NPY/AgRP neurons are not essential for feeding responses to glucoprivation.
Animals respond to hypoglycemia by eating and by stimulating gluconeogenesis. These responses to glucose deprivation are initiated by glucose-sensing neurons in the brain, but the neural circuits that control feeding behavior are not well established. Neurons in the arcuate region of the hypothalamus that express neuropeptide Y (NPY) and agouti-related protein (AgRP) have been implicated in mediating the feeding response to glucoprivation. We devised a method to selectively ablate these neurons in neonatal mice and then tested adult mice for their feeding responses to fasting, mild hypoglycemia, 2-deoxy-d-glucose and a ghrelin receptor agonist. Whereas the feeding response to the ghrelin receptor agonist was completely abrogated, the feeding response to glucoprivation was normal. The feeding response after a fast was attenuated when standard chow was available but normal with more palatable solid or liquid diet. We conclude that NPY/AgRP neurons are not necessary for generating or mediating the orexigenic response to glucose deficiency, but they are essential for the feeding response to ghrelin and refeeding on standard chow after a fast.


Numerical cognition: age-related differences in the speed of executing biologically primary and biologically secondary processes.
Groups of younger and older adults were administered numerical and arithmetical tasks that varied in the extent to which they assess evolved versus culturally specific forms of cognition, termed biologically primary and biologically secondary abilities, respectively. Componential analyses of solution times suggested that younger adults are faster than older adults in the execution of biologically primary processes. For biologically secondary competencies, a pattern of no age-related differences or an advantage for older adults in speed of processing was found. The results are consistent with the view that there has been a cross-generational decline in arithmetical competencies in the United States and are discussed in terms of models of age-related change in cognitive performance.


Evidence for the aquatic binding of arsenate by natural organic matter-suspended Fe(III).
Dialysis experiments with arsenate and three different NOM samples amended with Fe(lll) showed evidence confirming the formation of aquatic arsenate-Fe(Ill)-NOM associations. A linear relationship was observed between the amount of complexed arsenate and the Fe(lll) content of the NOM. The dialysis results were consistent with complex formation through ferric iron cations acting as bridges between the negatively charged arsenate and NOM functional groups and/or a more colloidal association, in which the arsenate is bound by suspended Fe(lll)-NOM colloids. Sequential filtration experiments confirmed that a significant proportion of the iron present at all Fe/C ratios used in the dialysis experiments was colloidal in nature. These colloids may include larger NOM species that are coagulated by the presence of chelated Fe(lll) and/or NOM-stabilized ferric (oxy)hydroxide colloids, and thus, the solution-phase arsenate-Fe(Ill)-NOM associations are at least partially colloidal in nature.


Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location.
As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel density, vascular permeability, lymphatics, stromal content, and tumor-associated immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four subcutaneous flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochemistry staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concentrated close to the blood vessels, while signal from the smaller particle was observed throughout the tissue. Differences were also observed for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we observed higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was constant for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.


Treatment and prevention of Lyme disease, with emphasis on antimicrobial therapy for neuroborreliosis and vaccination.
Antibiotic therapy is recommended for all forms of neuroborreliosis. Although stage 2 neuroborreliosis will usually resolve without any treatment, antibiotic therapy has been associated with faster resolution of symptoms and may prevent additional non-neurologic disease manifestations. Ceftriaxone is the most convenient parenteral agent for stage 2 and 3 neuroborreliosis because of its once-daily dosage. Available data indicate that a 2-4-week treatment course is adequate for most patients. Patients with isolated seventh nerve palsy may be treated with an oral agent (for example, doxycycline). Recombinant outer surface protein A of Borrelia burgdorferi is a highly protective immunogen for prevention of Lyme disease in experimental animals. Humoral immunity is sufficient for protection. A recombinant OspA vaccine has been licensed for prevention of Lyme disease in dogs. Licensure of an OspA vaccine for humans will depend on a critical analysis of the results of recently completed efficacy studies.


Risks to Healthcare Organizations and Staff Who Manage Obese (Bariatric) Patients and Use of Obesity Data to Mitigate Risks: A Literature Review.
This literature review explores obesity risks to healthcare staff and organizations that manage and caring for obese (bariatric) patients. These risks are anticipated to increase due to Australian population obesity rate projections increasing from 31% in 2018 to 42% by the year 2035, which will result in increased hospital admissions of patients with obesity. Literature searches were conducted through the Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, Scopus, and Web of Science. Thirty studies met the inclusion criteria and were tabulated and critiqued using appropriate appraisal techniques. High risk of injury to healthcare staff was identified relating to bariatric patient handling tasks. High liability and financial risks of organizations were also identified relating to workers' compensation and common law claims by injured staff and medical negligence claims by patients with obesity. Availability of obesity data was identified within clinically captured information, which could be utilized to inform obesity risk management programs. Future research should focus on improving the use and quality of obesity data to better understand obesity risks to healthcare organizations and staff, including accurate identification of obese patient admissions, enhanced ability to measure bariatric patient handling hazards and related staff injuries and improved assessment of bariatric intervention effectiveness.


Aggregation of chlorophylls in monolayers. V. The effect of water on chlorophyll a and chlorophyll b in mono and multilayer arrays.
The nature of the interactions between water molecules and monolayers and multilayers of chlorophyll a (Chl a), and monolayers and multilayers of Chl b. obtained by the Langmuir-Blodgett technique, is examined by infrared spectroscopy. Following deposition of the monolayer or multilayer of Chl a or Chl b onto a plate, repetitive scans showed some modifications in the infrared spectra which are interpreted as a reorganization of the molecules as some water molecules leave the array. Drying the sample further modifies the spectra, which indicates the departure of more tenacious water molecules. Putting the sample in a moist atmosphere does not restore the original spectrum. This is an indication of a nonreversibie reorganization in the chlorophyll array. The spectra of the monolayer of chlorophyll are much more complicated than those of the multilayer, owing to the nonintegrating effect of the monolayer, which reveals the perturbing effect of the different dielectric milieux on each functional group. On the basis of the analysis of the spectra and the information gathered from the surface pressure isotherms, a model is proposed for the monolayer arrangement at the air/water interface which implies two set of dimers of water per molecule of chlorophyll. One pair of dimers constitutes the water of the first kind and is composed of vapor-like dimers. This kind of water is situated between the porphyrin planes of chlorophyll molecules and is easily removed from the monolayer. The second pair of dimers is composed of water of the second and third kinds situated between the Mg atom of the chlorophyll molecules and the water of the subphase. The second kind of water is closest to the Mg atom and is the most difficult one to remove. The third kind of water is closest to the surface and its mobility is intermediate between that of water of the first kind and that of water of the second kind. Comparing the infrared spectra of a freshly prepared monolayers of Chl a with the resonance Raman spectra of intact chloroplasts (M. Lutz, Biochim. Biophys. Acta 460 (1977) 408), we notice great similarities. This is an indication that the model we propose for the monolayer of Chl a could play an important role in the chloroplast.


Three-dimensional structure of the human transglutaminase 3 enzyme: binding of calcium ions changes structure for activation.
Transglutaminase (TGase) enzymes catalyze the formation of covalent cross-links between protein-bound glutamines and lysines in a calcium-dependent manner, but the role of Ca(2+) ions remains unclear. The TGase 3 isoform is widely expressed and is important for epithelial barrier formation. It is a zymogen, requiring proteolysis for activity. We have solved the three-dimensional structures of the zymogen and the activated forms at 2.2 and 2.1 A resolution, respectively, and examined the role of Ca(2+) ions. The zymogen binds one ion tightly that cannot be exchanged. Upon proteolysis, the enzyme exothermally acquires two more Ca(2+) ions that activate the enzyme, are exchangeable and are functionally replaceable by other lanthanide trivalent cations. Binding of a Ca(2+) ion at one of these sites opens a channel which exposes the key Trp236 and Trp327 residues that control substrate access to the active site. Together, these biochemical and structural data reveal for the first time in a TGase enzyme that Ca(2+) ions induce structural changes which at least in part dictate activity and, moreover, may confer substrate specificity.


Restricting Sales of Menthol Tobacco Products: Lessons Learned from Policy Passage and Implementation in Minneapolis, St. Paul, and Duluth, Minnesota.
Purpose: Commercial tobacco products have historically been target marketed to African American, Latinx, Asian American Pacific Islander, Indigenous, and Lesbian, Gay, Bisexual, Transgender, Queer (LGBTQ) communities, as well as to youth. Menthol cigarettes increase smoking initiation and decrease smoking cessation, particularly among African Americans who smoke menthol cigarettes at higher rates than their white peers. Due to disproportionate tobacco-related health consequences for members of these communities, effective tobacco control policies that restrict availability of menthol products by focusing on retail sales are an important element of addressing health disparities, and require policy efforts informed by leadership and the voice of communities most impacted. This study examines the organizing efforts of three successful policy initiatives in 2017-2018 in Minneapolis, St. Paul, and Duluth, Minnesota, and identifies facilitators and barriers of these campaigns. Methods: We conducted 50 key informant interviews with city council/staff, advocates, and community members and analyzed them for emerging themes. The analysis employed a process-oriented qualitative matrix process to identify emerging themes and divergent perspectives. Results: Following policy implementation, outlets selling commercial menthol tobacco products substantially decreased. Facilitators included strong city council support, leadership from impacted communities, community awareness-building campaigns, and understanding tobacco industry counter-tactics. Challenges included the need to counter tobacco industry misinformation and retailer attempts to circumvent the intent of restrictions. Conclusion: Well-planned advocacy campaigns led by community members most impacted by commercial tobacco can overcome opposition and challenges to restrict sales of menthol tobacco products and successfully reduce availability of these products in their communities.


Impact of effectiveness information format on patient choice of therapy and satisfaction with decisions about chronic disease medication: the "Influence of intervention Methodologies on Patient Choice of Therapy (IMPACT)" cluster-randomised trial in general practice.
Risk communication is an integral part of shared decision-making in health care. In the context of interventions for chronic diseases it represents a particular challenge for all health practitioners. By using two different quantitative formats to communicate risk level and effectiveness of a cholesterol-lowering drug, we posed the research question: how does the format of risk information influence patients' decisions concerning therapy, patients' satisfaction with the communication as well as confidence in the decision. We hypothesise that patients are less prone to accept therapy when the benefits of long-term intervention are presented in terms of prolongation of life (POL) in months compared to the absolute risk reduction (ARR). We hypothesise that patients presented with POL will be more satisfied with the communication and confident in their decision, suggesting understanding of the time-related term. In 2009 a sample of 328 general practitioners (GPs) in the Region of Southern Denmark was invited to participate in a primary care-based clinical trial among patients making real-life clinical decisions together with their GP. Interested GPs were cluster-randomised to inform patients about cardiovascular disease (CVD) risk and the effectiveness of statin therapy using either POL or ARR. The GPs attended a training session before informing their patients. Before training and after the trial period they received a questionnaire about their attitudes to risk communication and the use of numerical information. Patients' redemptions of statin prescriptions will be registered in a regional prescription database to evaluate a possible association between redemption rates and effectiveness format. The Combined Outcome Measure for Risk Communication And Treatment Decision Making Effectiveness (COMRADE) questionnaire will be used to measure patients' confidence and satisfaction with the risk communication immediately after the conversation with their GPs. This randomised clinical trial compares the impact of two effectiveness formats on real-life risk communication between patients and GPs, including affective patient outcomes and actual choices about acceptance of therapy. Though we found difficulties in recruiting GPs, according to the study protocol we have succeeded in engaging sufficient GPs for the trial, enabling us to perform the planned analyses.


First-principles calculation of local atomic polarizabilities.
Common methods of determining atomic polarizabilities suffer from the inclusion of nonlocal effects such as charge polarization. A new method is described for determining fully ab initio atomic polarizabilities based on calculating the response of atomic multipoles to the local electrostatic potential. The localized atomic polarizabilities are then used to calculate induction energies that are compared to ab initio induction energies to test their usefulness in practical applications. These polarizabilities are shown to be an improvement over the corresponding molecular polarizabilities, in terms of both absolute accuracy and the convergence of the multipolar induction series. The transferability of localized polarizabilities for the alkane series is also discussed.


Bacteriological quality of drinking water from dispensers (coolers) and possible control measures.
Three water dispensers (coolers) were bacteriologically monitored over a period of 3 months to evaluate their hygienic status. For this purpose, 174 samples of chilled and unchilled water were analyzed for levels of mesophilic aerobic bacteria and the presence of Escherichia coli and enterococci in 100-ml samples, and the presence of Pseudomonas aeruginosa in 10- and 100-ml samples. Additionally, 12 samples from 20-liter plastic bottles of spring water used to supply the coolers and 36 samples of 12 different brands of noncarbonated bottled mineral water were similarly analyzed. Water from the coolers yielded aerobic plate counts of 3 to 5 log CFU/ml with a geometric mean of 3.86 log CFU/ml, whereas water from the 20-liter bottles had a mean aerobic plate count of 3.3 log CFU/ml. Aerobic plate counts for noncarbonated mineral waters were generally lower (13 samples, < 10 CFU/ml; 6 samples, 10 to 10(2) CFU/ml; 13 samples, 10(2) to 10(3) CFU/ml; 3 samples, 10(3) to 10(4) CFU/ ml; 1 sample, 2 x 10(4) CFU/ml). Although occasional professional cleaning of the coolers did not affect the aerobic plate count, P. aeruginosa was successfully eliminated 2 weeks after cleaning, with only one cooler becoming recolonized. Neither E. coli nor enterococci was found in any of the water samples tested. However, P. aeruginosa was identified in three (25%) of twelve 100-ml samples from 20-liter bottles of spring water; a similar frequency of 24.1% was seen for water samples from coolers. Overall, 35 (21.6%) of 162 water samples (10 ml) from coolers also yielded P. aeruginosa, suggesting potential growth of P. aeruginosa in the dispensers. Pulsed-field gel electrophoresis typing and antibiotic susceptibility testing found 19 P. aeruginosa isolates from the coolers and bottles to be identical, indicating that a single strain originated from the bottled water rather than the surroundings of the coolers. Because P. aeruginosa can cause serious nosocomial infections, its spread should be strictly controlled in institutions caring for vulnerable people such as hospitals and nursing homes. Consequently, in keeping with legal requirement for bottled spring and mineral water in Switzerland, it is also advisable that P. aeruginosa be absent in 100-ml samples of cooler water.


Transient binocular visual loss: a rare presentation of ventriculoperitoneal shunt malfunction.
The authors report the case of a 27-year-old male with ventriculoperitoneal shunt (VPS) for hydrocephalus presenting with episodic transient binocular visual loss (TBVL) and headache. Complete physical, bedside shunt examination and funduscopy were unremarkable. Laboratory investigation, shunt series and imaging studies failed to reveal any acute abnormalities. Interrogation of the shunt system identified a valve malfunction which was corrected with resultant symptomatic relief and the patient was discharged home in stable condition. VPS malfunction occurs secondary to infection or mechanical failure such as obstruction, tubing fracture, shunt migration and over drainage. Resultant raised intracranial pressure leads to symptoms of headache, nausea, vomiting and gait abnormalities. Visual defects including blindness has been occasionally reported from shunt malfunction. Rare complications include cerebrospinal fluid oedema, colonic perforation, paraparesis and parkinsonism. TBVL due to shunt malfunction remains an uncommon presentation and requires a high index of clinical suspicion while evaluating these patients.


The important role of physical activity in the prevention and management of gestational diabetes mellitus.
The actual pathophysiology behind gestational diabetes mellitus (GDM) is still unclear, but a deterioration in insulin resistance beyond that induced by pregnancy, combined with beta cell dysfunction, plays a key role. Interventions that help improve glucose tolerance by attenuating pregnancy-induced insulin resistance or achieve glycaemic control may therefore help in preventing and managing GDM. In non-pregnant populations, physical activity has been associated with an improvement in glucose homeostasis and insulin sensitivity and a risk reduction for type 2 diabetes mellitus (T2DM) and is a cornerstone for T2DM treatment. However, there is still controversy regarding the benefits of physical activity in preventing and managing GDM. The objective of this review is therefore to provide a comprehensive overview of the effect of prenatal physical activity-based interventions on (1) glucose tolerance, insulin sensitivity and GDM prevention and (2) glycaemic control and insulin use in GDM women. On the basis of the available literature, there is a lack of consistent evidence regarding the benefits of physical activity on improving glucose tolerance and insulin sensitivity and preventing GDM. However, it appears that physical activity may help to achieve good glycaemic control and limit insulin use in GDM women. Compliance appears to be a major problem in physical activity-based intervention studies aimed at GDM prevention. Rigorous scientific research is still required to make an informed decision about the role of physical activity in the prevention and management of GDM and to develop evidence-based physical activity guidelines for GDM prevention and management.


Oxidation and ceramic coatings on 80Ni20Cr alloys.
Additives and/or impurities in NiCr alloys would be expected to affect the oxidation and adherence of dental glasses. Oxidation characteristics and bonding of several glasses to a commercial impure 80Ni20Cr alloy and laboratory-prepared purer alloys were thus studied at 1000 degrees C. The commercial alloy formed a porous and buckled single-layer oxide scale with lenticular voids at the interface. The scale was penetrated by glass which formed a chemical bond at the alloy/glass interface, resulting in excellent adherence with fracture in the glassy phase. The purer alloy formed a complex multilayer oxide scale to which the glass bonded but did not penetrate; the assembly was not satisfactory, since fracture occurred in the oxide scale.


Do Cannabis and Cannabinoids Have a Psychopharmacotherapeutic Effect?
Written historical evidence reveals that Cannabis sativa has been used medically, recreationally and spiritually for more than five centuries in many cultures. It is considered the most-used plant-based psychoactive substance with millions of different usages across the world. To review what the studies, conducted over the past two decades, indicate about effects of the cannabis on physical and mental health as well as the impact on social functioning. We selected literature review using PubMed resources, to summarize the findings of the existing publications on cannabis and cannabinoids and their possible psychopharmacological therapeutic effects only. Research supports cannabis' clear acute effect on neurocognition, while non-acute effects for prolonged use of marijuana are unclear and still insufficiently explored. Due to cannabidiol's (CBD) safety and tolerability, the absence of psychoactive or cognitive effects, the existence of clinical trials with positive results and its broad pharmacological spectrum, CBD is a cannabinoid whose initial results will likely lead to implementation into clinical practice. The fact that the results of previous studies establish the claim of CBD as an antipsychotic and anxiolytic, makes the above developments even more likely. However, long-term, double-blind, placebo studies with samples of patients with different psychotic and anxiety disorders are still necessary. Likewise, due to CBD's biphasic effects, determining an adequate therapeutic dose remains a challenge to conclude, the cannabinoid system represents a promising target for new therapeutic interventions in psychiatry. Further controlled studies are essential to determine the precise mechanisms of action of cannabinoids on various neuropsychiatric disorders as well as the safety of their use are needed. Never just the use of 'smoking cannabis in an unlicenced way'. The use of simple 'smoked cannabis' remains dangerous because of the effects on inducing psychosis which the article itself refers to, and needs to remain illegal.


Goals Form: Reliability, validity, and clinical utility of an idiographic goal-focused measure for routine outcome monitoring in psychotherapy.
This study aimed to assess the reliability, validity, and clinical utility of an idiographic, goal-focused patient-reported outcome measure: The Goals Form. Data were analyzed from 88 participants, across three samples, who had participated in collaborative-integrative psychotherapy at university-based clinics in the UK. The samples were approximately 70% female with mean age of 30 years old. The psychometric properties of the Goals Form were generally good. Noncompletion of individual items was low, temporal stability tended to be at target levels, and mean change scores showed moderate to good convergent validity against measures of psychological distress. The measure appeared sensitive to change in psychotherapy and was experienced by most patients as helpful. The Goals Form shows acceptable psychometric and clinical properties for routine outcome monitoring in psychotherapy.


Cordycepin induces apoptosis in human bladder cancer cells via activation of A3 adenosine receptors.
Bladder cancer is a neoplasm originated from bladder epithelial cells. The therapy for bladder cancer is so far not satisfactory. In this study, we examined the effects of Cordyceps militaris hot water extracts containing cordycepin on human bladder cells. Cordyceps militaris hot water extracts containing cordycepin was used to treat human T24 bladder carcinoma cells, and we found that Cordyceps militaris hot water extracts containing cordycepin decreased T24 cell survival in a dose-dependent manner, which was seemingly mediated by activation of A3 adenosine receptor and the subsequent inactivation of Akt pathways, resulting in increases in cleaved Caspase-3 and apoptosis. Overexpression of A3 adenosine receptor in T24 cells mimicked the effects of Cordyceps militaris hot water extracts, while A3 adenosine receptor depletion abolished the effects of Cordyceps militaris hot water extracts containing cordycepin. Together, these data suggest that Cordyceps militaris hot water extracts containing cordycepin may be a promising treatment for bladder cancer via A3 adenosine receptor activation.


Cost-utility analysis of ceftazidime-avibactam versus colistin-meropenem in the treatment of infections due to Carbapenem-resistant Klebsiella pneumoniae in Colombia.
Ceftazidime-Avibactam (CAZ-AVI) is a new antimicrobial against carbapenem-resistant Klebsiella pneumoniae. The aim of the study is to examine the cost-effectiveness of CAZ-AVI compared to colistin-meropenem (COL+MEM) in Colombia. A decision tree model was developed from health-care system perspective assuming a 30-day time horizon. The clinical course was simulated based on treatment response between 48 and 72 hours, and the duration of the treatment was 7-14 days. Cost inputs were extracted from a published Colombian manual tariffs and official databases, expressed in 2019 dollars (USD). In the base case analysis, CAZ-AVI was associated with reduced mortality, length of hospital stay and fewer add-on antibiotics, resulting in an increase of 1.76 QALYs per patient versus COL+MEM and incremental costs associated in CAZ-AVI were $2,521 higher per patient compared to COL+MEM ($755 versus $3,276). The incremental costs were partially increased due to the lower mortality rate observed with CAZ-AVI. The incremental cost-effectiveness ratio was estimated to be $3,317 per QALY. In the probabilistic sensitivity analysis, with a willingness to pay above $2,438, CAZ-AVI has higher probability of being cost-effective. CAZ-AVI demonstrates cost-effectiveness as a treatment for Carbapenem-resistant Klepsiella pneumoniae infections by reducing the number of deaths and increasing QALYs. Previous studies and surveillance programs from Colombia have reported prevalence of pathogens and the antimicrobial susceptibility of infections caused by multidrug-resistant Gram-negative bacteria. The health authorities have to consider and plan adequate surveillance systems in order to predict the resistance type and in choose the optimal antibiotics when infections occur.


Synthesis and characterization of new nitrogen-donor-stabilized N-silylphosphoranimine cations.
The phosphoranimine Br(CF3CH2O)2P=NSiMe3 (12) reacts quantitatively with nitrogen bases pyridine, 4,4'-bipyridine, and quinuclidine (quin) to form the N-donor stabilized phosphoranimine cations [N-donor.P(OCH2CF3)2=NSiMe3] ([15]+) in the presence of the halide abstractor AgOTf. In contrast to quinuclidine, in the absence of a halide abstractor, the weak bases pyridine and 4,4'-bipyridine do not undergo reactions with 12 or with the phosphoranimine Cl3P=NSiMe3 (7). Furthermore, unlike the weaker bases, quinuclidine also reacts with 7 to form the expected quinuclidine-stabilized phosphoranimine cation [quin.PCl2=NSiMe3]+ ([16]+) in the presence of AgOTf. However, in the absence of AgOTf, quinuclidine reacts with 7 to presumably yield the salt [16]Cl, which then undergoes a further quinuclidine ring-opening reaction to yield the cationic piperidyl-substituted phosphoranimine [(quin)CH2CH2C5H9N-PCl2=NSiMe3]Cl ([19]Cl). Reactions involving 7 and 12 with other halide abstraction reagents, such as GaCl3, are also described.


Variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RAR(alpha) gene and identification of a new clinical subtype resistant to retinoic acid therapy.
The physiologic actions of retinoic acids (RAs) are mediated through RA receptors (RARs) and retinoid X receptors (RXRs). The RAR(alpha) gene has drawn particular attention because it is the common target in all chromosomal translocations in acute promyelocytic leukemia (APL), a unique model in cancer research that responds to the effect of RA. In the great majority of patients with APL, RAR(alpha) is fused to the PML gene as a result of the t(15;17) translocation. Three distinct types of PML-RAR(alpha) transcripts, long (L), short (S), and variant (V), were identified. The V-type is characterized by truncation of exon 6 of PML and in some cases by the insertion of a variable "spacer" sequence between the truncated PML and RAR(alpha) mRNA fusion partners, although the precise mechanisms underlying formation of the V-type transcript remain unclear. To get further insights into the molecular basis of the t(15;17), we sequenced the entire genomic DNA region of RAR(alpha). Of note, all previously reported "spacer" sequences in V-type transcripts were found in intron 2 of the RAR(alpha) gene and most of these sequences were flanked by gt splice donor sites. In most cases, these "cryptic" coding sequences maintained the ORF of the chimeric transcript. Interestingly, two cases with a relatively long spacer sequence showed APL cellular and clinical resistance to RA treatment. In these cases, the aberrant V-type PML-RAR(alpha) protein displayed increased affinity to the nuclear corepressor protein SMRT, providing further evidence that RA exerts the therapeutic effect on APL through modulation of the RAR-corepressor interaction. Finally, among patients with the L- or S-type PML-RAR(alpha) fusion transcript, some consensus motifs were identified at the hotspots of the chromosome 17q breakpoints within intron 2 of RAR(alpha), strengthening the importance of this intron in the molecular pathogenesis of APL.


Effects of a self-care educational program via telerehabilitation on quality of life and caregiver burden in amyotrophic lateral sclerosis: a single-blinded randomized clinical trial protocol.
The implementation of a telerehabilitation protocol for self-care in the routine of caregivers of individuals with amyotrophic lateral sclerosis (ALS) has been associated with reduced levels of stress and improved quality of life. Moreover, it may reduce the difficulty of traveling to perform physical or other self-care activities. Thus, this study designed a clinical trial protocol to investigate the effects of a self-care education program via telerehabilitation on the burden and quality of life of caregivers of individuals with ALS. This single-blinded randomized clinical trial will recruit 26 caregivers and randomly allocate them to the experimental (EG = 13) or control group (CG = 13). The EG will receive an informative booklet and participate in a 6-week synchronous telerehabilitation program with a neuropsychologist, nutritionist, and physiotherapist to discuss physical and mental health. The CG will receive an informative booklet on self-care and physical activity and weekly phone calls for 6 weeks to solve questions about the booklet. Outcomes will include the caregiver burden (Zarit scale), quality of life (World Health Organization Quality of Life BREF), pain (McGill Pain Questionnaire), stress (Perceived Stress Scale), and depression (Beck Depression Inventory), which will be evaluated at the baseline after the six-week program and 30 days after the program. Additionally, we will assess daily the nocturnal awakenings, sleep patterns, level of physical activity, and heart rate variability. This study aimed to investigate the effectiveness of telerehabilitation for caregivers of individuals with ALS. If effective, this program could be disseminated among health professionals, increasing the possibility of remotely monitoring individuals with difficulty performing physical activities. NCT05884034 (clinicaltrials.gov).


The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation.
Improperly folded proteins in the endoplasmic reticulum (ER) are eliminated via ER-associated degradation, a process that dislocates misfolded proteins from the ER membrane into the cytosol, where they undergo proteasomal degradation. Dislocation requires a subclass of ubiquitin ligases that includes gp78 in addition to the AAA ATPase p97/VCP and its cofactor, the Ufd1-Npl4 dimer. We have previously reported that gp78 interacts directly with p97/VCP. Here, we identify a novel p97/VCP-interacting motif (VIM) within gp78 that mediates this interaction. We demonstrate that the VIM of gp78 recruits p97/VCP to the ER, but has no effect on Ufd1 localization. We also show that gp78 VIM interacts with the ND1 domain of p97/VCP that was shown previously to be the binding site for Ufd1. To evaluate the role of Ufd1 in gp78-p97/VCP-mediated degradation of CD3delta, a known substrate of gp78, RNA interference was used to silence the expression of Ufd1 and p97/VCP. Inhibition of p97/VCP, but not Ufd1, stabilized CD3delta in cells that overexpress gp78. However, both p97/VCP and Ufd1 appear to be required for CD3delta degradation in cells expressing physiological levels of gp78. These results raise the possibility that Ufd1 and gp78 may bind p97/VCP in a mutually exclusive manner and suggest that gp78 might act in a Ufd1-independent degradation pathway for misfolded ER proteins, which operates in parallel with the previously established p97/VCP-Ufd1-Npl4-mediated mechanism.


The Eating Assessment Tool-10 Predicts Aspiration in Adults with Stable Chronic Obstructive Pulmonary Disease.
Adults with COPD frequently present with dysphagia, which often leads to clinical complications and hospital admissions. This study investigates the ability of the Eating Assessment Tool (EAT-10) to predict aspiration during objective dysphagia evaluation in adults with stable COPD. Thirty adults (20 male, 10 female; mean age = 69.07 ± 16.82) with stable COPD attended an outpatient dysphagia clinic for a fiberoptic endoscopic evaluation of swallowing (FEES) in an acute teaching hospital (January 2015-November 2016). During evaluations, individuals completed an EAT-10 rating scale followed immediately by a standardised FEES exam. Aspiration status during FEES was rated using the penetration-aspiration scale by clinicians blinded to EAT-10 scores. Data were retrospectively analysed. Significant differences in mean EAT-10 scores were found between aspirators (16.3; SEM = 2.165) and non-aspirators (7.3; SEM = 1.009) (p = 0.000). The EAT-10 predicted aspiration with a high level of accuracy (AUC = 0.88). An EAT-10 cut-off value of >9 presented a sensitivity of 91.67, specificity of 77.78 with positive and negative likelihood ratios of 4.12 and 0.11, respectively. Positive and negative predictive values were 73.30 and 93.30, respectively. Diagnostic odds ratio was 38.50 (p < 0.01, CI 3.75-395.42). EAT-10 is a quick, easy to administer tool, which can accurately predict the presence of aspiration in adults with COPD. The scale can also very accurately exclude the absence of aspiration, helping clinicians to determine the need for onward referral for a comprehensive dysphagia evaluation. This may ultimately reduce clinical complications and hospital admissions resulting from dysphagia in this clinical population.


Guided versus unguided chatbot-delivered cognitive behavioral intervention for individuals with moderate-risk and problem gambling: A randomized controlled trial (GAMBOT2 study).
Internet-based interventions can be a promising option for individuals with problem gambling facing barriers to seeking help. This study aimed to directly compare the effects of therapist-guided Internet interventions with unguided ones on gambling-related behavior, cognition, and stage of change including help-seeking intention. We conducted a participant-blinded randomized controlled trial of therapist-guided versus unguided groups with a 12-week follow-up. Both groups received self-help chatbot-delivered cognitive behavioral therapy. Additionally, at baseline and weeks 1, 2, 3, and 4, the guided group received personalized feedback messages from therapists based on their gambling diary and questionnaire responses. The unguided group received reminders of assessments from research assistants. The primary outcome was the change in scores on the Gambling Symptoms Assessment Scale (G-SAS) over 12 weeks. Secondary outcomes included the stage of change including help-seeking intention, money wagered, gambling frequency, and gambling-related cognitions. We included 139 participants with a mean Problem Gambling Severity Index total score of 14.6 and a mean G-SAS total score of 27.0 who sought information about gambling problems. Both groups demonstrated substantial decreases in their G-SAS scores from baseline to week 12 (-10.2, 95% CI: -7.67 to -12.7 for the guided group, and 11.7, 95% CI: -9.05 to -14.3 for the unguided group). However, we did not find a significant between-group difference (1.49, 95% CI: -2.20 to 5.17). Regarding the stage of change including help-seeking intention, there were also no between-group differences. Minimum therapist support did not have an additive effect on the self-help chatbot intervention on gambling symptoms, behavior, and the stage of change including help-seeking intention.


Soil temperature effects on the structure and diversity of plant and invertebrate communities in a natural warming experiment.
Global warming is predicted to significantly alter species physiology, biotic interactions and thus ecosystem functioning, as a consequence of coexisting species exhibiting a wide range of thermal sensitivities. There is, however, a dearth of research examining warming impacts on natural communities. Here, we used a natural warming experiment in Iceland to investigate the changes in above-ground terrestrial plant and invertebrate communities along a soil temperature gradient (10°C-30°C). The α-diversity of plants and invertebrates decreased with increasing soil temperature, driven by decreasing plant species richness and increasing dominance of certain invertebrate species in warmer habitats. There was also greater species turnover in both plant and invertebrate communities with increasing pairwise temperature difference between sites. There was no effect of temperature on percentage cover of vegetation at the community level, driven by contrasting effects at the population level. There was a reduction in the mean body mass and an increase in the total abundance of the invertebrate community, resulting in no overall change in community biomass. There were contrasting effects of temperature on the population abundance of various invertebrate species, which could be explained by differential thermal tolerances and metabolic requirements, or may have been mediated by changes in plant community composition. Our study provides an important baseline from which the effect of changing environmental conditions on terrestrial communities can be tracked. It also contributes to our understanding of why community-level studies of warming impacts are imperative if we are to disentangle the contrasting thermal responses of individual populations.


Acute bilateral extensor pollicis longus tendon rupture following bilateral displaced distal radius fracture: A case report.
Extensor pollicis longus tendon ruptures are rarely reported after traumatic events, especially after distal radius fractures. Its classical presentation is a late-onset and unilateral rupture after a non-displaced distal radius fracture. In this case report, we present the treatment of a patient with acute bilateral extensor pollicis longus tendon ruptures after bilateral displaced distal radius fractures. The patient was treated with bilateral open reduction and volar plate fixation via a volar Henry approach for distal radius fractures and bilateral extensor indicis proprius tendon transfer for extensor pollicis longus tendon ruptures. We achieved satisfactory results, and no complications were reported with these treatment approaches. However, this case report demonstrates that extensor pollicis longus tendon rupture may occur at the time of fracture; thus, clinicians should be aware of this issue.


Characterization of four major allergens of hen egg-white by IEF/SDS-PAGE combined with electrophoretic transfer and IgE-immunoautoradiography.
The antigenic and allergenic epitope maps of the hen egg-white ovalbumin, ovomucoid, ovotransferrin and lysozyme were obtained using one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and two-dimensional sodium dodecyl sulfate gel electrophoresis following isoelectric focusing. The isoelectric points of egg-white proteins were assigned by the isoelectric focusing technique. Two-dimensional electrophoresis following isoelectric focusing provided further information regarding epitope mapping. Furthermore, electrophoretic transfer of the proteins to nitrocellulose and subsequent immunoautoradiography, clearly demonstrated the allergenicity of these proteins. An important benefit of these methods was confirming that lysozyme bound strongly to IgE in all the human sera from egg-allergic individuals and that lysozyme, in addition to ovalbumin, ovomucoid and ovotransferrin, was one of the major allergens of hen egg-white.


Effect of alloying on the dynamics of coherent acoustic phonons in bismuth double perovskite single crystals.
The bismuth double perovskite Cs2AgBiBr6 has been regarded as a potential candidate for lead-free perovskite photovoltaics. A detailed study on the coherent acoustic phonon dynamics in the pure, Sb- and Tl-alloyed Cs2AgBiBr6 single crystals is performed to understand the effects of alloying on the phonon dynamics and band edge characteristics. The coherent acoustic phonon frequencies are found to be independent of the alloying, while the damping rates are highly dependent on the alloying. Based on the mechanism of coherent acoustic phonon damping, a technique has been successfully developed that can accurately extract the absorption spectra near the indirect band gap for these single crystals with coefficients on the order of 102 cm-1.


Transforming Growth Factor β1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression.
Transforming growth factor β1 (TGFβ1)/Smad4 signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through TGFβ1/Smad4 signaling. Here, we present that TGFβ1 elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR-155 induced by TGFβ1. The results of luciferase reporter experiments and ChIP assays demonstrated that TGFβ1 promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the TGFβ1/Smad4 pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the TGFβ1-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that TGFβ1/Smad4 signaling affects osteoclast differentiation by regulation of miR-155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise.


Exposure to atmospheric Ag, TiO2, Ti and SiO2 engineered nanoparticles modulates gut inflammatory response and microbiota in mice.
The development of nanotechnologies is leading to greater abundance of engineered nanoparticles (EN) in the environment, including in the atmospheric air. To date, it has been shown that the most prevalent EN found in the air are silver (Ag), titanium dioxide (TiO2), titanium (Ti), and silicon dioxide (SiO2). As the intestinal tract is increasingly recognized as a target for adverse effects induced by inhalation of air particles, the aim of this study was to assess the impact of these 4 atmospheric EN on intestinal inflammation and microbiota. We assessed the combined toxicity effects of Ag, Ti, TiO2, and SiO2 following a 28-day inhalation protocol in male and female mice. In distal and proximal colon, and in jejunum, EN mixture inhalation did not induce overt histological damage, but led to a significant modulation of inflammatory cytokine transcript abundance, including downregulation of Tnfα, Ifnγ, Il1β, Il17a, Il22, IL10, and Cxcl1 mRNA levels in male jejunum. A dysbiosis was observed in cecal microbiota of male and female mice exposed to the EN mixture, characterized by sex-dependent modulations of specific bacterial taxa, as well as sex-independent decreased abundance of the Eggerthellaceae family. Under dextran sodium sulfate-induced inflammatory conditions, exposure to the EN mixture increased the development of colitis in both male and female mice. Moreover, the direct dose-response effects of individual and mixed EN on gut organoids was studied and Ag, TiO2, Ti, SiO2, and EN mixture were found to generate specific inflammatory responses in the intestinal epithelium. These results indicate that the 4 most prevalent atmospheric EN could have the ability to disturb intestinal homeostasis through direct modulation of cytokine expression in gut epithelium, and by altering the inflammatory response and microbiota composition following inhalation.


Post-transcriptional regulation of transcript abundance by a conserved member of the tristetraprolin family in Candida albicans.
Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins bind to AU-rich regions in target mRNAs, leading to their deadenylation and decay. Family members in Saccharomyces cerevisiae influence iron metabolism, whereas the single protein expressed in Schizosaccharomyces pombe, Zfs1, regulates cell-cell interactions. In the human pathogen Candida albicans, deep sequencing of mutants lacking the orthologous protein, Zfs1, revealed significant increases (> 1.5-fold) in 156 transcripts. Of these, 113 (72%) contained at least one predicted TTP family member binding site in their 3'UTR, compared with only 3 of 56 (5%) down-regulated transcripts. The zfs1Δ/Δ mutant was resistant to 3-amino-1,2,4-triazole, perhaps because of increased expression of the potential target transcript encoded by HIS3. Sequences of the proteins encoded by the putative Zfs1 targets were highly conserved among other species within the fungal CTG clade, while the predicted Zfs1 binding sites in these mRNAs often 'disappeared' with increasing evolutionary distance from the parental species. C. albicans Zfs1 bound to the ideal mammalian TTP binding site with high affinity, and Zfs1 was associated with target transcripts after co-immunoprecipitation. Thus, the biochemical activities of these proteins in fungi are highly conserved, but Zfs1-like proteins may target different transcripts in each species.


Comparison of UV-A photolytic and UV/TiO2 photocatalytic effects on Microcystis aeruginosa PCC7813 and four microcystin analogues: A pilot scale study.
To date, the high cost of supplying UV irradiation has prevented the widespread application of UV photolysis and titanium dioxide based photocatalysis in removing undesirable organics in the water treatment sector. To overcome this problem, the use of UV-LEDs (365 nm) for photolysis and heterogeneous photocatalysis applying TiO2 coated glass beads under UV-LED illumination (365 nm) in a pilot scale reactor for the elimination of Microcystis aeruginosa PCC7813 and four microcystin analogues (MC-LR, -LY, -LW, -LF) with a view to deployment in drinking water reservoirs was investigated. UV-A (365 nm) photolysis was shown to be more effective than the UV/TiO2 photocatalytic system for the removal of Microcystis aeruginosa cells and microcystins. During photolysis, cell density significantly decreased over 5 days from an initial concentration of 5.8 × 106 cells mL-1 until few cells were left. Both intra- and extracellular microcystin concentrations were significantly reduced by 100 and 92 %, respectively, by day 5 of the UV treatment for all microcystin analogues. During UV/TiO2 treatment, there was great variability between replicates, making prediction of the effect on cyanobacterial cell and toxin behavior difficult.


Association between Patient History and Physical Examination and Osteoarthritis after Ankle Sprain.
Structural abnormalities on MRI are frequent after an ankle sprain. To determine the association between patient history, physical examination and early osteoarthritis (OA) in patients after a previous ankle sprain, 98 patients with persistent complaints were selected from a cross-sectional study. Patient history taking and physical examination were applied and MRI was taken. Univariate and multivariable analyses were used to test possible associations. Signs of OA (cartilage loss, osteophytes and bone marrow edema) were seen in the talocrural joint (TCJ) in 40% and the talonavicular joint (TNJ) in 49%. Multivariable analysis showed a significant positive association between swelling (OR 3.58, 95%CI 1.13;11.4), a difference in ROM of passive plantar flexion (OR 1.09, 95%CI 1.01;1.18) and bone edema in the TCJ. A difference in ROM of passive plantar flexion (OR 1.07, 95%CI 1.00;1.15) and pain at the end range of dorsiflexion/plantar flexion (OR 5.23, 95%CI 1.88;14.58) were associated with osteophytes in the TNJ. Pain at the end of dorsiflexion/plantar flexion, a difference in ROM of passive plantar flexion and swelling seem to be associated with features of OA (bone marrow edema, osteophytes) in the TCJ and TNJ. Our findings may guide physicians to predict structural joint abnormalities as signs of osteoarthritis. 1b.


[Reverse of the resistance to paclitaxel of the heparin binding-epidermal growth factor-like growth factor inhibitor in ovarian cancer].
Objective: To investigate the effect and mechanism of CRM197, the heparin binding-epidermal growth factor-like growth factor (HB-EGF) inhibitor, on the reverse of the resistance of ovarian cancer to paclitaxel. Methods: (1)The effect of CRM197 on the 50% inhibitory concentrations (IC(50)) of human ovarian carcinoma cell line A2780 and paclitaxel-resistant ovarian carcinoma cell line A2780/Taxol was tested by methyl thiazolyl tetrazolium (MTT) assay. Western blot was used to detect the effect of CRM197 on the expression of HB-EGF, epidermal growth factor receptor (EGFR) and plasma membrane glycoprotein (P-gp) protein in A2780 and A2780/Taxol cells. Real-time PCR was used to examine the MDR1 mRNA expression in these cells. (2) A2780/Taxol cells were divided into 4 groups, including the cells transfected with empty vector and saline treatment (empty vector group), MDR1 small interference RNA (siRNA) vector and saline treatment (MDR1 siRNA group), empty vector and CRM197 treatment (empty vector+CRM197 group) and MDR1 siRNA vector and CRM197 treatment (MDR1 siRNA+CRM197 group), respectively. Flow cytometry was used to detecte the effect of intracellular rhodomine 123 (Rh123) accumulation, and caspase-3 activity assay was used to test the effect of apoptosis in four groups of A2780/Taxol cells. (3) In experiments in vivo, A2780/Taxol cells were inoculated to nude mouse subcutaneously to determine the EGFR and P-gp protein expression following CRM197 treatment by immunohistochemistry. Results: (1) In vitro, MTT examination showed that the IC(50) of A2780/Taxol cells to paclitaxel in A2780/Taxol+CRM197 group [(6.4±0.3) μmol/L] was significantly lower than the IC(50) in A2780/Taxol group [ (34.1±0.5) μmol/L, P<0.01], and the reveral fold of CRM197 was 5.3. The expression level of HB-EGF protein in A2780/Taxol+CRM197 group (1.44±0.29) was significantly lower than HB-EGF protein in A2780/Taxol group (2.72±0.32), respectively (P<0.05). The expression level of EGFR protein (0.71±0.25) and P-gp protein (0.82±0.19) in A2780/Taxol+CRM197 group was significantly lower than EGFR protein (1.87±0.31) and P-gp protein (1.84±0.27) of A2780/Taxol group (P<0.05). Compared with A2780/Taxol group (1.78±0.27) , MDR1 mRNA was significantly down-regulated in A2780/Taxol+CRM197 group (0.79±0.13, P<0.05). (2) The fluorescence intensity of Rh123 of the A2780/Taxol cells in empty vector group, MDR1 siRNA group,empty vector+CRM197 group, MDR1 siRNA+CRM197 group was 33.4±1.6, 56.3±3.3, 43.5±3.1,100.4±7.4, and the pNA of the A2780/Taxol cells was (11.4±1.2) , (52.8±0.9) , (71.2±3.6) , (82.7±3.8) μmol/L. The expression levels in MDR1 siRNA+CRM197 group were both higher than the expression levels in empty vector+CRM197 group, and the expression levels in empty vector+CRM197 group, MDR1 siRNA group were both higher than the expression levels in empty vector group (P<0.05). (3) In vivo, the expression scores of EGFR protein in A2780/Taxol+CRM197 tumors (4.4±1.4) were lower than that in A2780/Taxol tumors (10.2±3.1, P<0.05). The expression scores of P-gp protein in A2780/Taxol+CRM197 tumors (3.8±1.1) were lower than that in A2780/Taxol tumors (8.8±2.7, P<0.05). Conclusion: CRM197 reverses the resistance of ovarian cancer to paclitaxel by increasing caspase-3 activity to advance apoptosis via EGFR/MDR1/P-gp pathway.


HMM-Kalign: a tool for generating sub-optimal HMM alignments.
Recent development of strategies using multiple sequence alignments (MSA) or profiles to detect remote homologies between proteins has led to a significant increase in the number of proteins whose structures can be generated by comparative modeling methods. However, prediction of the optimal alignment between these highly divergent homologous proteins remains a difficult issue. We present a tool based on a generalized Viterbi algorithm that generates optimal and sub-optimal alignments between a sequence and a Hidden Markov Model. The tool is implemented as a new function within the HMMER package called hmmkalign.


Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).
We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A-->G and INV11+18A-->G) and six novel AKU mutations (INV1-1G-->A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.


ESM-1 siRNA Knockdown Decreased Migration and Expression of CXCL3 in Prostate Cancer Cells.
Endothelial cell-specific molecule-1 (ESM-1), also known as endocan, is a soluble proteoglycan expressed by the vascular endothelium, which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels have been reported in several cancer types and immunocompetent patients with sepsis. The aim of this study was to analyze the expression profile of CXC-chemokines and the effects of ESM-1 gene knockdown in proliferation, migration and CXC-chemokine expression in highly metastatic human prostate PC-3 cells. Expression profiles of CXC-chemokines were analyzed in metastatic PC-3 and non-tumorigenic PWR-1E cells. siRNA-mediated knockdown of ESM-1 was performed into PC-3 cells, which were subsequently tested for cell migration and proliferation. Effect of siRNA transfection on CXC-chemokine expression was further quantified at the transcript and protein level. RT-qPCR analysis and sandwich ELISA assay revealed higher levels of ESM-1 and several CXC-chemokines in metastatic PC-3 cells compared to non-tumorigenic PWR-1E. Transfection of PC-3 cells with ESM-1-siRNA decreased cell migration with no effect on proliferation, and it was accompanied by decrease in the transcript and protein levels of the angiogenic chemokine CXCL3. We report here for the first time the ESM-1 targeting in PC-3 cells, which resulted in decreased migration, which may be related, at least in part, to decreased expression of the angiogenic CXCL3 chemokine, whose expression was found to be reduced in ESM-1-siRNA transfected cells. Additional studies are required to ascertain the biological role of ESM-1 in prostate cancer cells and the link with the expression of CXCL3.


Good medical ethics, from the inside out--and back again.
I argue here that good medical ethics requires an empirically-informed moral psychology of medical virtue along with sound action-guiding prescriptions for virtuous medical practice. After distinguishing between three levels of justification, I indicate how medical virtue ethics can draw constructively on relevant empirical research in developing feasible and realistic aspirational standards for doctors, and in evaluating how policymakers can support doctors in acting on the virtues that doctors agreed to be guided by when they joined the profession.


Integrated multi-omic analyses in Biomphalaria-Schistosoma dialogue reveal the immunobiological significance of FREP-SmPoMuc interaction.
The fresh water snail Biomphalaria glabrata is one of the vectors of the trematode pathogen Schistosoma mansoni, which is one of the agents responsible of human schistosomiasis. In this host-parasite interaction, co-evolutionary dynamic results into an infectivity mosaic known as compatibility polymorphism. Integrative approaches including large scale molecular approaches have been conducted in recent years to improve our understanding of the mechanisms underlying compatibility. This review presents the combination of integrated Multi-Omic approaches leading to the discovery of two repertoires of polymorphic and/or diversified interacting molecules: the parasite antigens S. mansoni polymorphic mucins (SmPoMucs) and the B. glabrata immune receptors fibrinogen-related proteins (FREPs). We argue that their interactions may be major components for defining the compatible/incompatible status of a specific snail/schistosome combination.


The climate change challenge for general practice in New Zealand.
Climate change is one of the greatest public health challenges of our time. Despite some inherent uncertainties in making predictions about climate change, there is wide scientific consensus that global warming is occurring; that it is largely due to manmade greenhouse gas emissions; and that it will have substantial health implications for the future. The predicted health impacts of climate change are now clearer for New Zealand, and general practitioners can take action to mitigate these impacts and adapt to the future environment. Actions required involve a combination of 'top-down' and 'ground-up' approaches; effective leadership and policy from our health institutions and, importantly, individual practice initiatives that transform these goals into practical outcomes.


Isolation and identification of bovine Brucella isolates from Pakistan by biochemical tests and PCR.
Brucellosis is endemic in bovines in Pakistan. The Brucella species and biovars involved, however, are unknown. The objectives of the present study were to isolate and characterize brucellae from seropositive milk samples, aborted fetuses, and vaginal swabs of cattle and buffaloes which had recently aborted. The seropositive milk samples, aborted fetuses, and vaginal swabs of cattle and buffaloes were collected from the Potohar Plateau, Pakistan. Isolation of brucellae was done on modified Farrell's serum dextrose agar. Isolates were characterized by conventional biotyping methods, while molecular typing was done by genus (B4/B5) and species-specific (Brucella abortus, Brucella melitensis, Brucella ovis, and Brucella suis) polymerase chain reaction (PCR). A total of 30 isolates were recovered from milk (n = 5), aborted fetuses (n = 13), and vaginal swabs (n = 12). Most isolates were from cattle (56.7 %). All of them were identified as B. abortus biovar 1 based on conventional biotyping methods and genus and species-specific PCR. This preliminary study provides the first report on the prevalence of B. abortus biovar 1 in cattle and buffaloes in Pakistan.


Color and the Cone Mosaic.
Vision is limited by the measurements taken by the cone photoreceptors. To provide useful perceptual representations, the brain must go beyond the measurements and make inferences about the scene being viewed. This article considers the first stages of spatiochromatic vision. We show how spatial and chromatic information become intertwined by the optics of the eye and because of the structure of the retinal cone mosaic, and we consider the consequent implications for perception. Because there is at most one cone at each retinal location, the standard treatment of human trichromacy does not apply at fine spatial scales. Rather, trichromacy results from a perceptual inference based on measurements from cones of different classes at different locations. Our treatment emphasizes linking physics, biology, and computation with the goal of providing a framework for a larger understanding of how the brain interprets photoreceptor excitations to see objects and their properties.


Exploring bovine pancreatic trypsin inhibitor phase transitions.
This paper presents an investigation of the phase diagram of BPTI (bovine pancreatic trypsin inhibitor)/350 mM KSCN at pH 4.9 by direct observation and numerical simulations. We report optical microscopy and light and X-ray scattering experiments coupled with theoretical data analysis using numerical tools. The phase diagram is thoroughly determined, as a function of temperature. Two polymorphs are observed by video microscopy and their solubility measured. In this phase diagram, the liquid-liquid phase separation (LLPS) is metastable with respect to the solid-liquid phase separation. Above the T(L-L) boundary curve, solutions are composed of a mixture of BPTI monomers and decamers. Attractive interactions are stronger between decamers than between monomers. Below the T(L-L) boundary curve, the dense phase is highly concentrated in protein and composed of BPTI decamers alone. Thus, the driving force for liquid-liquid or liquid-solid phase separation is the attraction between decamers at low pH. The structure factors of the dense phases are characteristic of repulsive dense phases because of a hard sphere repulsion core, meaning that in the dense phase proteins are actually in contact (interparticle distance of 53 A). In agreement with the Oswald rule of stages, LLPS occurs prior to and impedes the solid nucleation.


Semiautomated renal region-of-interest selection method: validation in a dog model.
A successful method of automated region-of-interest (ROI) selection by polar edge search for use in technetium-99m-diethylenetriaminepentacetate (99mTc-DTPA) renography is presented in a dog model. The accuracy of the resultant ROI was tested by comparing renal uptake within the ROI to simultaneously monitored arterial 99mTc-DTPA concentration. The automatically selected ROI resulted in renal uptake curves that better matched arterial clearance than either systematically larger and smaller ROIs or a manually chosen ROI.


[The relationship between the abnormal behavior and serum C-reactive protein in children with obstructive sleep apnea-hypopnea syndrome].
To explore the pathogenesis of abnormal behavior in children with obstructive sleep apnea-hypopnea syndrome (OSAHS). The behavioral problems and C-reactive protein were measured in 40 children with OSAHS and 30 children with habitual snoring who underwent overnight Polysomnography, 40 cases of healthy children for the control group. The ratio of abnormal behavior in OSAHS and habitual snoring children was significantly higher than that of the healthy control group, while no significant difference between the two groups. The content of C-reactive protein in OSAHS children (4.24 mg/L) was significantly higher than habitual snoring (2.76 mg/L) and healthy control group (1.27 mg/L); in habitual snoring children C-reactive protein was higher than in healthy control group. The content of serum C-reactive protein in OSAHS children accompanied by abnormal behavior (4.63 mg/L) was significantly higher than that without abnormal behavior (3.23 mg/L). The content of serum C-reactive protein content in habitual snoring children accompanied by abnormal behavior (3.63 mg/L) was significantly higher than that without abnormal behavior (1.76 mg/L). OSAHS and habitual snoring children have more behavior problems. C-reactive protein levels are higher in children with OSAHS and habitual snoring, and the levels of C-reactive protein are related to the abnormal behavior in these children.


Risk behaviours by type of concurrency among young people in three STI clinics in the United States.
Concurrent sexual partnerships can increase sexually transmissible infections (STI) transmission on a population level. However, different concurrency types may be associated with differential risks for transmission. To investigate this, we describe the prevalence and correlates of four specific concurrency types. Between 2001 and 2004, 1098 young adults attending three STI clinics were interviewed and tested for STIs. Characteristics associated with concurrency types were identified using logistic regression. Approximately one-third of respondents reported reactive (34%), transitional (36%), compensatory (32%) and experimental (26%) concurrency. Among men, reactive concurrency was associated with not identifying as heterosexual, drug use and having sex the same day as meeting a partner. Among women, reactive concurrency was associated with African-American race and having >3 lifetime partners. Transitional concurrency was associated with >3 lifetime partners for men and women. Among men, compensatory concurrency was associated with African-American race; among women, there were no associations with compensatory concurrency. Among men, experimental concurrency was associated with >3 lifetime partners and having sex the same day as meeting a partner. Among women, experimental concurrency was associated with not identifying as heterosexual, drug use and having sex the same day as meeting a partner. All concurrency types were common in this population and each was associated with a set of demographic and risk factors. Reactive and experimental concurrency types were associated with other high-risk behaviours, such as drug use.


Overview of the pharmacoeconomics of pharmacogenetics.
Pharmacoeconomics and pharmacogenetics are two fields converging together as it is increasingly recognized that genetic markers predicting efficacy and toxicity to drugs can cost-effectively improve patient care. While pharmacogenetics aims at identifying genetic markers underlying the response to drugs, pharmacoeconomics aims at delivering healthcare cost-effectively. Several studies have investigated the potential cost-effectiveness of pharmacogenetic-based approaches. Recent evidences include screening for thiopurine methyltransferase gene polymorphisms to prevent azathioprine-induced myelosuppression, or screening for human leukocyte antigen (HLA)B5701 to prevent hypersensitivity reactions to abacavir therapy. Furthermore, examples suggesting a cost-effectiveness of markers predicting drug efficacy include screening the angiotensin-converting enzyme gene polymorphisms for statins therapy, the alpha-adducin gene variant for diuretic therapy and the assessment of human epidermal growth factor receptor (HER2) expression for trastuzumab therapy. However, thus far, all these pharmacoeconomic analyses are exploratory and validations in prospective randomized clinical trials are warranted.


Functional role for a 2-oxo acid dehydrogenase in the halophilic archaeon Haloferax volcanii.
The archaeon Haloferax volcanii was previously shown to contain and transcribe the genes for a 2-oxo acid dehydrogenase (OADH) complex, but their presence remained a mystery because no enzymatic activity with any of the known OADH substrates could be found, and an inactivation of one of the genes did not lead to any phenotype. Here we report the identification of an additional oadh gene cluster in the genome of H. volcanii. In contrast to previously known oadh loci, it contains three genes, oadh2A1, oadh2A2, and oadh2ld, with coding capacity for the E1alpha and E1beta subunits and an unattached lipoyl domain, but it is devoid of the genes for a complete E2 and an E3. The genes were isolated by complementation of a nitrate respiration-deficient mutant of H. volcanii and therefore were shown to be functional in vivo. Phylogenetic analyses revealed that the deduced E1alpha and E1beta subunits of OADH2 group with bacterial acetoin dehydrogenases but not with the OADH1 subunits, and thus, H. volcanii has obtained the two gene groups independently. Comparison of the wild type and the mutant allowed us to exclude a function of OADH2 in the aerobic or anaerobic degradation of acetoin or glucose. Instead, it could be shown that OADH2 is important during nitrate-respirative growth on Casamino Acids. Many physiological and biochemical experiments failed to indicate that OADH2 uses any of the previously known OADH substrates. Growth potentials of the mutant were markedly different in media with a single carbon source versus media with mixed carbon sources.


Structural genomics of eukaryotic targets at a laboratory scale.
Structural genomics programs are distributed worldwide and funded by large institutions such as the NIH in United-States, the RIKEN in Japan or the European Commission through the SPINE network in Europe. Such initiatives, essentially managed by large consortia, led to technology and method developments at the different steps required to produce biological samples compatible with structural studies. Besides specific applications, method developments resulted mainly upon miniaturization and parallelization. The challenge that academic laboratories faces to pursue structural genomics programs is to produce, at a higher rate, protein samples. The Structural Biology and Genomics Department (IGBMC - Illkirch - France) is implicated in a structural genomics program of high eukaryotes whose goal is solving crystal structures of proteins and their complexes (including large complexes) related to human health and biotechnology. To achieve such a challenging goal, the Department has established a medium-throughput pipeline for producing protein samples suitable for structural biology studies. Here, we describe the setting up of our initiative from cloning to crystallization and we demonstrate that structural genomics may be manageable by academic laboratories by strategic investments in robotic and by adapting classical bench protocols and new developments, in particular in the field of protein expression, to parallelization.


Double-bundle medial patellofemoral ligament reconstruction with a single patellar tunnel.
Medial patellofemoral ligament (MPFL) reconstruction is an established method to prevent patellofemoral instability. Nevertheless, the anatomy and the biomechanical behavior of native MPFL are still under investigation, but in recent years they have become more defined. We propose a technique for MPFL reconstruction based on the results of recent anatomic studies regarding the patellar insertion of the MPFL. A double-bundle MPFL is reconstructed by use of the semitendinosus tendon passed through a single patellar tunnel, which crosses the patella from the midpoint of its medial border until its superolateral corner is reached. This method permits a strong patellar fixation, potentially reducing the risk of patellar fracture compared with double-patellar tunnel techniques. Moreover, it requires no fixation devices at the patella and only a single interference screw on the femoral side.


Aspects of body composition in human immunodeficiency virus (HIV) infection.
In the mid-1980s, body composition studies of symptomatic AIDS patients, utilizing total body potassium counting and isotope dilution. indicated that the pattern weight loss observed in advanced HIV infection was similar to a stressed or injured state, rather than one of starvation. A disproportionate depletion of body cell mass (of which skeletal muscle is a major component), relative to loss of body weight, was seen along with a relative expansion of the extracellular fluid volume The same researches observed that this decline in body cell mass was predictive of mortality. Cross-sectional studies in HIV infection have also indicated that a reduction in body cell mass can occur early in the disease process; these studies utilising bioelectrical impedance analysis as a means of body composition assessment.


Using participant event monitoring in a cohort study of unintentional injuries among children and adolescents.
We conducted a 3-year cohort study of 407 youths aged 9 to 18 years to develop multivariable risk prediction models of agriculture-related injuries. Data were obtained via participant event monitoring, with youths self-reporting injuries and exposures in daily diaries over a 13-week period. We evaluated data quality by comparing injury self-reports with other injury data. Semilogarithmic plots of rates of all unintentional injuries combined (US data from 2000) as well as of agriculture-related injuries (US and Canadian data from 19 previous studies) graphed as a function of injury severity exhibited linearity, as did plots based on the present results. Severity-specific unintentional injury rates were 1.4- to 4.3-times higher than national rates, suggesting that our methodology can significantly reduce injury underreporting. In addition, at each severity level, estimated agriculture-related injury rates were 5.8- to 9.3-times higher than rates from previous national, regional, and state-based studies. Our approach to participant event monitoring can be implemented with youths aged 9 to 18 years and will yield reliable daily data on unintentional injuries.


Hepatic transcriptomics analysis reveals that fructose intervention down-regulated xenobiotics-metabolising enzymes through aryl hydrocarbon receptor signalling suppression in C57BL/6N mice.
For decades, fructose intake has been recognised as an environmental risk for metabolic syndromes and diseases. Here we comprehensively examined the effects of fructose intake on mice liver transcriptomes. Fructose-supplemented water (34 %; w/v) was fed to both male and female C57BL/6N mice at their free will for 6 weeks, followed by hepatic transcriptomics analysis. Based on our criteria, differentially expressed genes (DEG) were selected and subjected to further computational analyses to predict key pathways and upstream regulator(s). Subsequently, predicted genes and pathways from the transcriptomics dataset were validated via quantitative RT-PCR analyses. As a result, we identified eighty-nine down-regulated and eighty-eight up-regulated mRNA in fructose-fed mice livers. These DEG were subjected to bioinformatics analysis tools in which DEG were mainly enriched in xenobiotic metabolic processes; further, in the Ingenuity Pathway Analysis software, it was suggested that the aryl hydrocarbon receptor (AhR) is an upstream regulator governing overall changes, while fructose suppresses the AhR signalling pathway. In our quantitative RT-PCR validation, we confirmed that fructose suppressed AhR signalling through modulating expressions of transcription factor (AhR nuclear translocator; Arnt) and upstream regulators (Ncor2, and Rb1). Altogether, we demonstrated that ad libitum fructose intake suppresses the canonical AhR signalling pathway in C57BL/6N mice liver. Based on our current observations, further studies are warranted, especially with regard to the effects of co-exposure to fructose on (1) other types of carcinogens and (2) inflammation-inducing agents (or even diets such as a high-fat diet), to find implications of fructose-induced AhR suppression.


Promoter methylation of p16(INK4A), hMLH1, and MGMT in liquid-based cervical cytology samples compared with clinicopathological findings and HPV presence.
Cervical cancer is a common cancer inflicting women worldwide. Even though, persistent infection with oncogenic Human Papillomavirus (HPV) types is considered the most important risk factor for cervical cancer development, less than 5% of women with HPV will eventually develop cervical cancer supporting that other molecular events, like methylation-dependent inactivation of tumor suppressor genes, may cocontribute in cervical carcinogenesis. We analyzed promoter methylation of three candidate genes (p16, MGMT, and hMLH1) in 403 liquid-based cytology samples. Methylation was commonly identified in both benign and pathologic samples and correlated with higher lesion grade determined by cytological, colposcopical, or histological findings, with HPV DNA and mRNA positivity of specific HPV types and p16(INK4A) protein expression. Overall accuracy of methylation is much lower than traditional diagnostic tests ranking it as an ancillary technique with more data needed to identify the exact value of methylation status in cervical carcinogenesis.


Water retention capabilities of collagen, gelatin and peptide as studied by IR/QCM/RH system.
In this study, water retention properties of triple helix collagen, gelatin (separated single chains) and peptide (broken peptide fragments) were studied by using IR micro-spectroscopy equipped with a relative humidity (RH) control system and quartz crystal microbalance (QCM). Adsorbed water ratios (wt%) are found to be in the order of collagen, gelatin and peptide (at about RH = 60%, 22 wt% for collagen, 14 wt% for gelatin and 9 wt% for peptide). Free water molecules with longer H bonds are the major adsorbed water species for collagen, gelatin and peptide. IR band shifts and changes in normalized band areas of functional groups are generally larger for collagen than gelatin and peptide, indicating larger interactions of water molecules with functional groups such as aliphatic CH2, CH3, amides, COO- and C-O for collagen. Relations between normalized band areas show that water molecules are interacting with aliphatic CH species and C-O bonds of collagen. Since the fibril structures of collagen triple helices are reported to be cross-linked by sugars, water molecules can be attracted to polar C-O bonds of sugars linking collagen triple helices in fibrils and they are interacting with adjacent aliphatic CH side chains on the surface of fibrils.


Supported ionic-liquid films (SILF) as two-dimensional nanoreactors for enantioselective reactions: surface-mediated selectivity modulation (SMSM).
Supported ionic-liquid films (SILF) of nanometric thickness containing bis(oxazoline)-copper complexes can be used as recoverable catalysts for enantioselective cyclopropanation reactions. When a thin film of ionic liquid is supported on a clay, the system behaves as a nearly two-dimensional nanoreactor in which the restrictions in rotational mobility and the close proximity to the surface support produce variations in the stereo- and enantioselectivities, leading to a complete reversal of the overall selectivity of the reaction. As an example, the cyclopropanation of styrene changes from a preference for the (1S,2S)-trans isomer in bulk solution to the (1R,2S)-cis isomer in the SILF. This variation is strongly dependent on both the thickness of the film and the nature of the support. Only layered solids with negative charges in the layers (clays) give rise to this type of behaviour, showing that the formation of ion pairs may be a decisive factor. This unexpected effect also shows the existence of differences between bulk and supported ionic liquids.


History of Seborrheic Dermatitis: Conceptual and Clinico-Pathologic Evolution.
Seborrheic dermatitis is an inflammatory and chronic disease with a high incidence and prevalence (1% to 3% in the general population, 3% to 5% in young adults, and 40% to 80% in HIV-positive individuals). Although the condition was first described in 1887, its clinical aspects and clinical forms have still not been well individualized, nor has its etiopathogenesis been fully elucidated. The disease, despite having clinical features similar to dermatitis, does not have the same histopathologic features or the same progressive clinical behavior. This contribution reviews the history of seborrheic dermatitis.


Best practice in primary care pathology: review 12.
This twelfth best practice review examines four series of common primary care questions in laboratory medicine: (i) antiepileptic drug monitoring; (ii) infectious diarrhoea; (iii) methicillin resistant Staphylococcus aureus; and (iv) brain natriuretic peptide. The review is presented in question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by MEDLINE EMBASE searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence-based. They will be updated periodically to take account of new information.


[Genetic problems in occupational medicine].
The investigation has been aimed at the genetically conditioned increased sensitivity to occupational hazards. Special attention should be paid to population's genetic differentiation at setting up hygienic standards and interpretation of results of biological absorption tests. As problems related to genetically conditioned increased sensitivity to hazards are particularly significant in the countries with the population's considerable biochemical differentiation or considerable rate of the so called biochemical deficits, therefore the problem gets more intense as more immigrants from Asiatic and African countries are employed in European industries. In the authors' opinion, correctly arranged pre-employment studies should reduce the number of poisonings in chemical industry.


[Catamnesis of psychiatrically evaluated automobile drivers].
The present catamnestic study covers 100 petitioners, who either applied for the first time for a driving licence or for readmission to traffic after confiscation of their license by the police. 99 of them were former inpatients or still inpatients at the time of judgement. For all of them, the decision of the police depended upon our expertise. For the judgement we considered our psychiatric investigation, the clinical report and the police traffic record. Normally, our mode of admission was quite generous. The duration of catamnesis lasted at least two years. Our of the 100 petitioners, 88 were considered to be fit for driving; 67 unconditionally and 21 under the condition of regular survey or treatment. Subsequently seven of the petitioners showed a poor probation, i.e. their licenses were taken away by the police, one due to a severe and two due to minor accidents. Nobody was injured. In comparison to the experience of other authors about probation in traffic of former psychiatric inpatients, we think we can report a favourable result. A rather generous mode of admission to traffic seems to be justified in these patients.


Primary pulmonary hypertension: a continuing diagnostic and therapeutic challenge.
Primary pulmonary hypertension (PPH) continues to present both diagnostic and therapeutic challenges to the physician, reflecting the lack of understanding about the basic mechanism of the disease. The onset of the condition is usually insidious, the main symptoms of dyspnoea, syncope and angina often being ascribed to functional or emotional causes. As a result, delay in diagnosis is the norm, with an interval from onset of symptoms to diagnosis of up 2 yrs. The ability of the vasodilator drugs that are now available to produce sustained improvement in patients with PPH is limited by a number of factors. The prognosis is generally severe; however, despite the overall dismal prognosis, duration of survival ranges up to 10 years or more. It is important to consider the possibility of an early stage, when functional changes are prevalent in a substantial number of patients with primary pulmonary hypertension. At this stage, an optimized therapy would be expected to interrupt the course of pulmonary hypertension or, at the very least, retard its progression.


Attachment and psychotherapy.
Attachment theory provides a model for understanding (1) development within the context of the child's primary, and formative relationships, and (2) an adult's orientation toward lifelong intimate connections, social relationships, and autonomous exploration. Psychotherapy researchers have linked measures of patient attachment with therapeutic alliance, process, and outcomes. Studies of ruptures and discourse analysis distinguish in-session behaviors associated with different patterns of insecure attachments, and identify distinct ways of working with them. The therapist's own attachment organization and mentalizing capacity also play a significant role in therapeutic success. The key tenets of attachment-informed psychotherapy are: (1) the therapist-patient attachment relationship is central to promoting change, (2) the in vivo recognition of attachment dynamics during therapy guides formulation and intervention, and (3) therapy can reshape attachment dynamics.


Trends in the Surgical Management of Lower Extremity Gustilo Type IIIB/IIIC Injuries.
Over the past 20 years, innovations in microsurgical technique have coincided with advances in orthoplastic approaches. However, no single algorithm exists to guide management of limb salvage versus amputation. As such, one would expect these procedures to be performed at equal rates given studies showing similar outcomes. Anecdotally, the observation at the authors' institution is that amputations are being performed more frequently. The purpose of this study was to determine trends in lower extremity trauma management. A retrospective cohort study was conducted at a Level I trauma center on patients with Gustilo type IIIB/IIIC lower extremity trauma from 2005 to 2014. Overall, 148 patients were included. Patients were subdivided into amputation (n = 69) and reconstruction (n = 79) cohorts. The Spearman rank correlation coefficient was used to compare trends in amputation and reconstruction groups. Plastic surgery consultation data were analyzed using the Mann-Whitney U and chi-square tests and the Pearson correlation coefficient. Amputation was performed more frequently over the study period (r = 0.292; p < 0.001). Plastic surgeons were consulted in 67.5 percent of cases. A plastic surgery consultation was obtained in only 30 percent of amputation cases (p < 0.001). Although the data show a trend toward amputation and a shift in management of lower extremity trauma, the observed trend may be attributable in part to deviation from an orthoplastic approach to lower extremity trauma. However, lower extremity reconstruction remains a viable option in select patients, and advances in microsurgery can provide excellent outcomes in the face of severe lower extremity trauma.


Clinical relevance of amphiregulin and VEGF in primary breast cancers.
The characterization of novel prognostic markers in breast cancer is necessary to improve the identification of high-risk populations. In our study, the prognostic significance of VEGF and amphiregulin (AR) was investigated and compared to conventional prognostic factors in primary breast cancers. The analysis was performed using enzyme-linked immuno-assay in a series of 193 patients, and univariate and multivariate analysis were performed in the overall population as well as in pre- and post-menopausal patients subdivided in node-negative (N-) and node-positive (N+) subsets. AR (median, 44.8 pg/mg protein) appeared strongly correlated with progesterone receptors (PgR) (p = 0.0018) in the premenopausal N+ population, and with uPA (p= 0.020) and VEGF (p= 0.0053) in the postmenopausal/N+ patients. Despite these attractive data, AR expression was not significant for recurrence or survival outcome. Data revealed strong correlation between VEGF and uPA, and PAI-1, in the N+ population. Moreover, patients with high VEGF levels displayed poor outcome, with an increased risk for N+ subset. These data were confirmed by multivariate analysis that presented histologic grade (HR, 10.55, p = 0.001) and VEGF (HR, 3.89, p = 0.03) as the prominent prognostic markers for overall survival for the N+ population. Furthermore, infiltrating ductal carcinomas (IDC) were shown to express higher levels of both uPA (p < 0.0001) and VEGF (p = 0.002) than intralobular carcinomas. This retrospective study reinforces the pejorative biological role of VEGF in the progression of breast tumors. Our data also suggest that VEGF and uPA might play particular role in the biology and progression of IDC.


A Randomized Controlled Trial to Investigate the Impact of Tango Argentino versus Tai Chi on Quality of Life in Patients with Parkinson Disease: A Short Report.
Parkinson disease (PD) is a neurodegenerative disorder with increasing impairments in disease progression. The aim of the pilot study was to investigate the influence of Tango argentino on the quality of life of people with PD compared to Tai Chi. Design, Setting, Interventions: In the two-arm, randomized controlled pilot study, patients with PD received a 10-week Tango argentino or Tai Chi intervention (once per week, 60 min each). The outcome parameters were assessed at three time points (after the 1st course, after the 5th course, and after the 10th course) using standardized instruments, i.e., Parkinson's Disease Questionnaire-39 (PDQ-39), Brief Multidimensional Life Satisfaction Scale (BMLSS), Inner Congruence with Practices (ICPH). Overall, 14 patients and their partners received Tango argentino (9 male, 5 female; mean age: 69 ± 8 years) and 15 received Tai Chi (3 male, 12 female; mean age: 69 ± 11 years). Four patients in each group were lost during the trial. No improvements were found in both groups for all outcomes. Patients in the tango group reported better emotional well-being (p = 0.039) after 10 weeks of intervention compared to the Tai Chi group. Further studies are needed taking into account findings from this study to improve recruitment and attrition of patients during the trial and to justify the potential implementation of Tango argentino into clinical care.


Progress and prospects of magnetic iron oxide nanoparticles in biomedical applications: A review.
Nanoscience has been considered as one of the most substantial research in modern science. The utilization of nanoparticle (NP) materials provides numerous advantages in biomedical applications due to their unique properties. Among various types of nanoparticles, the magnetic nanoparticles (MNPs) of iron oxide possess intrinsic features, which have been efficiently exploited for biomedical purposes including drug delivery, magnetic resonance imaging, Magnetic-activated cell sorting, nanobiosensors, hyperthermia, and tissue engineering and regenerative medicine. The size and shape of nanostructures are the main factors affecting the physicochemical features of superparamagnetic iron oxide nanoparticles, which play an important role in the improvement of MNP properties, and can be controlled by appropriate synthesis strategies. On the other hand, the proper modification and functionalization of the surface of iron oxide nanoparticles have significant effects on the improvement of physicochemical and mechanical features, biocompatibility, stability, and surface activity of MNPs. This review focuses on popular methods of fabrication, beneficial surface coatings with regard to the main required features for their biomedical use, as well as new applications.


Supramolecular spin-crossover iron complexes based on imidazole-imidazolate hydrogen bonds.
The [Fe(II)(H(3)L)](BF(4))(2).3H(2)O (1) complex was synthesized, where H(3)L (tris[[2-[(imidazole-4-yl)methylidene]amino]ethyl]amine) is a tripodal ligand obtained by condensation of tris(2-aminoethyl)amine and 4-formylimidazole (fim) in a 1:3 molar ratio. Starting from 1, a series of complexes, [Fe(II)(H(1.5)L)](BF(4))(0.5) (2) (=[Fe(II)(H(3)L)][Fe(II)(L)]BF(4)), [Fe(H(1.5)L)]BF(4) (3) (=[Fe(II)(H(3)L)][Fe(III)(L)](BF(4))(2)), [Fe(III)(H(3)L)](BF(4))(3).fim.H(2)O (4), and [Fe(III)(L)].2.5H(2)O (5), has been synthesized and characterized. The single-crystal X-ray structure of each complex has been determined. The Fe(II) compound, 2, and a mixed valence Fe(II)-Fe(III) compound, 3, involve formally hemi-deprotonated ligands, H(1.5)L. The structure of 3 consists of a homochiral two-dimensional assembled sheet, arising from the intermolecular hydrogen bonds between [Fe(II)(H(3)L)](2+) and [Fe(III)(L)](0) (3). All but 5 exhibit spin crossover between low-spin (LS) and high-spin (HS) states. This is a rare case where both Fe(II) and Fe(III) complexes containing the same ligand exhibit spin-crossover behavior. Magnetic susceptibility and Mössbauer studies showed that 3 has three accessible electronic states: LS Fe(II)-LS Fe(III), HS Fe(II)-LS Fe(III), and HS Fe(II)-HS Fe(III). Compounds 1-3 show the light-induced excited spin-state trapping effect at the Fe(II) sites upon irradiation with green light. The solution magnetic properties, electronic spectra, and electrochemical properties of 1, 4, and 5 were also studied.


Reduction of Sleep Deprivation and Fatigue in Mass Transit Rail Operators.
Sleep and work schedules differ considerably between rail workers and the broader U.S. workforce. Due to extended work hours and night shift schedules, train and engine service workers who operate passenger trains or move freight are most vulnerable to fatigue. This article addresses the need for comprehensive fatigue risk management systems (FRMS) for rail operators. Using a transactional ergonomic perspective, FRMS are discussed with a focus on fatigue education and administrative controls to reduce feelings of tiredness, low motivation, poor concentration, and low physical activity among mass transit rail operators. Recommendations for intervention implementation and evaluation are provided.


An extended epistemology for fostering transformative learning in holistic nursing education and practice.
The transformation from traditional nursing practice to holistic nursing is one that requires recognition of multiple ways of knowing. Transformative learning theory reflects a strong bias toward cognitive epistemology and propositional knowing. This epistemology, labeled here as truncated, rests on an understanding of experience derived from pragmatism. This article describes an extended epistemology derived from the work of John Heron that better reflects the full range of knowing utilized by holistic nurses. This epistemology provides a foundation for innovative approaches for the development of holistic awareness in the training and continuing professional development of nurses. One such approach, collaborative inquiry, is described.