Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis.
The effect of blocking IL-12, a potent inducer of interferon-gamma (IFN-gamma) and promoter of Th1 cell responses, during the induction phase of CIA was investigated. Arthritis was elicited in male DBA/1 mice by immunizing with type II collagen (CII) in Freund's complete adjuvant. Neutralizing anti-IL-12 antibodies were administered twice weekly from CII immunization. It was found that administration of anti-IL-12 from immunization until the onset of clinical arthritis did not lower the incidence of arthritis, but dramatically attenuated the severity of the disease, both clinically and histopathologically. This regime was associated with reduced IFN-gamma levels produced by ex vivo CII-stimulated draining lymph node cells, and with diminished spontaneous ex vivo production of tumour necrosis factor (TNF), IL-6 and IL-10 by freshly isolated synovial cells. Total anti-CII antibody serum levels in these mice were lower than in the controls, but there was no change in the IgG2a/IgG1 ratio. These findings confirm that IL-12 has a major role in the induction of murine CIA and suggests that this disease is propagated, in part, by cells of the Th1 phenotype.


The effects of fathers on daughters' expectations for men.
Guided by paternal investment theory (PIT), the current research examines the effects of fathers on daughters' expectations for men in adulthood, and the role of these expectations in mediating women's short-term (casual or uncommitted) sexual behavior. Using a genetically informed differential sibling-exposure design (N = 223 sister pairs from divorced/separated families), we found that developmental exposure to low-quality paternal behavior (but not paternal absence per se) predicted adult women's expectations for men as partners. For older sisters, who spent much of their childhoods living with their fathers, lower-quality paternal behavior predicted lower expectations for male investment in their relationships as adults. Moreover, lower expectations for men as partners predicted higher numbers of sexual partners (past and anticipated) among these women. By contrast, for younger sisters, who spent relatively little time coresiding with their fathers, no such effects of quality of paternal behavior were observed. The current work provides evidence that exposure to low-quality paternal behavior during development may help calibrate daughters' expectations for the behavior of male relationship partners, and these expectations may shape their sexual behavior in adulthood. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Staffing, capacity, and ambulance diversion in emergency departments: United States, 2003-04.
The increased demand for emergency department (ED) services over the past decade has resulted in crowding. This report presents estimates of structure and process characteristics of hospital EDs related to their capacity to treat medical and surgical emergencies. Estimates of EDs experiencing crowded conditions are also presented. Several facility supplements were added to the 2003-04 National Hospital Ambulatory Medical Care Survey (NHAMCS), which were completed by hospital staff. NHAMCS samples nonfederal, short-stay, and general hospitals in the United States. Of all sample hospitals that operated 24-hour EDs, 83 percent completed the supplemental questionnaires. Data from 467 hospitals were weighted to produce national annual estimates of ED characteristics. There was an annual average of 4,500 EDs operating in the United States during 2003 and 2004. Over one-half of EDs saw less than 20,000 patients annually, but 1 out of 10 had an annual visit volume of more than 50,000 patients. Although 16.1 percent of hospitals expanded their ED physical space within the last 2 years, approximately one-third of others planned to do so within the next 2 years. Most EDs used outside contracts to provide physicians (64.7 percent). One-half of EDs in metropolitan statistical areas (MSAs) had more than 5 percent of their nursing positions vacant. Of all on-call specialists, the services of plastic and hand surgeons were most frequently reported as somewhat or very difficult to obtain (49.4 percent). Approximately one-third of U.S. hospitals reported going on ambulance diversion sometime in the previous year. About 12 percent of hospitals in MSAs reported having spent between 5 and 19 percent of their operating time in diversion status. Between 40 and 50 percent of U.S. hospitals experienced crowded conditions in the ED with almost two-thirds of metropolitan EDs experiencing crowding.


State-to-state chemiluminescence in reactions of Mn atoms with S2Cl2.
A combined experimental and time-dependent density functional theory (TDDFT) investigation of the title reaction is presented. Both 'hot' and 'cold' laser-ablated Mn atom beams have been employed to determine the translational excitation functions for production of MnCl*(c(5)Σ(+), d(5)Π, e(5)Δ, e(5)Σ(+), A(7)Π). Analysis in terms of the multiple line-of-centres approach shows that the 'hot' results are dominated by reactions of the second metastable state of Mn, z(8)P(J), all with very low thresholds; while the first metastable state, a(6)D(J), and the ground state, a(6)S, are the precursors in the 'cold' results, all with significant excess barriers. The post-threshold behaviour of most z(8)P(J) and a(6)D(J) reaction channels implies that the transition states shift forward with increasing collision energy. The TDDFT calculations suggest that, while Mn*(z(8)P(J), a(6)D(J)) insertion into the S-Cl bond is facile, the observed chemiluminescence channels mostly derive from abstraction in a preferred linear Mn-Cl-S configuration, and that the low z(8)P(J) thresholds originate from attractive but excited reagent potentials which either reach a seam of interactions in the product valley or (in the c(5)Σ(+) case) lead to an octet potential very close in energy to the product sextet. The excess barriers in the Mn*(a(6)D(J)) and Mn(a(6)S) reactions appear for the most part to derive from exit channel mixing with lower-lying product potentials. The observed transition state shifts are consistent with the system being forced to ride up the repulsive wall of the entrance valley as collision energy increases, the location of that wall being different for the z(8)P(J) and a(6)D(J) cases.


Evaluation and results of treatments for prostatism.
Men with symptoms of prostatism form a heterogenous group. The best treatment of proven obstruction or retention in fit men remains transurethral prostatectomy (TURP). Men presenting with symptoms of prostatism may have bladder outflow obstruction, detrusor instability or weak bladder contraction leading to low pressure/low flow voiding so it is perhaps not surprising that only 75% of men selected for TURP purely on the basis of symptoms have a good outcome. Pressure flow studies are the only precise method of diagnosing outflow obstruction. The problem of accurately diagnosing obstruction before treatment is started applies particularly to trials of new treatments such as lasers, high energy focused ultrasound and drugs. Laser treatment is producing short term results that are slightly inferior to TURP but may have less morbidity. The role of conservative treatment is important in selected men. Men who have severe intercurrent illness may be treated by means of intra-prostatic stents. In order to accurately assess a new treatment it is necessary to determine the short-term mortality, the morbidity, complication rate and outcome as well as the cost-effectiveness, long-term outcome and patient preference. These conditions have not yet been met for any of the new treatments for prostatism.


Facilitators and Barriers to Successful Engagement in a Complex Care Management Program: Patient and Care Manager Perspectives.
Complex care management (CCM) interventions have been developed across the United States to address the challenges of high-need, high-cost patients. Though their heterogeneity makes it challenging to determine their general effectiveness, there are calls in the literature to continue to implement and evaluate them. This article presents CCM patient and care manager perspectives on facilitators and barriers to success in such a program in a safety-net hospital. Our findings suggest that motivated patients, team-based care, and the ability to form trusting, supportive relationships are important contributors to success in a CCM program while patients' own mental health and socioeconomic challenges impede success. Given the relatively short-term nature of most CCM programs and the complicated challenges faced by many CCM patients, this work poses larger questions to consider around the general alignment of the program model to the patient population and the definition of success for CCM programs.


Seasonal variation of semen quality and fertility.
At many locations in the northern hemisphere human sperm counts are reduced during the summer. Experiments with rhesus monkeys suggest that such seasonal variation may be induced by an endogenous biological clock reset annually by changes in the length of daylight. Little is known about seasonal variation in human female reproductive function, although fecundity may be lower during the summer, as it is for men. Variation in fecundity could help explain seasonal patterns of birth in countries such as the United States, where there is a deficit of spring births. But the relationship to patterns of birth in Canada and Europe, where the birth rate is highest during late winter and spring, is unclear.


Attachment in adolescence: A move to the level of emotion regulation.
The early adolescent's state of mind in the Adult Attachment Interview (AAI) is more closely linked to social interactions with peers, who are unlikely to serve as attachment figures, than it is to (i) qualities of the adolescent's interactions with parents, (ii) the AAI of the adolescent's mother, or (iii) the adolescent's prior Strange Situation behavior. This unexpected finding suggests the value of reconceptualizing AAI autonomy/security as a marker of the adolescent's capacity for emotion regulation in social interactions. Supporting this, we note that the AAI was originally validated not as a marker of attachment experiences or expectations with one's caregivers, but as a predictor of caregiving capacity sufficient to produce secure offspring. As such, the AAI may be fruitfully viewed as primarily assessing social emotion regulation capacities that support both strong caregiving skills and strong skills relating with peers.


Circular Polarization Luminescence of Groove Anchor Driving Optically Active Poly(methyl methacrylate) Stereocomplexes.
This paper presents a facile method for fabricating a thin-film sample with a high asymmetry value of induced circularly polarized luminescence (iCPL) (|glum| = 2.0 × 10-3). The method involves mixing stereoregular poly(methyl methacrylate) (PMMA) and chiral chromophore (2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE)) to form a complex with a dynamic helical conformation of poly(methyl methacrylate) (PMMA) associated with TFAE via hydrogen bonding. This dynamic helical conformation can be stabilized by the stereocomplexation of a pair of stereoregular PMMA, where the TFAE is sandwiched between a double-helix isotactic PMMA and single-helix syndiotactic PMMA, resulting in a preferential one-handed helical conformation with a high value of iCPL from self-assembly.


Incenp and an aurora-like kinase form a complex essential for chromosome segregation and efficient completion of cytokinesis.
In animal cells, cytokinesis begins shortly after the sister chromatids move to the spindle poles. The inner centromere protein (Incenp)has been implicated in both chromosome segregation and cytokinesis, but it is not known exactly how it mediates these two distinct processes. We identified two Caenorhabditis elegans proteins, ICP-1 and ICP-2, with significant homology in their carboxyl termini to the corresponding region of vertebrate Incenp. Embryos depleted of ICP-1 by RNA-mediated interference had defects in both chromosome segregation and cytokinesis. Depletion of the Aurora-like kinase AIR-2 resulted in a similar phenotype. The carboxy-terminal region of Incenp is also homologous to that in Sli15p, a budding yeast protein that functions with the yeast Aurora kinase Ipl1p. ICP-1 bound C. elegans AIR-2 in vitro, and the corresponding mammalian orthologs Incenp and AIRK2 could be co-immunoprecipitated from cell extracts. A significant fraction of embryos depleted of ICP-1 and AIR-2 completed one cell division over the course of several cell cycles. ICP-1 promoted the stable localization of ZEN-4 (also known as CeMKLP1), a kinesin-like protein required for central spindle assembly. ICP-1 and AIR-2 are part of a complex that is essential for chromosome segregation and for efficient completion of cytokinesis. We propose that this complex acts by promoting dissolution of sister chromatid cohesion and the assembly of the central spindle.


Efficient implementation of a spatial light modulator as a diffractive optical microlens array in a digital Shack-Hartmann wavefront sensor.
A traditional Shack-Hartmann wavefront sensor (SHWS) uses a physical microlens array to sample the incoming wavefront into a number of segments and to measure the phase profile over the cross section of a given light beam. We customized a digital SHWS by encoding a spatial light modulator (SLM) with a diffractive optical lens (DOL) pattern to function as a diffractive optical microlens array. This SHWS can offer great flexibility for various applications. Through fast-Fourier-transform (FFT) analysis and experimental investigation, we studied three sampling methods to generate the digitized DOL pattern, and we compared the results. By analyzing the diffraction efficiency of the DOL and the microstructure of the SLM, we proposed three important strategies for the proper implementation of DOLs and DOL arrays with a SLM. Experiments demonstrated that these design rules were necessary and sufficient for generating an efficient DOL and DOL array with a SLM.


An olfactory stimulus modifies nighttime sleep in young men and women.
Aromatherapy is an anecdotal method for modifying sleep and mood. However, whether olfactory exposure to essential oils affects night-time objective sleep remains untested. Previous studies also demonstrate superior olfactory abilities in women. Therefore, this study investigated the effects of an olfactory stimulus on subsequent sleep and assessed gender differences in such effects. Thirty-one young healthy sleepers (16 men and 15 women, aged 18 to 30 yr, mean+/-SD, 20.5+/-2.4 yr) completed 3 consecutive overnight sessions in a sleep laboratory: one adaptation, one stimulus, and one control night (the latter 2 nights in counterbalanced order). Subjects received an intermittent presentation (first 2 min of each 10 min interval) of an olfactory (lavender oil) or a control (distilled water) stimulus between 23:10 and 23:40 h. Standard polysomnographic sleep and self-rated sleepiness and mood data were collected. Lavender increased the percentage of deep or slow-wave sleep (SWS) in men and women. All subjects reported higher vigor the morning after lavender exposure, corroborating the restorative SWS increase. Lavender also increased stage 2 (light) sleep, and decreased rapid-eye movement (REM) sleep and the amount of time to reach wake after first falling asleep (wake after sleep onset latency) in women, with opposite effects in men. Thus, lavender serves as a mild sedative and has practical applications as a novel, nonphotic method for promoting deep sleep in young men and women and for producing gender-dependent sleep effects.


Making a reconfigurable artificial crystal by ordering bistable magnetic nanowires.
Spin-wave excitations (magnons) are investigated in a one-dimensional (1D) magnonic crystal fabricated out of Ni80Fe20 nanowires. We find two different magnon band structures depending on the magnetic ordering of neighboring wires, i.e., parallel and antiparallel alignment. At a zero in-plane magnetic field H the modes of the antiparallel case are close to those obtained by zone folding of the spin-wave dispersions of the parallel case. This is no longer true for nonzero H which opens a forbidden frequency gap at the Brillouin zone boundary. The 1D stop band gap scales with the external field, which generates a periodic potential for Bragg reflection of the magnons.


Exposure to bioterrorism and mental health response among staff on Capitol Hill.
The October 2001 anthrax attacks heralded a new era of bioterrorism threat in the U.S. At the time, little systematic data on mental health effects were available to guide authorities' response. For this study, which was conducted 7 months after the anthrax attacks, structured diagnostic interviews were conducted with 137 Capitol Hill staff workers, including 56 who had been directly exposed to areas independently determined to have been contaminated. Postdisaster psychopathology was associated with exposure; of those with positive nasal swab tests, PTSD was diagnosed in 27% and any post-anthrax psychiatric disorder in 55%. Fewer than half of those who were prescribed antibiotics completed the entire course, and only one-fourth had flawless antibiotic adherence. Thirty percent of those not exposed believed they had been exposed; 18% of all study participants had symptoms they suspected were symptoms of anthrax infection, and most of them sought medical care. Extrapolation of raw numbers to large future disasters from proportions with incorrect belief in exposure in this limited study indicates a potential for important public health consequences, to the degree that people alter their healthcare behavior based on incorrect exposure beliefs. Incorrect belief in exposure was associated with being very upset, losing trust in health authorities, having concerns about mortality, taking antibiotics, and being male. Those who incorrectly believe they were exposed may warrant concern and potential interventions as well as those exposed. Treatment adherence and maintenance of trust for public health authorities may be areas of special concern, warranting further study to inform authorities in future disasters involving biological, chemical, and radiological agents.


Is poverty a driver for risky sexual behaviour? Evidence from national surveys of adolescents in four African countries.
This paper contributes to conflicting evidence on the link between poverty and risky sexual behaviour by examining the effect of wealth status on age at first sex, condom use, and multiple partners using nationally representative adolescents' data from Burkina Faso, Ghana, Malawi, and Uganda. The results show that the wealthiest girls in Burkina Faso, Ghana, and Malawi had later sexual debut compared with their poorer counterparts but this association was not significant for Uganda. Wealth status was weaker among males and significant only in Malawi, where those in the middle quintile had earlier sexual debut. Wealthier adolescents were most likely to use condoms at the last sexual act, but wealth status was not associated with number of sexual partners. Although the link between wealth status and sexual behaviour is not consistent, there is evidence that poor females are vulnerable to infection because of earlier sexual debut and non-use of condoms.


Antibiotic dose impact on resistance selection in the community: a mathematical model of beta-lactams and Streptococcus pneumoniae dynamics.
Streptococcus pneumoniae is a major pathogen in the community and presents high rates of resistance to the available antibiotics. To prevent antibiotic treatment failure caused by highly resistant bacteria, increasing the prescribed antibiotic dose has recently been suggested. The aim of the present study was to assess the influence of beta-lactam prescribed doses on the emergence of resistance and selection in the community. A mathematical model was constructed by combining S. pneumoniae pharmacodynamic and population-dynamic approaches. The received-dose heterogeneity in the population was specifically modeled. Simulations over a 50-year period were run to test the effects of dose distribution and antibiotic exposure frequency changes on community resistance patterns, as well as the accuracy of the defined daily dose as a predictor of resistance. When the frequency of antibiotic exposure per year was kept constant, dose levels had a strong impact on the levels of resistance after a 50-year simulation. The lowest doses resulted in a high prevalence of nonsusceptible strains (> or =70%) with MICs that were still low (1 mg/liter), whereas high doses resulted in a lower prevalence of nonsusceptible strains (<40%) and higher MICs (2 mg/liter). Furthermore, by keeping the volume of antibiotics constant in the population, different patterns of use (low antibiotic dose and high antibiotic exposure frequency versus high dose and low frequency) could lead to markedly different rates of resistance distribution and prevalence (from 10 to 100%). Our results suggest that pneumococcal resistance patterns in the community are strongly related to the individual beta-lactam doses received: limiting beta-lactam use while increasing the doses could help reduce the prevalence of resistance, although it should select for higher levels of resistance. Surveillance networks are therefore encouraged to collect both daily antibiotic exposure frequencies and individual prescribed doses.


EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interactions.
p185neu is a receptor-like protein encoded by the neu/erbB-2 proto-oncogene. This protein is closely related to the epidermal growth factor (EGF) receptor, but does not bind EGF. We report here that incubation of Rat-1 cells with EGF stimulates tyrosine phosphorylation of p185. This effect is specific to EGF since neither platelet derived growth factor (PDGF) nor insulin, which also bind to receptors with ligand-stimulated tyrosine kinase activity, induced tyrosine phosphorylation of p185. The EGF-stimulated tyrosine phosphorylation of p185 and of the EGF receptor occurred with similar kinetics and EGF dose-responses, and both phosphorylations were prevented by down-regulation of the EGF receptor with EGF. Since p185 does not bind EGF, these results suggested that p185 is a substrate for the EGF receptor kinase. Incubation of cells with EGF before lysis stimulated the tyrosine phosphorylation of p185 in immune complexes. This suggested that EGF, acting through the EGF receptor, can regulate the intrinsic kinase activity of p185.


Families and caregivers of older people: expectations, communication and care decisions.
While family caregivers may temporarily relinquish responsibility for daily care to health professionals for the period of hospitalization, new expectations and demands are placed upon them. Family caregivers can be asked to commit to new relationships with health professionals, contribute to care decisions and discharge planning. For the caregivers of older patients these new expectations may be challenging, and contribute to feelings of burden and increased stress. The aim of this qualitative descriptive study was to explore the experience of family caregivers when their relative is an inpatient in this outer Melbourne geriatric evaluation and management facility. This study found that the burden associated with the experience of caregiving continued despite the hospitalization of their relative. The challenges faced by families included communicating with health professionals, and being asked to contribute to care decisions, in particular those regarding discharge planning, and managing conflict. In conclusion, the issues and challenges faced by family caregivers needs to be acknowledged and considered as an extension of patient care planning.


Cost analysis of screening for, diagnosing, and staging prostate cancer based on a systematic review of published studies.
The reported estimates of the economic costs associated with prostate cancer screening, diagnostic testing, and clinical staging are substantial. However, the resource costs (i.e., factors such as physician's time, laboratory tests, patient's time away from work) included in these estimates are unknown. We examined the resource costs for prostate cancer screening, diagnostic tests, and staging; examined how these costs differ in the United States from costs in other industrialized countries; and estimated the cost per man screened for prostate cancer, per man given a diagnostic test, and per man given a clinically staged diagnosis of this disease. We searched the electronic databases MEDLINE, EMBASE, and CINAHL for articles and reports on prostate cancer published from January 1980 through December 2003. Studies were selected according to the following criteria: the article was published in English; the full text was available for review; the study reported the resource or input cost data used to estimate the cost of prostate cancer testing, diagnosing, or clinical staging; and the study was conducted in an established market economy. We used descriptive statistics, weighted mean, and Monte Carlo simulation methods to pool and analyze the abstracted data. Of 262 studies examined, 28 met our selection criteria (15 from the United States and 13 from other industrialized countries). For studies conducted in the United States, the pooled baseline resource cost was $37.23 for screening with prostate-specific antigen (PSA) and $31.77 for screening with digital rectal examination (DRE). For studies conducted in other industrialized countries, the pooled baseline resource cost was $30.92 for screening with PSA and $33.54 for DRE. For diagnostic and staging methods, the variation in the resource costs between the United States and other industrialized countries was mixed. Because national health resources are limited, a decision about whether to invest in early detection of prostate cancer requires an understanding of the factors included in estimates of the economic cost of this disease. This study may benefit health policy makers charged with allocating resources for prostate cancer.


Perception while watching movies: Effects of physical screen size and scene type.
Over the last decade, television screens and display monitors have increased in size considerably, but has this improved our televisual experience? Our working hypothesis was that the audiences adopt a general strategy that "bigger is better." However, as our visual perceptions do not tap directly into basic retinal image properties such as retinal image size (C. A. Burbeck, 1987), we wondered whether object size itself might be an important factor. To test this, we needed a task that would tap into the subjective experiences of participants watching a movie on different-sized displays with the same retinal subtense. Our participants used a line bisection task to self-report their level of "presence" (i.e., their involvement with the movie) at several target locations that were probed in a 45-min section of the movie "The Good, The Bad, and The Ugly." Measures of pupil dilation and reaction time to the probes were also obtained. In Experiment 1, we found that subjective ratings of presence increased with physical screen size, supporting our hypothesis. Face scenes also produced higher presence scores than landscape scenes for both screen sizes. In Experiment 2, reaction time and pupil dilation results showed the same trends as the presence ratings and pupil dilation correlated with presence ratings, providing some validation of the method. Overall, the results suggest that real-time measures of subjective presence might be a valuable tool for measuring audience experience for different types of (i) display and (ii) audiovisual material.


Multimodal Spectroscopic Study of Amyloid Fibril Polymorphism.
Amyloid fibrils are a large class of self-assembled protein aggregates that are formed from unstructured peptides and unfolded proteins. The fibrils are characterized by a universal β-sheet core stabilized by hydrogen bonds, but the molecular structure of the peptide subunits exposed on the fibril surface is variable. Here we show that multimodal spectroscopy using a range of bulk- and surface-sensitive techniques provides a powerful way to dissect variations in the molecular structure of polymorphic amyloid fibrils. As a model system, we use fibrils formed by the milk protein β-lactoglobulin, whose morphology can be tuned by varying the protein concentration during formation. We investigate the differences in the molecular structure and composition between long, straight fibrils versus short, wormlike fibrils. We show using mass spectrometry that the peptide composition of the two fibril types is similar. The overall molecular structure of the fibrils probed with various bulk-sensitive spectroscopic techniques shows a dominant contribution of the β-sheet core but no difference in structure between straight and wormlike fibrils. However, when probing specifically the surface of the fibrils with nanometer resolution using tip-enhanced Raman spectroscopy (TERS), we find that both fibril types exhibit a heterogeneous surface structure with mainly unordered or α-helical structures and that the surface of long, straight fibrils contains markedly more β-sheet structure than the surface of short, wormlike fibrils. This finding is consistent with previous surface-specific vibrational sum-frequency generation (VSFG) spectroscopic results ( VandenAkker et al. J. Am. Chem. Soc. , 2011 , 133 , 18030 - 18033 , DOI: 10.1021/ja206513r ). In conclusion, only advanced vibrational spectroscopic techniques sensitive to surface structure such as TERS and VSFG are able to reveal the difference in structure that underlies the distinct morphology and rigidity of different amyloid fibril polymorphs that have been observed for a large range of food and disease-related proteins.


The reliability of anterior segment lesions as indicators of onchocercal eye disease in Guatemala.
World Health Organization certification criteria for onchocerciasis elimination use anterior segment eye lesion prevalence as an indicator of mass ivermectin treatment program success. Lesions either contain visible microfilaria (noninflammatory punctate keratitis [PK] or microfilariae in anterior chamber [MFAC]), or microfilaria obscured by inflammation (inflammatory PK). To assess the utility of these disease indicators, two experienced ophthalmologists independently examined persons from endemic (N = 325) and nonendemic (N = 348) Guatemalan communities. Thirty-six (11.1%) and nine (2.6%) persons from endemic and nonendemic areas respectively had lesions found by either ophthalmologist (prevalence ratio = 4.3, 95% CI 2.1-8.8, P < 0.001). All lesions in nonendemic areas were inflammatory PK in whom no persons were seropositive for onchocerciasis. Overall, observer agreement was moderate (Kappa = 0.49), and most (61%) discordance occurred with inflammatory PK lesions. Our findings suggest that inflammatory punctate keratitis is neither a specific nor a reliable indicator of onchocercal eye disease. Future prevalence surveys should rely upon noninflammatory lesions as disease indicators.


Prospective Coding by Spiking Neurons.
Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron's firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ).


Mitochondrial DNA phylogeography of the Mesoamerican spiny-tailed lizards (Ctenosaura quinquecarinata complex): historical biogeography, species status and conservation.
Through the examination of past and present distributions of plants and animals, historical biogeographers have provided many insights on the dynamics of the massive organismal exchange between North and South America. However, relatively few phylogeographic studies have been attempted in the land bridge of Mesoamerica despite its importance to better understand the evolutionary forces influencing this biodiversity 'hotspot'. Here we use mitochondrial DNA sequence data from fresh samples and formalin-fixed museum specimens to investigate the genetic and biogeographic diversity of the threatened Mesoamerican spiny-tailed lizards of the Ctenosaura quinquecarinata complex. Species boundaries and their phylogeographic patterns are examined to better understand their disjunct distribution. Three monophyletic, allopatric lineages are established using mtDNA phylogenetic and nested clade analyses in (i) northern: México, (ii) central: Guatemala, El Salvador and Honduras, and (iii) southern: Nicaragua and Costa Rica. The average sequence divergence observed between lineages varied between 2.0% and 3.7% indicating that they do not represent a very recent split and the patterns of divergence support the recently established nomenclature of C. quinquecarinata, Ctenosaura flavidorsalis and Ctenosaura oaxacana. Considering the geological history of Mesoamerica and the observed phylogeographic patterns of these lizards, major evolutionary episodes of their radiation in Mesoamerica are postulated and are indicative of the regions' geological complexity. The implications of these findings for the historical biogeography, taxonomy and conservation of these lizards are discussed.


In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases.
Potent, selective, and cell active small molecule kinase inhibitors are useful tools to help unravel the complexities of kinase signaling. As the biological functions of individual kinases become better understood, they can become targets of drug discovery efforts. The small molecules used to shed light on function can also then serve as chemical starting points in these drug discovery efforts. The Nek family of kinases has received very little attention, as judged by number of citations in PubMed, yet they appear to play many key roles and have been implicated in disease. Here we present our work to identify high quality chemical starting points that have emerged due to the increased incidence of broad kinome screening. We anticipate that this analysis will allow the community to progress towards the generation of chemical probes and eventually drugs that target members of the Nek family.


Comparative study of Cronobacter identification according to phenotyping methods.
Microbiological criteria applied to powdered infant formula (PIF) require the absence of all Cronobacter spp. Consequently, misidentification of isolates from finished products can lead to significant financial losses for manufacturers and could increase the risk of neonatal infection. Biochemical identification of suspect isolates using commercially available test panels is recommended for use by PIF manufacturers by both the US FDA and ISO standard methods for Cronobacter species; however, phenotyping can be unreliable, particularly for a genus such as Cronobacter where the taxonomy has been subject to frequent changes. This study compared the predicted identification by commonly used phenotyping kits (API20E and ID32E) for over 240 strains of Cronobacter from diverse sources, which had been identified using DNA sequence analysis. In 2015, the databases associated with the API20E and ID32E biochemical test panels were updated, including the recognition of the Cronobacter genus. Thus, the identifications from multiple versions the databases were compared to each other and to identifications based on DNA sequencing methods. Using previous versions of the API20E database, 90.0 % of strains (216/240) resulted in a match for the species identification; however, version 5.0 produced matches for only 82.3 % of strains (237/288). Similarly, the update to version 4.0 in the ID32E database caused the percentage of matches to drop from 88.9 % (240/270) to 43.2 % (139/322). A smaller study showed that the Vitek GN system identified all 14 strains, belonging all seven Cronobacter species, as members of the 'C. sakazakii group,' but also attributed three strains of Franconibacter helveticus and F. pulveris to this group. In silco analysis of a PCR-based method targeting ompA predicted that amplification would only occur with Cronobacter species and this method may be a feasible alternative to biochemical phenotyping. These results indicate that commercially available biochemical test panels are not sufficiently reliable for speciation of Cronobacter isolates. Although DNA-sequence based methods would be the more reliable approach; however, this is not currently feasible for many food microbiology laboratories. Instead, a previously published PCR-based method targeting ompA is suggested as an alternative for identification of Cronobacter species based on in silico analysis.


High-intensity interval training enhances mitochondrial bioenergetics of platelets in patients with heart failure.
Exercise improves cardiopulmonary fitness and reduces the risk of vascular thrombosis in patients with cardiovascular diseases. In platelets, mitochondria carry out cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of high-intensity interval training (HIIT) on systemic aerobic capacity and platelet mitochondrial bioenergetics in patients with heart failure (HF). Thirty-four randomly selected HF patients engaged in HIIT (3-min intervals at 40% and 80% of VO2peak, n = 17) for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC; n = 17). Systemic aerobic capacity (i.e., peak O2 consumption, VO2peak) and platelet mitochondrial O2 consumption rate (OCR) in the HF patients were measured through automatic gas analysis and high-resolution respirometry, respectively. The HIIT group exhibited higher VO2peak and O2 uptake efficiency slope and lower VE-VCO2 slope after 12-week intervention, compared to those of the GHC group. Moreover, the HIIT regimen increased the maximal and reserve OCR capacities, enhanced the Complex I- and II-mediated OCRs, and elevated the bioenergetic health index in platelet mitochondria; however, these effects were not observed with the GHC regimen. Additionally, the VO2peak levels were positively correlated with the maximal and reserve OCR capacities and Complex I- and II-mediated OCRs in platelet mitochondria. Platelet mitochondrial function is an ideal bioenergetic indicator in patients with HF. HIIT for 12 weeks elevates platelet mitochondrial OCRs via increasing Complex I and II activities. Moreover, systemic aerobic capacity is positively associated with platelet mitochondrial OCRs in HF patients.


Gemcitabine Combination Nano Therapies for Pancreatic Cancer.
Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy.


Non-toxic ubiquitous over-expression of utrophin in the mdx mouse.
Duchenne muscular dystrophy (DMD) is an inherited, severe muscle wasting disease caused by the loss of the cytoskeletal protein, dystrophin. Patients usually die in their late teens or early twenties of cardiac or respiratory failure. We have previously demonstrated that the dystrophin related protein, utrophin is able to compensate for the loss of dystrophin in the mdx mouse, the mouse model of the disease. Expression of a utrophin transgene under the control of an HSA promoter results in localization of utrophin to the sarcolemma and prevents the muscle pathology. Here we show that the over-expression of full-length utrophin in a broad range of tissues is not detrimental in the mdx mouse. These findings have important implications for the feasibility of the up-regulation of utrophin in therapy for DMD since they suggest that tissue specific up-regulation may not be necessary.


Mouse modeling for anxiety disorders in older adults.
Anxiety disorders are common in older adults and are strongly associated with increased risk for numerous age-related conditions. Preclinical mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these disorders. Mice serve as excellent preclinical models as they have been used extensively in aging studies, and behavioral tests have been developed. A panel of tests would capture the important clinical aspects of apathy, anxiety, and psychomotor behavior and allow longitudinal testing strategies in a rigorous and minimally stressful manner.


A study of mycobacterial transcriptional apparatus: identification of novel features in promoter elements.
Our earlier studies on transcriptional signals of mycobacteria had revealed that (i) strong promoters occur less frequently in the slowly growing pathogen Mycobacterium tuberculosis H37Rv than in the fast-growing saprophyte M. smegmatis and (ii) mycobacterial promoters function poorly in Escherichia coli. We now present evidence that RNA polymerases of M. smegmatis, M. tuberculosis, and M. bovis BCG recognize promoter elements with comparable efficiencies. Analysis of these randomly isolated mycobacterial promoters by DNA sequencing, primer extension, and deletion experiments revealed that their -10 regions are highly similar to those of E. coli promoters, in contrast to their -35 regions, which can tolerate a greater variety of sequences, owing presumably to the presence of multiple sigma factors with different or overlapping specificities for -35 regions, as reported earlier for the Streptomyces promoters. A comparison of the -10 and -35 binding domains of MysA, HrdB, and RpoD (the principal sigma factors of M. smegmatis, Streptomyces aureofaciens, and E. coli, respectively) showed that all three sigma factors have nearly identical -10 binding domains. However, the -35 binding domains of the principal mycobacterial and streptomycete sigma factors, although nearly identical to each other, are vastly different from the corresponding region of the sigma factor of E. coli. Thus, the transcriptional signals of mycobacteria have features in common with Streptomyces promoters but differ from those of E. coli because of major differences in the -35 regions of the promoters and the corresponding binding domain in the sigma factor.


Clinical features, management, and prognosis of spontaneous coronary artery dissection.
Spontaneous coronary artery dissection (SCAD) is an acute coronary event of uncertain origin. Clinical features and prognosis remain insufficiently characterized. A retrospective single-center cohort study identified 87 patients with angiographically confirmed SCAD. Incidence, clinical characteristics, treatment modalities, in-hospital outcomes, and long-term risk of SCAD recurrence or major adverse cardiac events were evaluated. Mean age was 42.6 years; 82% were female. Extreme exertion at SCAD onset was more frequent in men (7 of 16 versus 2 of 71; P<0.001), and postpartum status was observed in 13 of 71 women (18%). Presentation was ST-elevation myocardial infarction in 49%. Multivessel SCAD was found in 23%. Initial conservative management (31 of 87) and coronary artery bypass grafting (7 of 87) were associated with an uncomplicated in-hospital course, whereas percutaneous coronary intervention was complicated by technical failure in 15 of 43 patients (35%) and 1 death. During a median follow-up of 47 months (interquartile range, 18-106 months), SCAD recurred in 15 patients, all female. Estimated 10-year rate of major adverse cardiac events (death, heart failure, myocardial infarction, and SCAD recurrence) was 47%. Fibromuscular dysplasia of the iliac artery was identified incidentally in 8 of 16 femoral angiograms (50%) undertaken before closure device placement and in the carotid arteries of 2 others with carotid dissection. SCAD affects a young, predominantly female population, frequently presenting as ST-elevation myocardial infarction. Although in-hospital mortality is low regardless of initial treatment, percutaneous coronary intervention is associated with high rates of complication. Risks of SCAD recurrence and major adverse cardiac events in the long term emphasize the need for close follow-up. Fibromuscular dysplasia is a novel association and potentially causative factor.


Exposure to norepinephrine enhances Brachyspira pilosicoli growth, attraction to mucin and attachment to Caco-2 cells.
Brachyspira pilosicoli is an anaerobic intestinal spirochaete that colonizes the large intestine of a variety of species of birds and mammals, including human beings. Colonization may result in a mild colitis and diarrhoea in a condition known as 'intestinal spirochaetosis'. The catecholamine norepinephrine (NE), which is known to influence the behaviour of many bacterial species, may be present in the colon. The purpose of the current study was to determine whether exposure of B. pilosicoli to NE would influence its in vitro behaviour in assays that may reflect in vivo colonization potential. B. pilosicoli strain 95/1000 was used in all the assays. Addition of NE at a concentration of 0.05 mM to B. pilosicoli growing in anaerobic broth significantly increased spirochaete numbers after 4 days incubation. The effect of higher concentrations of NE was not significant. Exposure to 0.05 mM NE, but not to higher concentrations, also resulted in significantly more spirochaete cells entering capillary tubes containing 4 % porcine gastric mucin than occurred with untreated cultures. When NE was added to chemotaxis buffer in capillary tubes, significantly more spirochaetes were attracted to the buffer containing NE at 0.1, 0.5 and 1.0 mM than to buffer containing 0.05 mM NE, or when no NE was added. Exposure of B. pilosicoli cultures to 0.05 mM NE prior to incubation with Caco-2 monolayers resulted in more attachment to the monolayer than occurred with non-exposed cultures. These results show that at higher concentrations, NE acts as a chemoattractant for B. pilosicoli, and at 0.05 mM it increases the spirochaete's growth rate, attraction to mucin and rate of attachment to cultured enterocytes. These activities are likely to enhance the ability of B. pilosicoli to colonize, and may be induced by conditions that increase NE concentrations in the intestinal tract, such as the stresses associated with crowding.


The major site of tyrosine phosphorylation in polyomavirus middle T antigen is not required for transformation.
The induction of tumors and cellular transformation mediated by polyomavirus requires the action of middle T antigen. Accordingly, we have begun to define the domains of the viral protein important for these processes to learn more about its site and mechanism of action. One of the domains of middle T antigen which is thought to be important for its function includes a stretch of acidic amino acids and a vicinal tyrosine residue (tyrosine 315), the major site of tyrosine phosphorylation in vitro. To determine whether these acidic amino acids and tyrosine 315 are required to maintain the transforming activity of middle T antigen, we constructed deletions within the DNA sequences encoding these amino acids and measured the capacity of the resulting mutants to transform Rat-1 cells in culture. This was accomplished by using in vitro mutagenesis techniques with molecularly cloned polyomavirus DNA. Seven mutants were isolated. Five of these proved incapable of transforming Rat-1 cells and were found to contain deletions which altered the reading frame for middle T antigen. However, two mutants, pPdl1-4 and pPdl2-7, retained the capacity to transform Rat-1 cells at high frequencies. The middle T antigen encoded by one of these mutants, pPdl1-4, lacks part of the acidic string of amino acids but not tyrosine 315 (amino acids 304 through 310 are deleted), whereas the middle T antigen encoded by the other mutant, pPdl2-7, lacks the entire acidic amino acid stretch as well as tyrosine 315 (amino acids 285 through 323 are deleted). Rat-1 cells transformed by one or the other mutant DNA displayed a fully transformed phenotype, including the capacity to form tumors in animals. These results prove that the major site of tyrosine phosphorylation in middle T antigen and the acidic amino acids which precede it are not essential for its transforming activity.


Recurrent neuroendocrine (Merkel cell) carcinoma of the skin presenting as marrow failure in a man with systemic lupus erythematosus.
Neuroendocrine carcinoma of the skin, Merkel cell carcinoma, is an aggressive malignancy with a high incidence of local recurrence and metastasis. We describe a case of neuroendocrine carcinoma of the skin with unusual metastatic spread to the bone marrow in a 55-year-old man with systemic lupus erythematosus. Following resection of a left temporal subcutaneous nodule and complete left parotidectomy and radical lymph node dissection, the patient presented with pancytopenia. Although focal bony metastatic disease was not identified, his bone marrow was diffusely replaced by metastatic carcinoma. High-dose chemotherapy allowed a brief remission; however, the patient subsequently died with central nervous system metastases.


eRegistries: governance for electronic maternal and child health registries.
The limited availability of maternal and child health data has limited progress in reducing mortality and morbidity among pregnant women and children. Global health agencies, leaders, and funders are prioritizing strategies that focus on acquiring high quality health data. Electronic maternal and child health registries (eRegistries) offer a systematic data collection and management approach that can serve as an entry point for preventive, curative and promotive health services. Due to the highly sensitive nature of reproductive health information, careful consideration must be accorded to privacy, access, and data security. In the third paper of the eRegistries Series, we report on the current landscape of ethical and legal governance for maternal and child health registries in developing countries. This research utilizes findings from two web-based surveys, completed in 2015 that targeted public health officials and health care providers in 76 countries with high global maternal and child mortality burden. A sample of 298 public health officials from 64 countries and 490 health care providers from 59 countries completed the online survey. Based on formative research in the development of the eRegistries Governance Guidance Toolkit, the surveys were designed to investigate topics related to maternal and child health registries including ethical and legal issues. According to survey respondents, the prevailing legal landscape is characterized by inadequate data security safeguards and weak support for core privacy principles. Respondents from the majority of countries indicated that health information from medical records is typically protected by legislation although legislation dealing specifically or comprehensively with data privacy may not be in place. Health care provider trust in the privacy of health data at their own facilities is associated with the presence of security safeguards. Addressing legal requirements and ensuring that privacy and data security of women's and children's health information is protected is an ethical responsibility that must not be ignored or postponed, particularly where the need is greatest. Not only are the potential harm and unintended consequences of inaction serious for individuals, but they could impact public trust in health registries leading to decreased participation and compromised data integrity.


Socio-Economic Predictors and Distribution of Tuberculosis Incidence in Beijing, China: A Study Using a Combination of Spatial Statistics and GIS Technology.
Evidence shows that multiple factors, such as socio-economic status and access to health care facilities, affect tuberculosis (TB) incidence. However, there is limited literature available with respect to the correlation between socio-economic/health facility factors and tuberculosis incidence. This study aimed to explore the relationship between TB incidence and socio-economic/health service predictors in the study settings. A retrospective spatial regression analysis was carried out based on new sputum smear-positive pulmonary TB cases in Beijing districts. Global Moran's I analysis was adopted to detect the spatial dependency followed by spatial regression models (spatial lag model, and spatial error model) along with the ordinary least square model were applied to examine the correlation between TB incidence and predictors. A high incidence of TB was seen in densely populated districts in Beijing, e.g., Haidian, Mentougou, and Xicheng. After comparing the R², log-likelihood, and Akaike information criterion (AIC) values among three models, the spatial error model (R² = 0.413; Log Likelihood = -591; AIC = 1199.76) identified the best model fit for the spatial regression model. The study showed that the number of beds in health institutes (p < 0.001) and per capita gross domestic product (GDP) (p = 0.025) had a positive effect on TB incidence, whereas population density (p < 0.001) and migrated population (p < 0.001) had an adverse impact on TB incidence in the study settings. High TB incidence districts were detected in urban and densely populated districts in Beijing. Our findings suggested that socio-economic predictors influence TB incidence. These findings may help to guide TB control programs and promote targeted intervention.


Engaging actively with issues in the responsible conduct of science: lessons from international efforts are relevant for undergraduate education in the United States.
Numerous studies are demonstrating that engaging undergraduate students in original research can improve their achievement in the science, technology, engineering, and mathematics (STEM) fields and increase the likelihood that some of them will decide to pursue careers in these disciplines. Associated with this increased prominence of research in the undergraduate curriculum are greater expectations from funders, colleges, and universities that faculty mentors will help those students, along with their graduate students and postdoctoral fellows, develop an understanding and sense of personal and collective obligation for responsible conduct of science (RCS). This Feature describes an ongoing National Research Council (NRC) project and a recent report about educating faculty members in culturally diverse settings (Middle East/North Africa and Asia) to employ active-learning strategies to engage their students and colleagues deeply in issues related to RCS. The NRC report describes the first phase of this project, which took place in Aqaba and Amman, Jordan, in September 2012 and April 2013, respectively. Here we highlight the findings from that report and our subsequent experience with a similar interactive institute in Kuala Lumpur, Malaysia. Our work provides insights and perspectives for faculty members in the United States as they engage undergraduate and graduate students, as well as postdoctoral fellows, to help them better understand the intricacies of and connections among various components of RCS. Further, our experiences can provide insights for those who may wish to establish "train-the-trainer" programs at their home institutions.


Overcoming artifacts from metallic orthopedic implants at high-field-strength MR imaging and multi-detector CT.
At magnetic resonance (MR) imaging and multidetector computed tomography (CT), artifacts arising from metallic orthopedic hardware are an obstacle to obtaining optimal images. Although various techniques for reducing such artifacts have been developed and corroborated by previous researchers, a new era of more powerful MR imaging and multidetector CT modalities has renewed the importance of a systematic consideration of methods for artifact reduction. Knowledge of the factors that contribute to artifacts, of related theories, and of artifact reduction techniques has become mandatory for radiologists. Factors that affect artifacts on MR images include the composition of the metallic hardware, the orientation of the hardware in relation to the direction of the main magnetic field, the strength of the magnetic field, the pulse sequence type, and other MR imaging parameters (mainly voxel size, which is determined by the field of view, image matrix, section thickness, and echo train length). At multidetector CT, the factors that affect artifacts include the composition of the hardware, orientation of the hardware, acquisition parameters (peak voltage, tube charge, collimation, and acquired section thickness), and reconstruction parameters (reconstructed section thickness, reconstruction algorithm used, and whether an extended CT scale was used). A comparison of images obtained with different hardware and different acquisition and reconstruction parameters facilitates an understanding of methods for reducing or overcoming artifacts related to metallic implants.


The maternity information concerns of Somali women in the United Kingdom.
The aims of the study were to explore the maternity information concerns of a group of Somali women in a Northern English city and to investigate the relationships of these women with maternity health professionals. The Somali community is one of the most established ethnic minorities in the United Kingdom (UK). The health needs of this group and in particular, the information needs of Somali women with respect to pregnancy, childbirth and post-natal care are poorly understood. To facilitate information provision to birthing mothers and to support maternal decision-making among minority ethnic women, research is required to understand and identify their information needs. A user-centred study utilizing a focus group and semi-structured interviews with English-speaking and non-English speaking Somali women was conducted in a large English city. Discussions were audiotaped, translated, transcribed and then analysed using a variation of the constant comparative Themes and categories were identified across transcripts during data collection and analysis and appropriate quotations are used to illustrate all themes. Major findings that emerged from the analysis related to contact with health professionals, language support and information and satisfaction with health professionals. The findings indicate key maternity information concerns of Somali women with regard to maternity issues and have a number of implications for midwifery and nursing practice. Poor communication between the non-English speaking Somali women and health workers was perceived as an underlying problem in seeking information. Fears about misinterpretation and confidentiality, limit the usefulness of interpreters. The Somali women perceived that they were denied information due to punitive attitudes and prejudiced views among health professionals.


Current approaches in familial colorectal cancer: a clinical perspective.
Individuals with a family history of colorectal cancer or colorectal adenomas have an increased risk for colorectal cancer. When no hereditary syndrome is evident, screening is based on empiric risk estimates. The risk is greatest for individuals with specific inherited cancer-predisposing disorders. When conditions such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer are diagnosed, specific neoplasm risk estimates can usually be performed based on advances in molecular genetics. These estimates lead to more straightforward and cost-effective approaches to surveillance and management. The National Comprehensive Cancer Center Network (NCCN) and other groups have provided detailed guidelines for evaluating patients based on recognition of clinical syndrome characteristics, followed by appropriate genetic counseling, genetic testing, and optimal surveillance. The NCCN guidelines are used as a frame of reference for this discussion of selected recent advances in human cancer genetics as they apply to clinical practice.


Safety of Tumor Necrosis Factor Inhibitors during Pregnancy and Breastfeeding.
Tumor necrosis factor (TNF) inhibitors are useful in the treatment of numerous inflammatory and immunologic disorders. Since many of these conditions occur in women of childbearing age, safety during pregnancy and breastfeeding is of considerable importance. This paper is a review of the literature on the safety of TNF inhibitors during pregnancy and breastfeeding published between 2001 and 2011. TNF inhibitors do not appear to be associated with a high risk of teratogenicity or intrauterine death. However, a small magnitude increase in risk cannot be ruled out given the paucity of data on the subject. Although TNF inhibitor use may be associated with a higher rate of preterm delivery, this may in fact be due to an active, underlying disease. Therefore, the decision to use these medications should be made on a case-by-case basis. If the disease cannot be managed with first line agents, TNF inhibitors may be helpful in reducing the number of disease exacerbations. Nevertheless, when using TNF inhibitors, it is prudent to discontinue treatment around the third trimester when transfer across the placenta is greatest and to restart postpartum.


Occurrence of Fusarium commune and F. oxysporum in Horseradish Roots.
This study was conducted to investigate the etiology of internal discoloration of horseradish roots. Several species of Fusarium and Verticillium were isolated from internally discolored horseradish roots collected from commercial fields in Illinois and research plots in Wisconsin during 2008 and 2009. Eleven isolates of Fusarium, identified as Fusarium oxysporum based on morphological features, were characterized by DNA sequencing of the nuclear translation elongation factor 1α (EF-1α) and mitochondrial small-subunit ribosomal DNA (mtSSU rDNA). Maximum parsimony analyses of DNA sequences from these two regions and the combined data set revealed that six isolates were clearly separated into a common clade that contained F. commune, with the remaining five isolates being grouped into a common clade with F. oxysporum. Based on the DNA sequence data, we considered the six isolates grouped into a common clade with F. commune to be F. commune. Pathogenicity tests of F. commune and F. oxysporum were conducted on two horseradish cultivars, '1573' and 'Big Top Western', in a greenhouse. Root segments were inoculated by dipping them in a conidial suspension and then growing them in pots in a greenhouse for 4 months. For plants inoculated with F. commune, internal root discoloration and root rot developed 1 month after inoculation and almost all roots of the plant were completely rotten 4 months after inoculation. Inoculation of the plants with F. oxysporum resulted in only internal root discoloration but not root rot symptoms. This is the first report of F. commune causing internal discoloration and root rot of horseradish.


cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action.
To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge.


Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate.
The COVID-19 pandemic caused by SARS-CoV-2 is in immediate need of an effective antidote. Although the Spike glycoprotein (SgP) of SARS-CoV-2 has been shown to bind to heparins, the structural features of this interaction, the role of a plausible heparan sulfate proteoglycan (HSPG) receptor, and the antagonism of this pathway through small molecules remain unaddressed. Using an in vitro cellular assay, we demonstrate HSPGs modified by the 3-O-sulfotransferase isoform-3, but not isoform-5, preferentially increased SgP-mediated cell-to-cell fusion in comparison to control, unmodified, wild-type HSPGs. Computational studies support preferential recognition of the receptor-binding domain of SgP by 3-O-sulfated HS sequences. Competition with either fondaparinux, a 3-O-sulfated HS-binding oligopeptide, or a synthetic, non-sugar small molecule, blocked SgP-mediated cell-to-cell fusion. Finally, the synthetic, sulfated molecule inhibited fusion of GFP-tagged pseudo SARS-CoV-2 with human 293T cells with sub-micromolar potency. Overall, overexpression of 3-O-sulfated HSPGs contribute to fusion of SARS-CoV-2, which could be effectively antagonized by a synthetic, small molecule.


Coaching the Debriefer: Peer Coaching to Improve Debriefing Quality in Simulation Programs.
Formal faculty development programs for simulation educators are costly and time-consuming. Peer coaching integrated into the teaching flow can enhance an educator's debriefing skills. We provide a practical guide for the who, what, when, where, why, and how of peer coaching for debriefing in simulation-based education. Peer coaching offers advantages such as psychological safety and team building, and it can benefit both the educator who is receiving feedback and the coach who is providing it. A feedback form for effective peer coaching includes the following: (1) psychological safety, (2) framework, (3) method/strategy, (4) content, (5) learner centeredness, (6) co-facilitation, (7) time management, (8) difficult situations, (9) debriefing adjuncts, and (10) individual style and experience. Institutional backing of peer coaching programs can facilitate implementation and sustainability. Program leaders should communicate the need and benefits, establish program goals, and provide assessment tools, training, structure, and evaluation to optimize chances of success.


Photoneutron yields from tungsten in the energy range of the giant dipole resonance.
Photoneutron production on the nuclei of high-Z components of medical accelerator heads can lead to a significant secondary dose during a course of bremsstrahlung radiotherapy. However, a quantitative evaluation of secondary neutron dose requires improved data on the photoreaction yields. These have been measured as a function of photon energy, neutron energy and neutron angle for natW, using tagged photons at the MAX-Lab photonuclear facility in Sweden. This work presents neutron yields for natW(gamma, n) and compares these with the predictions of the Monte Carlo code MCNP-GN, developed specifically to simulate photoneutron production at medical accelerators.


Implementation of close contact elicitation at the time of COVID-19 testing-Atlanta, GA, October-November 2020.
Contact tracing during the Coronavirus Disease 2019 (COVID-19) pandemic in the USA has been met with various challenges. In an attempt to improve the yield of close contact collection, the Fulton County Board of Health implemented a pilot approach to contact elicitation at the time of testing. Between October and November 2020, close contacts were elicited from persons under investigation (PUIs) at one COVID-19 testing site in Fulton County, GA. Secure online data collection forms were used to record PUI demographic data, close contact information and reasons for not providing contacts. Of 1238 PUIs, 48% reported at least one contact. Among the 66 people who tested positive, 16 (24%) reported contacts compared to 578/1165 (50%) who tested negative. PUIs of increasing age were less likely to provide contacts; Black and Hispanic PUIs were also less likely to report any contacts compared to White and Asian PUIs. Our study revealed that PUIs testing positive were less likely to provide contacts compared to PUIs testing negative. Age and racial differences were also noted in the provision of contacts. Further investigation is needed to understand these discrepancies in order to devise more effective strategies for contact elicitation.


All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity.
Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.


Microbiological and immunological effects of enteral feeding on the upper gastrointestinal tract.
Enteral feeding via a percutaneous endoscopic gastrostomy tube is required for nutritional support in patients with dysphagia. Enteral tube feeding bypasses the innate defence mechanisms in the upper gastrointestinal tract. This study examined the surface-associated microbial populations and immune response in the gastric and duodenal mucosae of eight enteral nutrition (EN) patients and ten controls. Real-time PCR and fluorescence in situ hybridization were employed to assess microbiota composition and mucosal pro-inflammatory cytokine expression. The results showed that EN patients had significantly higher levels of bacterial DNA in mucosal biopsies from the stomach and duodenum (P<0.05) than the controls, and that enterobacteria were the predominant colonizing species on mucosal surfaces in these individuals. Expression of the pro-inflammatory cytokines interleukin (IL)-1α, IL-6 and tumour necrosis factor-α was significantly higher in gastric and small intestinal mucosae from patients fed normal diets in comparison with those receiving EN (P<0.05). These results indicate that EN can lead to significant bacterial overgrowth on upper gastrointestinal tract mucosae and a significantly diminished pro-inflammatory cytokine response.


Frequency and characteristics of induced abortion among married and single women in São Paulo, Brazil.
This article presents the results of a study in the city of São Paulo, Brazil, aimed at estimating the frequency of induced abortion among women 15 to 49 years of age. The objective was to characterize the occurrence of induced abortion by comparing the ideal number of children, age, and contraceptive use between married and single women. Based on random sampling, 1,749 interviews were held, including 764 married women, 658 single women, and 327 with other marital status. The analysis included: mean number of abortions per woman by analysis of variance and proportions of abortions and pregnancy, using the chi-square test. The mean abortion rate for married women (45 per thousand) did not differ statistically from that of single women. However, the pregnancy rate was much lower in single women, and when single women became pregnant they used abortion more frequently; while fewer than 2% of pregnancies in married women ended in induced abortions, among single women the abortion rate exceeded 18%. Therefore, the priority in the reproductive health field should be to invest in the supply and dissemination of appropriate contraceptive methods for women's early sexually active life.


Differential associations of proinflammatory and anti-inflammatory cytokines with depression severity from noncancer status to breast cancer course and subsequent chemotherapy.
In this study, we examined the differential associations of various proinflammatory and anti-inflammatory cytokines with depression severity from the development of breast cancer to subsequent chemotherapy treatment. A cross-sectional study was conducted on a sample of 116 women: 29 controls without cancer, 55 patients with breast cancer who were not receiving chemotherapy, and 32 patients with breast cancer who were receiving chemotherapy. Blood samples were assayed to evaluate serum levels of the following cytokines: interferon-γ, interleukin (IL)-12 (p70), IL-1β, IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-10, IL-13, IL-6, and IL-17A. Depression severity was assessed using the Patient Health Questionnaire. After adjustment for sociodemographics, consistent patterns of the association between cytokine and depression were noted in the different groups. No significant associations were observed in the controls. Inverse associations were observed between cytokines levels and depression severity in patients with breast cancer who were not receiving chemotherapy, whereas positive associations were noted in patients with breast cancer who were receiving chemotherapy. Specific differential relationships between IL-5 levels and depression severity were found between patients with breast cancer who were receiving and not receiving chemotherapy. Our study revealed differential relationships between cytokine levels and depression severity with the development of cancer. Immunostimulation and immunosuppression in breast cancer and cancer treatment may account for the differential responses with the development of breast cancer.


Evidence that proliferation of golgi apparatus depends on both de novo generation from the endoplasmic reticulum and formation from pre-existing stacks during the growth of tobacco BY-2 cells.
In higher plants, the numbers of cytoplasmic-distributed Golgi stacks differ based on function, age and cell type. It has not been clarified how the numbers are controlled, whether all the Golgi apparatus in a cell function equally and whether the increase in Golgi number is a result of the de novo formation from the endoplasmic reticulum (ER) or fission of pre-existing stacks. A tobacco prolyl 4-hydroxylase (NtP4H1.1), which is a cis-Golgi-localizing type II membrane protein, was tagged with a photoconvertible fluorescent protein, mKikGR (monomeric Kikume green red), and expressed in tobacco bright yellow 2 (BY-2) cells. Transformed cells were exposed to purple light to convert the fluorescence from green to red. A time-course analysis after the conversion revealed a progressive increase in green puncta and a decrease in the red puncta. From 3 to 6 h, we observed red, yellow and green fluorescent puncta corresponding to pre-existing Golgi; Golgi containing both pre-existing and newly synthesized protein; and newly synthesized Golgi. Analysis of the number and fluorescence of Golgi at different phases of the cell cycle suggested that an increase in Golgi number with both division and de novo synthesis occurred concomitantly with DNA replication. Investigation with different inhibitors suggested that the formation of new Golgi and the generation of Golgi containing both pre-existing and newly synthesized protein are mediated by different machineries. These results and modeling based on quantified results indicate that the Golgi apparatuses in tobacco BY-2 cells are not uniform and suggest that both de novo synthesis from the ER and Golgi division contribute almost equally to the increase in proliferating cells.


Guidelines for treatment of atopic eczema (atopic dermatitis) part I.
The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. 'Eczema school' educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.


Etiology of Invasive Bacterial Infections in Immunocompetent Children in Korea (2006-2010): a Retrospective Multicenter Study.
Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea. A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005. Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996-2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001). S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children.


Motivation and Behaviour Change in Parkrun Participants in the Western Cape Province, South Africa.
Mass participation events are promoted in South Africa as a positive public health initiative. Parkrun has grown to be one of the most popular. The present study identifies the motives of residents in the Western Cape Province to join parkrun and how their involvement influences future physical activity levels. Participants (N = 1787) completed a survey consisting of demographic history, parkrun participation history, motivations for participation, and physical activity-related behaviour changes associated with parkrun participation. The majority of participants were female (n = 952) and over 50 years of age (median = 50; IQR = 38-59). Along with health-related benefits, the provision of a safe and organised event was reported as a key motive to participate. The social connectedness developed by parkrun encouraged continued participation and promoted uptake of more physical activity. Close to half the participants reported increases in physical activity levels after joining parkrun, which demonstrates the benefit obtained from participation in structured mass participation events. With the large diversity in socioeconomic status in South Africa related to physical activity levels, parkrun provides a protected and engaging environment that provides opportunity for increased physical activity and potentially reducing the burden on the healthcare system.


Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study.
Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aβ accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning). Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.


Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors.
This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.


Chemotherapy of East Coast fever. Treatment of infections induced by isolates of Theileria parva with halofuginone.
Cattle were infected with three isolates of Theileria parva and treated with halofuginone lactate during acute clinical disease. The health, weight gain and carrier state of the cattle were monitored for 15 months. Limited treatment rapidly reduced fever and parasitosis but parasite recrudescences occurred and 12 out of 21 treated cattle died. Persistent carrier states were identified with two T. p. parva isolate infections and a transient carrier state with T. p. lawrencei. Three cattle which died from a chronic wasting syndrome during the follow-up period showed exhaustion of lymph nodes but no Theileria macroschizonts were detected in any tissue.


Longitudinal axon guidance.
Our knowledge about molecular mechanisms underlying axon guidance along the antero-posterior axis in contrast to the dorso-ventral axis of the developing nervous system is very limited. During the past two years in vitro and in vivo studies have indicated that morphogens have a role in longitudinal axon guidance. Morphogens are secreted proteins that act in a concentration-dependent manner on susceptible groups of precursor cells and induce their differentiation to a specific cell fate. Thus, gradients of morphogens are responsible for the appropriate patterning of the nervous system during early phases of neural development. Therefore, it was surprising to find that gradients of two of these morphogens, Wnt4 and Shh, can be re-used for longitudinal axon guidance during later stages of nervous system development.


RhoA GTPase and F-actin dynamically regulate the permeability of Cx43-made channels in rat cardiac myocytes.
Gap junctions are clusters of transmembrane channels allowing a passive diffusion of ions and small molecules between adjacent cells. Connexin43, the main channel-forming protein expressed in ventricular myocytes, can associate with zonula occludens-1, a scaffolding protein linked to the actin cytoskeleton and to signal transduction molecules. The possible influence of Rho GTPases, major regulators of cellular junctions and of the actin cytoskeleton, in the modulation of gap junctional intercellular communication (GJIC) was examined. The activation of RhoA by cytoxic necrotizing factor 1 markedly enhanced GJIC, whereas its specific inhibition by the Clostridium botulinum C3 exoenzyme significantly reduced it. RhoA activity affects GJIC without major cellular redistribution of junctional plaques or changes in the Cx43 phosphorylation pattern. As these GTPases frequently act via the cortical cytoskeleton, the importance of F-actin in the modulation of GJIC was investigated by means of agents interfering with actin polymerization. Cytoskeleton stabilization by phalloidin slowed down the kinetics of channel rundown in the absence of ATP, whereas its disruption by cytochalasin D rapidly and markedly reduced GJIC despite ATP presence. Cytoskeleton stabilization by phalloidin markedly reduced the consequences of RhoA activation or inactivation. This mechanism appears to be the first described capable to both up- or down-regulate GJIC through RhoA activation or, conversely, inhibition. The inhibition of Rho downstream kinase effectors had no effect on GJIC. The present results provide further insight into the gating and regulation of junctional channels and identify a new downstream target for the small G-protein RhoA.


Administration of chemotherapy in patients admitted to a haematology service: a best practice implementation project.
To promote evidence-based practices related to the prevention of adverse events associated with medication administration (only chemotherapy) in a hospital service. The medication management process in a hospital setting is highly complex, going through multiple stages from drug selection, procurement and storage, to prescription, validation, dispensing, preparation, administration and monitoring. An evidence implementation project based on an audit and feedback approach was conducted from December 2019 to April 2021 using the JBI Practical Application of Clinical Evidence System and Getting Research into Practice. The results of the baseline audit showed that the 10 audit criteria were mostly met; however, two of the criteria (criterion 6: the expiry date of medication is checked before use and criterion 7: the nurse who prepares the medication administers the medication to the patient) had low compliance (respectively, 0 and 67.9%). After identifying the barriers and implementing strategies to deal with the identified barriers, we verified a significant improvement in compliance with best practices (criterion 6 improved to 64.3% and criterion 7 to 78.6%). This implementation project was a success, achieving a great improvement of the implementation of evidence-based guidelines concerning the prevention of adverse events associated with medication administration in a hospital in central Portugal. More such projects should be planned to sustain the implementation of evidence-based methods to improve health outcomes, patient safety, costs and health systems.


Tissue response to a membrane of demineralized bovine cortical bone implanted in the subcutaneous tissue of rats.
The treatment of persistent bone defects has encouraged the search for proper techniques or bone substitutes. In Dentistry, a common problem in the treatment of periodontal bone defects is the growth of tissues within the lesion, such as the junctional epithelium, which impair regeneration of these tissues. Guided tissue regeneration (GTR), based on the separation of the tissues by means of membranes or barriers, was developed in an attempt to improve periodontal regeneration. The aim of this study was to histologically evaluate the tissue response to a membrane of demineralized bovine cortical bone implanted in the subcutaneous tissue of rats. The study periods were 1, 3, 7, 15, 30 and 60 days after implantation. Analysis of the histological sections demonstrated a moderate to intense inflammatory response at 1 and 3 days, moderate at 7 and 15 days, and almost absent at 30 and 60 days. Resorption of the membrane began 15 days after implantation, and at 60 days only remnants could be detected in some animals. We concluded that the demineralized bovine cortical bone membrane was well tolerated by the tissues and is completely resorbed after 30-60 days by mononuclear cells and multinucleated giant cells, which disappear upon completion of the process.


Berries and oxidative stress markers: an overview of human intervention studies.
Berries are an excellent source of bioactive compounds such as vitamins, minerals but above all polyphenols with anthocyanins as the most representative compounds. Several in vitro and in vivo studies documented the beneficial effects of berries and their bioactives in the modulation of numerous cell functions related to oxidative stress and/or antioxidant protection. The following review summarizes published results about the role of berries (either fresh, juice, freeze-dried or dehydrated) on total plasma and serum antioxidant status and on the modulation of biomarkers of oxidative stress in acute and chronic human intervention trials. The biomarkers considered include DNA, protein and lipid oxidation, and endogenous antioxidant enzymes. Though limited, there is indication that the consumption of berries may reduce oxidative stress by modulating protein and lipid oxidation, and by improving total antioxidant status. In particular, these effects are more evident following chronic dietary interventions with respect to postprandial studies. Benefits are observed in healthy subjects as well as in those with cardiovascular risk factors or other diseases. On the contrary, data regarding the effect of berries on DNA damage and endogenous antioxidant enzyme activities are still scarce and inconclusive. In conclusion, much remains to be elucidated before a comprehensive understanding of the effects of berries on the modulation of oxidative stress markers is achieved. Robust clinical evidence supporting the role of berries in counteracting oxidative stress in humans is encouraged.