled, nonidentical phase oscillators subject to correlated noise, and we identify several important factors that cause noise and coupling to synchronize or desynchronize a system. By introducing noise in various ways, we find an estimate for the onset of synchrony of a system in terms of the coupling strength, noise strength, and width of the frequency distribution of its natural oscillations. We also demonstrate that noise alone can be sufficient to synchronize nonidentical oscillators. However, this synchrony depends on the first Fourier mode of a phase-sensitivity function, through which we introduce common noise into the system. We show that higher Fourier modes can cause desynchronization due to clustering effects, and that this can reinforce clustering caused by different forms of coupling. Finally, we discuss the effects of noise on an ensemble in which antiferromagnetic coupling causes oscillators to form two clusters in the absence of noise.


No longer lost in translation: the art and science of sports injury prevention implementation research.
It is now understood that sports injury interventions will not have significant public health impact if they are not widely accepted and adopted by target sports participants. Although there has been increasing recognition of the need for intervention studies conducted within the real-world context of sports delivery, very few studies have been conducted in this important area. A major reason for this is that there are significant challenges in conducting implementation research; the more traditional sports medicine approaches may not be fully appropriate and new ways of thinking about how to design, conduct and report such research is needed. Moreover, real-world implementation of sports injury interventions and evaluation of their effectiveness needs to start to take into account the broad ecological context in which they are introduced, as well as considering the best way to translate this knowledge to reach the audiences who most need to benefit from such research. This overview paper provides perspectives and guidance on the design, conduct and evaluation of sports injury intervention implementation studies, including better understanding of the complexity of the ecological settings for intervention delivery. Some conceptual approaches that could be adopted in future implementation studies are discussed; particular emphasis is given to intervention mapping as a tool to assist intervention development, diffusion of innovations theory to guide the planning of intervention strategies and the RE-AIM (reach, effectiveness, adoption, implementation and maintenance) framework for programme evaluation and programme design. Finally, a broad agenda for this emerging important field of sports medicine research is outlined.


Rapid, transient induction of ER stress in the liver and kidney after acute exposure to heavy metal: evidence from transgenic sensor mice.
Endoplasmic reticulum (ER) stress-responsive alkaline phosphatase (ES-TRAP) serves as a sensitive indicator for ER stress. In response to heavy metals including cadmium, nickel and cobalt, hepatocytes and renal tubular cells expressing ES-TRAP exhibited ER stress and decreased ES-TRAP activity. In ES-TRAP transgenic mice, acute exposure to cadmium showed rapid, transient decreases in the activity of serum ES-TRAP. It was inversely correlated with the induction of endogenous ER stress markers in the liver and kidney. Our result provides first evidence for the acute, reversible induction of ER stress in vivo after exposure to heavy metal.


Income disparities in healthcare use remain after controlling for healthcare need: evidence from Swedish register data on psoriasis and psoriatic arthritis.
We used a southern Swedish cohort of psoriasis (PSO) and psoriatic arthritis (PsA) patients and population-based referents (N = 57,800) to investigate the influence of socioeconomic and demographic factors on the probability of healthcare use and on healthcare costs when controlling for need as measured by PSO/PsA and common additional morbidities such as diabetes, depression and myocardial infarction. People with PSO/PsA were identified by ICD-10 codes in the Skåne Healthcare Register 1998-2007. Resource use and costs for years 2008-2011 were retrieved from the Skåne Healthcare Register and the Swedish Prescribed Drug Register, and socioeconomic data were retrieved from Statistics Sweden. After controlling for PSO/PsA and common additional morbidities, income, and to some extent education, had significant effects on the probability of five types of healthcare use. Overall, income showed a bell-shaped relationship to healthcare costs, with patients in income quintiles 2 and 3 having the highest mean annualized cost irrespective of model specification. Education did not have a significant effect in most specifications. Analyses including interaction effects indicated similarly higher costs across income quintiles in the PSO and PsA subgroups, though these cost differences were lower in magnitude for patients with PSO in quintile 5 and with PsA in quintile 1. In conclusion, our results show persistent socioeconomic disparities in healthcare use among a cohort of chronically ill patients and referents, even after controlling for the presence of PSO/PsA and common additional morbidities. These disparities persist even in a country with general healthcare coverage and low out-of-pocket payments.


A multicenter study evaluation of the digene hybrid capture II signal amplification technique for detection of hepatitis B virus DNA in serum samples and testing of EUROHEP standards.
We have evaluated the new Digene Hybrid Capture II HBV DNA Test (HCII HBV), which is a 96-well microtiter plate-based signal amplification assay. This test uses hybrid capture technology that specifically detects RNA-DNA hybrids. HCII HBV is able to quantify hepatitis B virus (HBV) DNA at between 1.4 x 10(5) and 1.7 x 10(9) HBV copies per ml in a standard format. By using a modified sample preparation method, which allows the input of 30-fold more serum for an ultrasensitive format, the sensitivity of the assay can be increased reproducibly to approximately 8,000 copies of HBV per ml. By using a combination of these two formats, the assay can quantify over a total range of 6 logs. In our multicenter evaluation study, the mean laboratory-to-laboratory coefficients of variation were 22, 7, and 12% at the three sites, respectively, with a combined specificity of 98.4%. The linearities of both the standard test and the ultrasensitive test were excellent, with Spearman correlation coefficients of 0.997 and 0.999, respectively. Furthermore, the intra-assay reproducibility for the standard assay gave coefficients of variation of from 13 to 33, 9 to 21, and 3 to 8% at the three sites, respectively. HCII HBV was shown to be genotype independent when the EUROHEP standards for genotypes A and D were used. This assay allows the accurate measurement of HBV DNA levels in serum and can be clinically used for the monitoring of responses to antiviral agents for patients chronically infected with HBV.


[Discontinuing medication in elderly: a checklist may be useful].
Elderly patients are at an increased risk of developing adverse drug events due to polypharmacy, co-morbidity and changes in physiology. Often, pharmacotherapy in frail elderly patients is initiated based on randomized trials from which this population has been excluded. In such cases, the question when to stop a medication may be as important as when to start it. It is important to consider whether the patient is using Potentially Inappropriate Medications (PIM) that should be stopped. Checklists can be helpful in detecting PIM. A recent study has shown that Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria can identify clinically relevant PIM much better than the Beers criteria often used. These outcomes indicate that patient safety can be improved if clinicians use checklists such as the STOPP.


High blood pressure in Hispanics in the United States: a review.
To provide an overview of the available data on the prevalence of hypertension (HTN) in various groups and segments of the Hispanic population; prevalence of awareness, treatment and control of HTN among Hispanics; and HTN-related disparities, through disproportionate effects on the Hispanic elderly, women, and young adults. Data on HTN in Hispanics has been lacking or aggregated and frequently not inclusive of certain groups of Hispanics but the available data do show a pattern of more prevalent HTN and HTN disparities among Hispanics compared with non-Hispanic whites. Hispanic adults have some of the highest prevalence of poorly controlled blood pressure compared with any other race-ethnic group in the United States. Further, the impact of the most recent iteration of the HTN guidelines among all segments of the Hispanic population has not been well studied. The most recent HTN guidelines will likely only further illuminate worsening HTN-related disparities among Hispanics. These findings suggest significant screening and treatment disparities must be addressed to reduce HTN risk among the Hispanic population.


The roles of polyamines during the lifespan of plants: from development to stress.
Compelling evidence indicates that free polyamines (PAs) (mainly putrescine, spermidine, spermine, and its isomer thermospermine), some PA conjugates to hydroxycinnamic acids, and the products of PA oxidation (hydrogen peroxide and γ-aminobutyric acid) are required for different processes in plant development and participate in abiotic and biotic stress responses. A tight regulation of PA homeostasis is required, since depletion or overaccumulation of PAs can be detrimental for cell viability in many organisms. In plants, homeostasis is achieved by modulation of PA biosynthesis, conjugation, catabolism, and transport. However, recent data indicate that such mechanisms are not mere modulators of PA pools but actively participate in PA functions. Examples are found in the spermidine-dependent eiF5A hypusination required for cell division, PA hydroxycinnamic acid conjugates required for pollen development, and the involvement of thermospermine in cell specification. Recent advances also point to implications of PA transport in stress tolerance, PA-dependent transcriptional and translational modulation of genes and transcripts, and posttranslational modifications of proteins. Overall, the molecular mechanisms identified suggest that PAs are intricately coordinated and/or mediate different stress and developmental pathways during the lifespan of plants.


Low-Density Lipoprotein Cholesterol Target Attainment in Patients With Established Cardiovascular Disease: Analysis of Routine Care Data.
Direct feedback on quality of care is one of the key features of a learning health care system (LHS), enabling health care professionals to improve upon the routine clinical care of their patients during practice. This study aimed to evaluate the potential of routine care data extracted from electronic health records (EHRs) in order to obtain reliable information on low-density lipoprotein cholesterol (LDL-c) management in cardiovascular disease (CVD) patients referred to a tertiary care center. We extracted all LDL-c measurements from the EHRs of patients with a history of CVD referred to the University Medical Center Utrecht. We assessed LDL-c target attainment at the time of referral and per year. In patients with multiple measurements, we analyzed LDL-c trajectories, truncated at 6 follow-up measurements. Lastly, we performed a logistic regression analysis to investigate factors associated with improvement of LDL-c at the next measurement. Between February 2003 and December 2017, 250,749 LDL-c measurements were taken from 95,795 patients, of whom 23,932 had a history of CVD. At the time of referral, 51% of patients had not reached their LDL-c target. A large proportion of patients (55%) had no follow-up LDL-c measurements. Most of the patients with repeated measurements showed no change in LDL-c levels over time: the transition probability to remain in the same category was up to 0.84. Sequence clustering analysis showed more women (odds ratio 1.18, 95% CI 1.07-1.10) in the cluster with both most measurements off target and the most LDL-c measurements furthest from the target. Timing of drug prescription was difficult to determine from our data, limiting the interpretation of results regarding medication management. Routine care data can be used to provide feedback on quality of care, such as LDL-c target attainment. These routine care data show high off-target prevalence and little change in LDL-c over time. Registrations of diagnosis; follow-up trajectory, including primary and secondary care; and medication use need to be improved in order to enhance usability of the EHR system for adequate feedback.


On stoichiometry and intermixing at the spinel/perovskite interface in CoFe2O4/BaTiO3 thin films.
The performance of complex oxide heterostructures depends primarily on the interfacial coupling of the two component structures. This interface character inherently varies with the synthesis method and conditions used since even small composition variations can alter the electronic, ferroelectric, or magnetic functional properties of the system. The focus of this article is placed on the interface character of a pulsed laser deposited CoFe2O4/BaTiO3 thin film. Using a range of state-of-the-art transmission electron microscopy methodologies, the roles of substrate morphology, interface stoichiometry, and cation intermixing are determined on the atomic level. The results reveal a surprisingly uneven BaTiO3 substrate surface formed after the film deposition and Fe atom incorporation in the top few monolayers inside the unit cell of the BaTiO3 crystal. Towards the CoFe2O4 side, a disordered region extending several nanometers from the interface was revealed and both Ba and Ti from the substrate were found to diffuse into the spinel layer. The analysis also shows that within this somehow incompatible composite interface, a different phase is formed corresponding to the compound Ba2Fe3Ti5O15, which belongs to the ilmenite crystal structure of FeTiO3 type. The results suggest a chemical activity between these two oxides, which could lead to the synthesis of complex engineered interfaces.


Bicuspid aortic valve disease and pulmonary autograft root dilatation after the Ross procedure: a clinicopathologic study.
Bicuspid aortic valve disease has been associated with histologic abnormalities of the aortic root. Recent reports have suggested similar alterations may exist in the pulmonary artery of patients with bicuspid aortic valve. The present study was undertaken to define the histologic condition of the aortic and pulmonary artery root in bicuspid aortic valve disease and the relationship with pulmonary autograft root dilatation after the Ross procedure. In 17 patients undergoing aortic root replacement with the pulmonary autograft, biopsy specimens of the aortic root and pulmonary artery trunk were collected. Clinical and histologic findings of patients with bicuspid aortic valves were compared with those with tricuspid aortic valves. There were 9 patients (8 male, 1 female) with bicuspid aortic valve (group 1) and 8 (all male) with tricuspid aortic valve (group 2). Mean age was comparable (24.4 +/- 9.8 vs 23.6 +/- 10.8 years, P =.9). Aortic insufficiency as an indication for operation was more common in group 1 (9/9 vs 5/8, P =.007), whereas preoperative aortic root dilatation was equally prevalent (4/9 vs 1/8, P =.1). Prior aortic valve repair had been performed in 2 patients (1/9 vs 1/8, P =.9). Prevalence of cystic medionecrosis of the aortic wall was similar in the 2 groups (4/9 vs 3/8, P =.6). Cystic medionecrosis of the pulmonary artery trunk was found only in 1 patient with tricuspid aortic valve (0/9 vs 1/8, P =.3). During a mean follow-up of 26.5 +/- 12.2 months (32.1 +/- 12.7 vs 20.1 +/- 7.4 months, P =.04), prevalence of pulmonary autograft root dilatation (greater than 4.0 cm) was equally represented in patients with native bicuspid or tricuspid aortic valve (3/9 vs 2/8, P =.6). Histologic abnormalities of the pulmonary artery root are rare and equally prevalent in young patients with bicuspid and tricuspid aortic valves. On the contrary, root dilatation is relatively common late after autograft root replacement but appears unrelated to bicuspid aortic valve disease or to pre-existing degenerative changes of the pulmonary artery root.


Microarray analysis in the archaeon Halobacterium salinarum strain R1.
Phototrophy of the extremely halophilic archaeon Halobacterium salinarum was explored for decades. The research was mainly focused on the expression of bacteriorhodopsin and its functional properties. In contrast, less is known about genome wide transcriptional changes and their impact on the physiological adaptation to phototrophy. The tool of choice to record transcriptional profiles is the DNA microarray technique. However, the technique is still rarely used for transcriptome analysis in archaea. We developed a whole-genome DNA microarray based on our sequence data of the Hbt. salinarum strain R1 genome. The potential of our tool is exemplified by the comparison of cells growing under aerobic and phototrophic conditions, respectively. We processed the raw fluorescence data by several stringent filtering steps and a subsequent MAANOVA analysis. The study revealed a lot of transcriptional differences between the two cell states. We found that the transcriptional changes were relatively weak, though significant. Finally, the DNA microarray data were independently verified by a real-time PCR analysis. This is the first DNA microarray analysis of Hbt. salinarum cells that were actually grown under phototrophic conditions. By comparing the transcriptomics data with current knowledge we could show that our DNA microarray tool is well applicable for transcriptome analysis in the extremely halophilic archaeon Hbt. salinarum. The reliability of our tool is based on both the high-quality array of DNA probes and the stringent data handling including MAANOVA analysis. Among the regulated genes more than 50% had unknown functions. This underlines the fact that haloarchaeal phototrophy is still far away from being completely understood. Hence, the data recorded in this study will be subject to future systems biology analysis.


Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain.
The key elements of circadian clockwork and oxygen homeostasis are the PAS protein family members PER and CLOCK and hypoxia-inducible factor 1alpha (HIF-1alpha). The PAS domain serves as an interface for protein-protein interactions. We asked whether a cross-talk exists between the PAS components of hypoxic and circadian pathways. We found several isoforms of PER1 protein that exhibit tissue-specific size differences. In the mouse brain, a predominantly nuclear 48 kDa isoform that followed a daily rhythm was observed. The 48 kDa form was found in the nuclear fractions derived from mouse liver, Swiss3T3 fibroblasts, and N2A neuroblastoma cells. In mouse kidney and human 293 kidney cells, a 55 kDa PER1 form was detected. CLOCK was observed as a predicted 100 kDa protein in rat-1 cells and in all analyzed mouse tissues including brain, liver, kidney, and spleen. In contrast to PER1, CLOCK protein expression was not rhythmic. Exposure to hypoxia led to increased PER1 and CLOCK protein levels in mice. Based on coimmunoprecipitation experiments that showed protein-protein interaction between PER1 and the alpha subunit of HIF-1, we suggest that these hypoxic effects may be modulated by HIF-1alpha.-Chilov, D., Hofer, T., Bauer, C., Wenger, R. H., Gassmann, M. Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain.


Retroperitoneal perforation of the colon caused by colonic tuberculosis: report of a case.
We present a 25-year-old, HIV-negative patient from Kosovo, with no significant past medical history, who was admitted to a local hospital for nonspecific upper abdominal discomfort. He was transferred to us after a retroperitoneal mass with contact to the right colonic flexure had been found during workup. Colonoscopy demonstrated an edemateous area with a central fistula in the right flexure, and histology showed caseous necrosis. Although neither bacteriology nor histology could detect any germs, gastrointestinal tuberculosis seemed to be very probable. Laparotomy with a segmental resection of the colon was performed to remove the fistula-bearing segment, and histologic examination of the resected specimen confirmed the intraoperative suspect of a retroperitoneal colonic perforation. Again, all cultures from the specimen were negative for tuberculosis, but polymerase chain reaction of a regional lymph node revealed acid-fast bacilli of the Mycobacterium tuberculosis/bovis species. Although the patient had no other sites of tuberculosis infection like pulmonary or urinary, he received adjuvant standard tuberculosis treatment for six months. At control examination one year after the operation, the patient was free of recurrence and in very good general condition. We report this extremely rare presentation of gastrointestinal tuberculosis to sensitize physicians to tuberculosis again, because incidence rates are increasing and this disease will certainly play a more important role in the future.


Nurses' impoliteness as an impediment to patients' rights in selected Kenyan hospitals.
The institutionalization of patients' rights is a recent phenomenon in Kenya. In 2006, Kenya's Ministry of Health initiated policy measures to improve patient satisfaction through a charter of patients' rights. The aim was to change the longstanding public perception that nurses in public hospitals routinely ignored patients' right to respectful treatment. This paper focuses on linguistic indicators of violation or promotion of patients' rights in the health care context. We examine the extent to which patients' rights to dignity, respect, and humaneness are observed or denied, and we argue that impolite utterances impede rather than promote the realization of other fundamental human rights. It appears that nurses' impoliteness does not merely constitute rudeness, but encodes a violation of dignity which, in turn, hampers the chances of enjoyment of broader human rights such as the right to autonomy, free expression, self-determination, information, personalized attention, and non-discrimination. We argue that, for patients to enjoy their rights in the hospital setting, a clear definition of roles and relationships and public education on strategies of asserting their rights without intimidation are necessary. It emerges that when patients' rights are denied, patients resort to retaliation by violating the dignity of the nurses. This jeopardizes the envisaged mutual support in the nurse-patient relationship and compromises patient satisfaction.


Occurrence of dorsal axis-inducing activity around the vegetal pole of an uncleaved Xenopus egg and displacement to the equatorial region by cortical rotation.
Specification of the dorsoventral axis is a subject of great importance in amphibian embryogenesis. We have found that cytoplasm of the vegetal dorsal cells of a 16-cell embryo of Xenopus laevis, when injected into the ventral vegetal cells of a recipient at the same stage, can induce formation of a second axis. In the present experiments,using the same assay procedure, we found that the cytoplasm around the vegetal pole of an egg before cortical rotation is also active in inducing a second axis,that the activity decreases throughout the second half of the cell cycle and appears in a presumptive dorsal equatorial region at the 2- to 16-cell stages. This is the first demonstration of the localization of dorsal forming activity in any specific region of an egg. After UV irradiation,a treatment that is known to block cortical rotation and thereby inhibit axis specification, the activity remains near the vegetal pole beyond the first cell cycle and does not appear in an equatorial region, at least at the 16-cell stage. This suggests that cortical rotation ora related force is in some way involved in changes in distribution of the activity.We also found that UV-irradiated 8-cell embryos can rescue dorsal development when they are cut into halves along the first cleavage plane. Histological examination revealed that the rescued embryos have a neural tube and notochord. In the half embryo, the animal and vegetal regions came into contact during wound healing, an event that enables the activity to localize in the new equator of an embryo. Therefore this rescue suggests that, if the activity is distributed only in the equatorial region, dorsal specification occurs. In fact, the dorsal side of the rescued embryos seems to correspond to the plane through which the embryos have been cut.Based on our results, we propose (1) that a determinant that carries axis-inducing activity is first present around the vegetal pole, (2) that the determinant shifts from the vegetal pole to an equatorial region by or in close association with cortical rotation and (3) that occurrence of the determinant in the equatorial region is a prerequisite for axis specification.


Restoration of fertility in a woman with giant prolactinoma in response to cabergoline treatment.
A 32-year-old woman presented with primary amenorrhoea, prolactin (PRL) level of 154 150 mIU/L and was diagnosed with a giant pituitary adenoma measuring maximum 6.2 cm. Cabergoline (CAB) treatment at a dose of 0.5 mg/week was prescribed to the patient. The treatment decreased the tumour size after 3 months (MRI scans of the brain) and brought back to normal the level of the PRL (345 mIU/L) after 6 months of CAB treatment. After 7 months of CAB treatment, menarche was achieved, and after 12 months, the patient became pregnant. She discontinued taking CAB at 4-week gestation. The pregnancy resulted in a missed miscarriage at 6-7 weeks; an abortion was conducted by the vacuum aspiration method. The MRI scans of the brain did not show any tumour enlargement. After 18 months from the start of the treatment the patient got pregnant for the second time. At 25-week gestation an MRI scan of the brain was conducted which did not show any increase in the tumour size. At 38 weeks the patient delivered a healthy full-term girl via C-section. The patient chose not to breastfeed and resumed CAB therapy after the delivery. During the treatment, the PRL level returned to the normal range and the menstrual cycle was restored. After 3 years the patient got pregnant for the third time. The patient did not receive CAB during the pregnancies; the examination did not show any tumour enlargement. Further MRI scans did not show any tumour growth. CAB therapy was effective in normalization of the PRL level, tumour shrinkage, menarche and pregnancy-induction which led to the birth of healthy children in a woman with primary amenorrhoea and a giant prolactinoma invading the skull base bones. Giant prolactinomas are very rarely found in women. Cabergoline therapy can be effective in the normalization of the PRL level, tumour shrinkage, menarche induction in a woman with primary amenorrhoea, and giant prolactinoma. Cabergoline therapy can be effective in pregnancy induction which leads to the birth of children in a woman with giant prolactinoma. Cabergoline discontinuation did not trigger tumour enlargement during pregnancy.


Altered expression of heme oxygenase-1 in the livers of patients with portal hypertensive diseases.
This study was designed to determine changes in expression of heme oxygenase (HO)-1, the stress-inducible and carbon monoxide-producing enzyme, in normotensive and portal hypertensive human livers. GTS-1, a monoclonal antibody against rat HO-1 cross-reacted with the human HO-1 and blocked its enzyme activity, allowing us to examine the activity and localization of HO-1. In controls, approximately 50% of the total HO activity was from HO-1 as judged by the sensitivity to GTS-1, while the rest of activity was from other isozymes such as HO-2. HO-1 was expressed mainly in a subpopulation of Kupffer cells, and the expression in hepatic stellate cells, sinusoidal endothelial cells, and hepatocytes was little, if any. The HO-1 expression exhibited quite different pictures in the livers of portal hypertensive diseases. In cirrhotic livers, which undergo portal hypertension through increases in intrasinusoidal resistance and regenerative changes in the parenchyma, HO-1 occurred in a majority of Kupffer cells and was also observed in hepatocytes. Consequently, the total HO-1 activities became significantly greater in these tissues than those from normal individuals. By contrast, livers of idiopathic portal hypertension that are characterized by an increase in presinusoidal resistance displayed a significant decrease in the HO-1 expression in Kupffer cells, and its hepatocellular expression was not detectable. Although factors involved in altered HO-1 expression in these cells remain unknown, the results suggest that Kupffer cells could alter their expression of HO-1 in response to local hemodynamic changes associated with chronic portal hypertension in humans.


Event-related potential correlates of the retrieval of emotional and nonemotional context.
In two experiments, we examined event-related potentials (ERPs) elicited in an old/new recognition memory test by emotionally neutral visual objects that, at encoding, had been associated with neutrally, negatively, or positively valenced background contexts. In Experiment 2, subjects also judged the context in which the item had been studied. In Experiment 1, "left parietal" old/new ERP effects were elicited by correctly recognized items. Items encoded in emotional contexts, but not those studied in neutral contexts, elicited additional effects early in the recording epoch over lateral temporal scalp and, later, over left temporo-frontal scalp. In Experiment 2, "left parietal" and "right frontal" ERP effects were elicited by recognized items that attracted correct source judgments. Additional effects, an early lateral temporal positivity and a late-onset, left-sided positivity, were elicited by items studied in emotionally valenced contexts and attracting correct source judgments. Together, the findings indicate that retrieval processing is influenced by the emotional valence of the context in which an item is encoded, regardless of whether contextual information is task relevant.


Risk factors for coronary artery disease in patients with systemic lupus erythematosus.
To estimate the frequency of and examine risk factors for coronary artery disease (CAD) in patients with systemic lupus erythematosus (SLE) in a prospective longitudinal study. Patients were SLE are enrolled in The Johns Hopkins Lupus Cohort, a prospective study of outcomes in 229 subjects with SLE. CAD was defined as angina, myocardial infarction, or sudden death. Data on CAD risk factors were obtained prospectively every 3 months and were analyzed using univariate and multiple logistic regression. CAD occurred in 19 (8.3%) of 229 patients with SLE and accounted for 3 (30%) of 10 deaths as of December 31, 1990. Compared to subjects without CAD, those with CAD were more likely to have been older at both diagnosis of SLE (37.1 years versus 28.9 years, p = 0.004) and at entry into the cohort (47.1 years versus 34.7 years, p < 0.0001), to have a longer mean duration of SLE (12.3 years versus 8.1 years, p = 0.013) and a longer mean duration of prednisone use (14.3 years versus 7.2 years, p < 0.0001), to have a higher mean serum cholesterol (271.2 mg/dL versus 214.9 mg/dL, p < 0.0001) or a cholesterol level greater than 200 mg/dL (odds ratio [OR] 14.5, 95% confidence intervals [CI] 1.9, 112.1), and to have both a history of hypertension (OR 3.5, 95% CI 1.3, 9.6) and a history of use of antihypertensive medications (OR 5.5, 95% CI 1.8, 17.2). There were no significant associations with other known CAD risk factors such as smoking, diabetes, family history of CAD, race, or sex, or variables related to steroid therapy including the presence of cushingoid features or ever use of corticosteroids. The best multiple logistic regression model for CAD included age at diagnosis, duration of prednisone use, requirement for antihypertensive treatment, maximum cholesterol level, and obesity (using NHANES-II [National Health and Nutrition Examination Survey] definitions). Primary and secondary prevention strategies directed at hypertension, hypercholesterolemia, and obesity, as well as other known CAD risk factors, should be routinely employed in the management of patients with SLE.


Evaluating automated dynamic contrast enhanced wrist 3T MRI in healthy volunteers: one-year longitudinal observational study.
Dynamic contrast enhanced (DCE)-MRI has great potential to provide quantitative measure of inflammatory activity in rheumatoid arthritis. There is no current benchmark to establish the stability of signal in the joints of healthy subjects when imaged with DCE-MRI longitudinally, which is crucial so as to differentiate changes induced by treatment from the inherent variability of perfusion measures. The objective of this study was to test a pixel-by-pixel parametric map based approach for analysis of DCE-MRI (Dynamika) and to investigate the variability in signal characteristics over time in healthy controls using longitudinally acquired images. 10 healthy volunteers enrolled, dominant wrists were imaged with contrast enhanced 3T MRI at baseline, week 12, 24 and 52 and scored with RAMRIS, DCE-MRI was analysed using a novel quantification parametric map based approach. Radiographs were obtained at baseline and week 52 and scored using modified Sharp van der Heidje method. RAMRIS scores and dynamic MRI measures were correlated. No erosions were seen on radiographs, whereas MRI showed erosion-like changes, low grade bone marrow oedema and low-moderate synovial enhancement. The DCE-MRI parameters were stable (baseline scores, variability) (mean±st.dev); in whole wrist analysis, MEmean (1.3±0.07, -0.08±0.1 at week 24) and IREmean (0.008±0.004, -0.002±0.005 at week 12 and 24). In the rough wrist ROI, MEmean (1.2±0.07, 0.04±0.02 at week 52) and IREmean (0.001±0.0008, 0.0006±0.0009 at week 52) and precise wrist ROI, MEmean (1.2±0.09, 0.04±0.04 at week 52) and IREmean (0.001±0.0008, 0.0008±0.001 at week 24 and 52). The Dynamic parameters obtained using fully automated analysis demonstrated strong, statistically significant correlations with RAMRIS synovitis scores. The study demonstrated that contrast enhancement does occur in healthy volunteers but the inherent variability of perfusion measures obtained with quantitative DCE-MRI method is low and stable, suggesting its suitability for longitudinal studies of inflammatory arthritis. These results also provide important information regarding potential cut-off levels for imaging remission goals in patients with RA using both RAMRIS and DCE-MRI extracted parametric parameters.


Analysis of human immunodeficiency virus type 1 matrix binding to membranes and nucleic acids.
The human immunodeficiency virus type 1 (HIV-1) matrix (MA) protein targets HIV-1 precursor Gag (PrGag) proteins to assembly sites at plasma membrane (PM) sites that are enriched in cholesterol and phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)]. MA is myristoylated, which enhances membrane binding, and specifically binds PI(4,5)P(2) through headgroup and 2' acyl chain contacts. MA also binds nucleic acids, although the significance of this association with regard to the viral life cycle is unclear. We have devised a novel MA binding assay and used it to examine MA interactions with membranes and nucleic acids. Our results indicate that cholesterol increases the selectivity of MA for PI(4,5)P(2)-containing membranes, that PI(4,5)P(2) binding tolerates 2' acyl chain variation, and that the MA myristate enhances membrane binding efficiency but not selectivity. We also observed that soluble PI(4,5)P(2) analogues do not compete effectively with PI(4,5)P(2)-containing liposomes for MA binding but surprisingly do increase nonspecific binding to liposomes. Finally, we have demonstrated that PI(4,5)P(2)-containing liposomes successfully outcompete nucleic acids for MA binding, whereas other liposomes do not. These results support a model in which RNA binding protects MA from associating with inappropriate cellular membranes prior to PrGag delivery to PM assembly sites.


Formal complaints against general practitioners: a study of 1000 cases.
This study was carried out to determine the reasons given by patients in making formal complaints against general practitioners. A sample of 1000 complaints made by UK patients about general practitioner principals over the period 1982-89 was randomly selected from the computer database of the Medical Protection Society and retrospectively analysed. Thirteen categories of criticism were identified. The most common circumstance in which patients complained was when they believed there had been failure to visit. In nearly one third of cases the complaints were associated with the death of a patient. In a quarter of the letters it was clear that the patient's motive for complaining was concern to protect other patients. General practitioners should bear in mind that in declining to visit they could be inviting criticism, particularly if the patient dies.


Marine biodiversity from zero to a thousand meters at Clipperton Atoll (Île de La Passion), Tropical Eastern Pacific.
Clipperton Atoll (Île de La Passion) is the only atoll in the Tropical Eastern Pacific (TEP) ecoregion and, owing to its isolation, possesses several endemic species and is likely an important stepping stone between Oceania, the remainder of the TEP, including other oceanic islands and the west coast of Central America. We describe the biodiversity at this remote atoll from shallow water to depths greater than one thousand meters using a mixture of technologies (SCUBA, stereo baited remote underwater video stations, manned submersible, and deep-sea drop cameras). Seventy-four unique taxa of invertebrates were identified during our expedition. The majority (70%) of these taxa were confined to the top 400 m and consisted mostly of sessile organisms. Decapod crustaceans and black corals (Antipatharia) had the broadest depth ranges, 100-1,497 m and 58-967 m, respectively. Decapods were correlated with the deepest depths, while hard corals were correlated with the shallow depths. There were 96 different fish taxa from 41 families and 15 orders, of which 70% were restricted to depths <200 m. While there was a decreasing trend in richness for both fish and invertebrate taxa with depth, these declines were not linear across the depth gradient. Instead, peaks in richness at ∼200 m and ∼750 m coincided with high turnover due to the appearance of new taxa and disappearance of other taxa within the community and is likely associated with the strong oxygen minimum zone that occurs within the region. The overall depth effect was stronger for fishes compared with invertebrates, which may reflect ecological preferences or differences in taxonomic resolution among groups. The creation of a no-take marine reserve 12 nautical miles around the atoll in 2016 will help conserve this unique and relatively intact ecosystem, which possesses high predator abundance.


Efficacy of abstinence promotion media messages: findings from an online randomized trial.
We conducted an online randomized experiment to evaluate the efficacy of messages from the Parents Speak Up National Campaign (PSUNC) to promote parent-child communication about sex. We randomly assigned a national sample of 1,969 mothers and fathers to treatment (PSUNC exposure) and control (no exposure) conditions. Mothers were further randomized into treatment and booster (additional messages) conditions to evaluate dose-response effects. Participants were surveyed at baseline, 4 weeks postexposure, and 6 months postexposure. We used multivariable logistic regression procedures in our analysis. Treatment fathers were more likely than control fathers to initiate conversations about sex at 4 weeks, and treatment fathers and mothers were more likely than controls at 6 months to recommend that their children wait to have sex. Treatment fathers and mothers were far more likely than controls to use the campaign Web site. There was a dose-response effect for mothers' Web site use. Using new media methods, this study shows that PSUNC messages are efficacious in promoting parent-child communication about sex and abstinence. Future research should evaluate mechanisms and effectiveness in natural settings.