EPR studies of amine radical cations. Part 2. Thermal and photo-induced rearrangements of propargylamine and allylamine radical cations in low-temperature freon matrices.
Matrix EPR studies and quantum chemical calculations have been used to characterize the consecutive H-atom shifts undergone by the nitrogen-centered parent radical cations of propargylamine (1b*+) and allylamine (5*+) on thermal or photoinduced activation. The radical cation rearrangements of these unsaturated parent amines occur initially by a 1,2 H-atom shift from C1 to C2 with pi-bond formation at the positively charged nitrogen; this is followed by a consecutive reaction involving a second H-atom shift from C2 to C3. Thus, exposure to red light (lambda > 650 nm) converts 1b*+ to the vinyl-type distonic radical cation 2*+ which in turn is transformed on further photolysis with blue-green light (lambda approximately 400-600 nm) to the allene-type heteroallylic radical cation 3*+. Calculations show that the energy ordering is 1b*+ > 2*+ > 3*+, so that the consecutive H-atom shifts are driven by the formation of more stable isomers. Similarly, the parent radical cation of allylamine 5*+ undergoes a spontaneous 1,2-hydrogen atom shift from C1 to C2 at 77 K with a t1/2 of approximately 1 h to yield the distonic alkyl-type iminopropyl radical cation 6*+; this thermal reaction is attributed largely to quantum tunneling, and the rate is enhanced on concomitant photobleaching with visible light. Subsequent exposure to UV light (lambda approximately 350-400 nm) converts 6*+ by a 2,3 H-shift to the 1-aminopropene radical cation 7*+, which is confirmed to be the lowest-energy isomer derived from the ionization of either allylamine or cyclopropylamine. Although the parent radical cations of N, N-dimethylallylamine (9*+) and N-methylallylamine (11*+) are both stabilized by the electron-donating character of the methyl group(s), the photobleaching of 9*+ leads to the remarkable formation of the cyclic 1-methylpyrrolidine radical cation 10*+. The first step of this transformation now involves the migration of a hydrogen atom to C2 of the allyl group from one of the methyl groups (rather than from C1); the reaction is then completed by the cyclization of the generated MeN + (=CH2) CH2CH2CH2* distonic radical cation, possibly in a concerted overall process. In contrast to the ubiquitous H-atom transfer from carbon to nitrogen that occurs in the parent radical cations of saturated amines, the alternate rearrangements of either 1b*+ or 5*+ to an ammonium-type radical cation by a hypothetical H-atom shift from C1 to the ionized NH2 group are not observed. This is in line with calculations showing that the thermal barrier for this transformation is much higher (approximately 120 kJ mol-1) than those for the conversion of 1b*+ --> 2*+ and 5*+--> 6*+ (approximately 40-60 kJ mol-1).


Depressive symptoms in lung transplant recipients: trajectory and association with mortality and allograft dysfunction.
Most studies observing an association between depressive symptoms following lung transplantation and mortality are limited to depressive symptom measurement at a single time point, unrelated to allograft function. We aimed to test the association of depressive symptoms over multiple assessments with allograft dysfunction and with mortality. We assessed depressive symptoms before and serially up to 3 years after lung transplantation in lung transplant recipients. We quantified depressive symptoms with the Geriatric Depression Scale (GDS; range 0-15; minimally important difference (MID): 2). We quantified changes in GDS using linear mixed effects models and tested the association with mortality using Cox proportional hazards models with GDS as a time-dependent predictor. To determine if worsening in GDS preceded declines in lung function, we tested the association of GDS as a time-dependent predictor with the lagged outcome of FEV1 at the following study visit. Among 266 participants, depressive symptoms improved early after transplantation. Worsening in post-transplant GDS by the MID was associated with mortality (HR 1.25, 95% CI 1.05 to 1.50), and in lagged outcome analyses with decreased per cent predicted FEV1 (Δ, -1.62%, 95% CI -2.49 to -0.76). Visual analyses of temporal changes in GDS demonstrated that worsening depressive symptoms could precede chronic lung allograft dysfunction. Depressive symptoms generally improve after lung transplantation. When they worsen, however, there is an association with declines in lung function and mortality. Depression is one of the few, potentially modifiable, risk factors for chronic lung allograft dysfunction and death.


Oral maxillary exostosis.
Oral maxillary exostoses are proliferating bone lesions with an unknown etiology occurring on the cortical plates both in the maxilla and in the mandible of young individuals, showing a typical slow but continuous enlargement. No treatment is usually required unless they create esthetic or functional limitations during follow-up; the biopsy is needed only for doubtful lesions. Furthermore, it is mandatory to collect an accurate familiar history of patients affected by exostosis, especially when occurring with atypical clinical presentation, in order to exclude or prevent potentially associated systemic diseases.


Bone abnormalities occurring in the follow-up of the patients with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease or peripheral neurofibromatosis, is a common autosomal dominant disorder characterized by multiple neurofibromas, "café au lait" spots and Lisch nodules of the iris with a variable clinical expression. Osseous anomalies appeared in the patients with NF1 including dysplasia, scoliosis and pseudoarthrosis. We propose a research of the osseous involvement at 11 patients, seven female and four male with ages from 9 to 60 at which the cutaneous aspect has the complete form, hyperpigmented spots and cutaneous neurofibromas and only more than six "café au lait" spots. All the patients suffered radiological exams, CT- and MRI-scan. The results were different from case to case from the extreme severe deformations, especially at the children, to clinical unapparent osseous involvement, incidental found or with occasion of our investigation. CONCLUSIONS. The patients with NF1 has osseous abnormalities specific of the disease, like dysplasia, scoliosis, pseudoarthrosis, often gentle but sometimes extremely severe. The most severe osseous involvement are presented in the cases when these development early in the childhood. Other times the osseous abnormalities are clinical asymptomatic, their finding been clinical incidental. We want to have a separate mention for the maxillary and mandible involvement, which according to our information is not a rare form.


A New Method Based on Graphics Processing Units for Fast Near-Infrared Optical Tomography.
The accuracy of images obtained by Diffuse Optical Tomography (DOT) could be substantially increased by the newly developed time resolved (TR) cameras. These devices result in unprecedented data volumes, which present a challenge to conventional image reconstruction techniques. In addition, many clinical applications require taking photons in air regions like the trachea into account, where the diffusion model fails. Image reconstruction techniques based on photon tracking are mandatory in those cases but have not been implemented so far due to computing demands. We aimed at designing an inversion algorithm which could be implemented on commercial graphics processing units (GPUs) by making use of information obtained with other imaging modalities. The method requires a segmented volume and an approximately uniform value for the reduced scattering coefficient in the volume under study. The complex photon path is reduced to a small number of partial path lengths within each segment resulting in drastically reduced memory usage and computation time. Our approach takes advantage of wavelength normalized data which renders it robust against instrumental biases and skin irregularities which is critical for realistic clinical applications. The accuracy of this method has been assessed with both simulated and experimental inhomogeneous phantoms showing good agreement with target values. The simulation study analyzed a phantom containing a tumor next to an air region. For the experimental test, a segmented cuboid phantom was illuminated by a supercontinuum laser and data were gathered by a state of the art TR camera. Reconstructions were obtained on a GPU-installed computer in less than 2 h. To our knowledge, it is the first time Monte Carlo methods have been successfully used for DOT based on TR cameras. This opens the door to applications such as accurate measurements of oxygenation in neck tumors where the presence of air regions is a problem for conventional approaches.


How a Clinical Trial Unit can improve independent clinical research in rare tumors: the Italian Sarcoma Group experience.
The Italian Sarcoma Group (ISG) is a nonprofit group of professionals established in 1997 aimed to improve the quality of care and promote the independent research in sarcomas. The increased regulatory requirements, the chance to increase the number of trials with other cooperative groups and an interest from pharmaceutical companies in supporting independent research, generated the need of an internal service for research management. In 2010, ISG implemented in its organization a Clinical Trial Unit (CTU). The CTU was appointed to fully manage Clinical Trial Operations, to guarantee regulation compliance and provide a central support to the investigators, fostering a collaboration both at national and international level. In 2016 ISG promoted 25 studies in about 120 centers, with a fivefold increase in the last 5 years: 68% were interventional and 32% observational. Nine of the 17 interventional studies (52%) were supported by pharmaceutical companies, while 4 (24%) were funded by European Commission within specific projects on sarcomas and 4 (24%) were supported by the ISG itself. The contribution of ISG researchers to the international community was striking from the earliest years of the ISG creation. The challenges of the regulatory clinical research scenario, which imposes solid and hard-fast methodology with deep knowledge and expertise, highlighted the need to identify qualified and dedicated experts able to run and follow the multifaceted aspects of trials. Our analysis demonstrated how this model has led to a growth in competitiveness of the group. The collaboration between clinicians and CTU made possible to support the research with high scientific and ethical standards and to increase the number of trials, sites and overall enrolled patients. The reduced time for approvals, the continuous support to sites, the increased speed in data collection and analysis make the ISG research attractive for pharmaceutical industries, despite the problems that have characterized the independent research in the last years. The ability to fully manage and oversight Clinical Operations and the high quality of delivered services, have led the ISG to be recognized as a reliable partner and coordinator within the international sarcoma networks.


Risk factors associated with cat parasites in a feline medical center.
The present study was carried out to evaluate the risk factors for and presence of intestinal parasites in cats at the feline hospital 'CEME Gatos', Mexico City. In total, 528 fecal samples from domestic cats were collected and analyzed in order to diagnose enteroparasites. The parasite with the highest prevalence was Giardia species (21.97%), followed by Cryptosporidium species (7%), Toxocara cati (6.45%), Cystoisospora species (5.11%) and Dipylidium caninum (0.76%). One hundred and twenty-one cats (55.50%) were infected with a single parasite, 80 (36.69%) were infected with two and 17 (14.04%) were infected with three parasites. The results of the prevalence study showed that a liquid consistency of feces was associated with the presence of Giardia species, whereas age <7 months and mucus in the stool were factors associated with the prevalence of Cystoisospora species. Regarding T cati, the associated risk factors were age <7 months, being male, contact with other animal species and access to the outdoors. The last factor was strongly associated with the presence of T cati (eight times more likely) in outdoor cats' feces. Brushing frequency was also an associated factor: T cati was present in cats that were never brushed. The results of the analysis of cats infected with D caninum showed that interaction with other species was a risk factor for infection. Age <7 months, mucus in feces, living with other animal species, outdoor access and frequency of brushing are risk factors for the presence of parasites.


Decoding leader cells in collective cancer invasion.
Collective cancer invasion with leader-follower organization is increasingly recognized as a predominant mechanism in the metastatic cascade. Leader cells support cancer invasion by creating invasion tracks, sensing environmental cues and coordinating with follower cells biochemically and biomechanically. With the latest developments in experimental and computational models and analysis techniques, the range of specific traits and features of leader cells reported in the literature is rapidly expanding. Yet, despite their importance, there is no consensus on how leader cells arise or their essential characteristics. In this Perspective, we propose a framework for defining the essential aspects of leader cells and provide a unifying perspective on the varying cellular and molecular programmes that are adopted by each leader cell subtype to accomplish their functions. This Perspective can lead to more effective strategies to interdict a major contributor to metastatic capability.


Cyclosporin A inhibits degranulation of rat basophilic leukemia cells and human basophils. Inhibition of mediator release without affecting PI hydrolysis or Ca2+ fluxes.
Cyclosporin A (CSA) inhibits IgE receptor-mediated exocytosis from rat basophilic leukemia (RBL) cells and human peripheral blood basophils in a dose-dependent manner over the therapeutic range of CSA concentrations achieved in vivo. Half-maximal inhibition was observed at 0.2 micrograms/ml CSA. The effect of CSA on several biochemical parameters involved in receptor-mediated activation of RBL cells was examined. Maximum inhibition of secretion occurred when CSA was added 5 min before activation, and inhibition was nearly maximum when the drug was added 2 min before the cells were triggered. The same results were observed when RBL cells were stimulated with A23187, a calcium ionophore. These results suggest a mechanism other than inhibition of protein synthesis is involved. Inhibition by CSA of release by either secretagogue persisted, even if CSA was removed from the buffer before the cells were triggered. No inhibition was observed of either receptor-mediated phosphatidylinositol hydrolysis, 45Ca2+ uptake, or the rise in the intracellular concentration of free Ca2+ under the same conditions that produced greater than 80% inhibition of serotonin release. These results demonstrate that the early events in signal transduction are not affected, and suggest that the intracellular target for CSA participates in a later stage of exocytosis. Furthermore, the data suggest that CSA suppresses cells other than T lymphocytes and predict that patients on CSA therapy may have altered response to allergens.


Protons, the thylakoid membrane, and the chloroplast ATP synthase.
According to the chemiosmotic theory, proton pumps and ATP synthases are coupled by lateral proton flow through aqueous phases. Three long-standing challenges to this concept, all of which have been loosely subsumed under 'localized coupling' in the literature, were examined in the light of experiments carried out with thylakoids: (1) Nearest neighbor interaction between pumps and ATP synthases. Considering the large distances between photosystem II and CFoCF1, in stacked thylakoids this is a priori absent. (2) Enhanced proton diffusion along the surface of the membrane. This could not be substantiated for the outer side of the thylakoid membrane. Even for the interface between pure lipid and water, two laboratories have reported the absence of enhanced diffusion. (3) Localized proton ducts in the membrane. Intramembrane domains that can transiently trap protons do exist in thylakoid membranes, but because of their limited storage capacity for protons, they probably do not matter for photophosphorylation under continuous light. Seemingly in favor of localized proton ducts is the failure of a supposedly permeant buffer to enhance the onset lag of photophosphorylation. However, it was found that failure of some buffers and the ability of others in this respect were correlated with their failure/ability to quench pH transients in the thylakoid lumen, as predicted by the chemiosmotic theory. It was shown that the chemiosmotic concept is a fair approximation, even for narrow aqueous phases, as in stacked thylakoids. These are approximately isopotential, and protons are taken in by the ATP synthase straight from the lumen. The molecular mechanism by which F0F1 ATPases couple proton flow to ATP synthesis is still unknown. The threefold structural symmetry of the headpiece that, probably, finds a corollary in the channel portion of these enzymes appeals to the common wisdom that structural symmetry causes functional symmetry. "Rotation catalysis" has been proposed. It is of heuristic value to visualize CFoCF1 as a mechanical coupling device. Its maximum turnover number ranges up to 400 s-1 for ATP and 1200 s-1 for protons. At about 200 mV electric driving force this implied a conductance of about 1 fS. Its channel portion (CFo), however, has revealed a very large protonic conductance of 1 pS (three orders of magnitude greater than the protonic conductance of gramicidin around neutral pH). (6) The sight and smell of food increased LH serotonin release; this effect was detectable when local fluoxetine was used to block serotonin reuptake.(ABSTRACT TRUNCATED AT 400 WORDS)


Understanding the information needs of general practitioners managing a rare genetic disorder (osteogenesis imperfecta).
Lack of adequate knowledge is a common problem in medicine, but is a particular problem in a rapidly advancing field like genetics. This study uses the example of a rare genetic disorder (osteogenesis imperfecta) to understand the information needs of primary care physicians (GPs). To determine whether a knowledge gap is recognised, how GPs currently attempt to overcome it, and what features of an information resource are preferred by GPs. GPs of children affected by osteogenesis imperfecta in and around Greater London were interviewed, using both questionnaire-based semi-structured interview and a qualitatively analysed open-ended discussion. Consultations in both primary and tertiary care settings over a 5-year period were compared. Problems due to osteogenesis imperfecta were presented to GPs in about one third of consultations with these patients. GPs reported finding such patients difficult to manage due to lack of knowledge. Knowledge from tertiary sources, which was authoritative, accessible and relevant, was preferred, particularly when reasoning was explained. Primary literature and clinical guidelines were not favoured. Empirical evidence supports and elaborates theoretical models for provision of clinically useful information. A model for improved information services using authoritative web-based information linked to electronic patient records is suggested.


Melanin: a unifying theory of disease as exemplified by Parkinson's, Alzheimer's, and Lewy body dementia.
Melanin, a ubiquitous dark pigment, plays important roles in the immune system, including scavenging reactive oxygen species formed in response to ultraviolet radiation absorption, absorbing metals, thermal regulation, drug uptake, innate immune system functions, redox, and energy transduction. Many tissue types, including brain, heart, arteries, ovaries, and others, contain melanin. Almost all cells contain precursors to melanin. A growing number of diseases in which there is a loss of melanin and/or neuromelanin are increasingly thought to have infectious etiologies, for example, Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and vitiligo. AD, PD, LBD, and vitiligo have been linked with herpesvirus, which enters melanosomes and causes apoptosis, and with gut dysbiosis and inflammation. Herpesvirus is also linked with gut dysbiosis and inflammation. We theorize that under normal healthy states, melanin retains some of the energy it absorbs from electromagnetic radiation, which is then used to fuel cells, and energy from ATP is used to compliment that energy supply. We further theorize that loss of melanin reduces the energy supply of cells, which in the case of AD, PD, and LBD results in an inability to sustain immune system defenses and remove the plaques associated with the disease, which appear to be part of the immune system's attempt to eradicate the pathogens seen in these neurodegenerative diseases. In addition, in an attempt to explain why removing these plaques does not result in improvements in cognition and mood and why cognitions and moods in these individuals have ebbs and flows, we postulate that it is not the plaques that cause the cognitive symptoms but, rather, inflammation in the brain resulting from the immune system's response to pathogens. Our theory that energy retained in melanin fuels cells in an inverse relationship with ATP is supported by studies showing alterations in ATP production in relationship to melanin levels in melanomas, vitiligo, and healthy cells. Therefore, alteration of melanin levels may be at the core of many diseases. We propose regulating melanin levels may offer new avenues for treatment development.


Peri-operative and critical care concerns in coronavirus pandemic.
World Health Organization (WHO) declared novel coronavirus outbreak a "pandemic" on March 11th, 2020. India has already reached Stage 2 (local transmission) and the Indian Government, in collaboration with the Indian Council of Medical Research (ICMR), is taking all necessary steps to halt the community transmission(Stage 3). Anaesthesiologists and intensivists around the globe are making untiring efforts akin to soldiers at the final frontier during war. All efforts pertaining to adequate staffing, Personal Protective Equipment (PPE) and strict adherence to hand hygiene measures are being stressed upon to prevent in-hospital transmission. In this article, all outbreak response measures including triaging, preparation of isolation rooms, decontamination and disinfection protocols as well as fundamental principles of critical care and anaesthetic management in Covid-19 cases is being discussed. All the recommendations have been derived from the past experiences of SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) outbreak as well as upcoming guidelines from the international health fraternity and Indian Health Services.


Ergonomic audit of a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare Flexcare, and the Oral-B Smart Series 5000.
The presence of ergonomic features can impact the marketplace success of a new product. Metaphase Design Group, Inc., in partnership with the Colgate-Palmolive Company, conducted an ergonomic audit on three electric toothbrushes: a specially engineered sonic powered toothbrush with unique sensing and control technologies, the Sonicare FlexCare, and the Oral-B Smart Series 5000. The ergonomic audit was conducted by Metaphase Design Groups's ergonomic and usability experts. Two experts used the toothbrushes over a one-week period and assessed the performance of each brush against a set of ergonomic principles. The three toothbrushes have some solid ergonomic features. They each have adequate grip zones, provide grip security with elastomeric materials, and provide easy access to the on/off button. The most distinctive feature is the longitudinal shape of the handle of the specially engineered sonic powered toothbrush with unique sensing and control technologies. This handle angles downward at the top end and provides additional advantages through improved grip security and visibility. Yet all three toothbrushes have different opportunities for improvement. The Sonicare Flex Care toothbrush has a cluttered and complicated user interface that is difficult to read. The disadvantages of the Oral-B Smart Series 5000 toothbrush are related to its physical dimensions and audible feedback. The specially engineered sonic powered toothbrush with unique sensing afid control technologies is surprising to use with its changes in speeds, brush movements, and resulting changes in audible feedback.


The adaptive strategies of cells in the face of CIN.
An increased frequency of chromosome segregation errors, known as chromosomal instability (CIN), leads to accumulation of aneuploid cells with abnormal chromosomal numbers, which impairs viability through negative effects on survival and proliferation under most conditions. Two recent papers find by independent approaches that the key to surviving high levels of CIN is reducing the instability itself, showcasing the remarkable adaptability of the chromosome segregation machinery, in particular the microtubule-kinetochore interface, and highlighting the crucial role that maintaining chromosomal stability plays in cell proliferation.


Randomized, double-blinded, placebo-controlled trial comparing two multimodal opioid-minimizing pain management regimens following transsphenoidal surgery.
OBJECTIVE Pain control is an important clinical consideration and quality-of-care metric. No studies have examined postoperative pain control following transsphenoidal surgery for pituitary lesions. The study goals were to 1) report postoperative pain scores following transsphenoidal surgery, 2) determine if multimodal opioid-minimizing pain regimens yielded satisfactory postoperative pain control, and 3) determine if intravenous (IV) ibuprofen improved postoperative pain scores and reduced opioid use compared with placebo. METHODS This study was a single-center, randomized, double-blinded, placebo-controlled intervention trial involving adult patients with planned transsphenoidal surgery for pituitary tumors randomized into 2 groups. Group 1 patients were treated with scheduled IV ibuprofen, scheduled oral acetaminophen, and rescue opioids. Group 2 patients were treated with IV placebo, scheduled oral acetaminophen, and rescue opioids. The primary end point was patient pain scores (visual analog scale [VAS], rated 0-10) for 48 hours after surgery. The secondary end point was opioid use as estimated by oral morphine equivalents (OMEs). RESULTS Of 136 patients screened, 62 were enrolled (28 in Group 1, 34 in Group 2). The study was terminated early because the primary and secondary end points were reached. Baseline characteristics between groups were well matched except for age (Group 1, 59.3 ± 14.4 years; Group 2, 49.8 ± 16.2 years; p = 0.02). Mean VAS pain scores were significantly different, with a 43% reduction in Group 1 (1.7 ± 2.2) compared with Group 2 (3.0 ± 2.8; p < 0.0001). Opioid use was significantly different, with a 58% reduction in Group 1 (26.3 ± 28.7 mg OME) compared with Group 2 (62.5 ± 63.8 mg OME; p < 0.0001). CONCLUSIONS Multimodal opioid-minimizing pain-management protocols resulted in acceptable pain control following transsphenoidal surgery. IV ibuprofen resulted in significantly improved pain scores and significantly decreased opioid use compared with placebo. Postoperative multimodal pain management, including a nonsteroidal antiinflammatory medication, should be considered after surgery to improve patient comfort and to limit opioid use. Clinical trial registration no.: NCT02351700 (clinicaltrials.gov) ■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: randomized, controlled trial; evidence: Class III.


The identification of sulfide oxidation as a potential metabolism driving primary production on late Noachian Mars.
The transition of the martian climate from the wet Noachian era to the dry Hesperian (4.1-3.0 Gya) likely resulted in saline surface waters that were rich in sulfur species. Terrestrial analogue environments that possess a similar chemistry to these proposed waters can be used to develop an understanding of the diversity of microorganisms that could have persisted on Mars under such conditions. Here, we report on the chemistry and microbial community of the highly reducing sediment of Colour Peak springs, a sulfidic and saline spring system located within the Canadian High Arctic. DNA and cDNA 16S rRNA gene profiling demonstrated that the microbial community was dominated by sulfur oxidising bacteria, suggesting that primary production in the sediment was driven by chemolithoautotrophic sulfur oxidation. It is possible that the sulfur oxidising bacteria also supported the persistence of the additional taxa. Gibbs energy values calculated for the brines, based on the chemistry of Gale crater, suggested that the oxidation of reduced sulfur species was an energetically viable metabolism for life on early Mars.


Efficiently loading a single photon into a single-sided Fabry-Perot cavity.
We demonstrate that a single photon with an optimal temporal waveform can be efficiently loaded into a cavity. Using heralded narrow-band single photons with exponential growth wave packet shaped by an electro-optical amplitude modulator, whose time constant matches the photon lifetime in the cavity, we demonstrate a loading efficiency of (87±2)% from free space to a single-sided Fabry-Perot cavity. We further demonstrate directly loading heralded single Stokes photons into the cavity with an efficiency of (60±5)% without the electro-optical amplitude modulator and verify the time reversal between the frequency-entangled paired photons. Our result and approach may enable promising applications in realizing large-scale quantum networks based on cavity quantum electrodynamics.


Controlled assembly of biodegradable plasmonic nanoclusters for near-infrared imaging and therapeutic applications.
Metal nanoparticles with surface plasmon resonance (SPR) in the near-infrared region (NIR) are of great interest for imaging and therapy. Presently, gold nanoparticles with NIR absorbance are typically larger than 50 nm, above the threshold size of approximately 5 nm required for efficient renal clearance. As these nanoparticles are not biodegradable, concerns about long-term toxicity have restricted their translation into the clinic. Here, we address this problem by developing a flexible platform for the kinetically controlled assembly of sub-5 nm ligand-coated gold particles to produce metal/polymer biodegradable nanoclusters smaller than 100 nm with strong NIR absorbance for multimodal application. A key novel feature of the proposed synthesis is the use of weakly adsorbing biodegradable polymers that allows tight control of nanocluster size and, in addition, results in nanoclusters with unprecedented metal loadings and thus optical functionality. Over time, the biodegradable polymer stabilizer degrades under physiological conditions that leads to disassembly of the nanoclusters into sub-5 nm primary gold particles which are favorable for efficient body clearance. This synthesis of polymer/inorganic nanoclusters combines the imaging contrast and therapeutic capabilities afforded by the NIR-active nanoparticle assembly with the biodegradability of a polymer stabilizer.


By blocking apoptosis, Bcl-2 in p38-dependent manner promotes cell cycle arrest and accelerated senescence after DNA damage and serum withdrawal.
E1A+ras-transformed rodent fibroblasts are unable to be arrested in the cell cycle and die by apoptosis in response to cytostatics, ionizing radiation (IR), or serum withdrawal. Overexpression of the human antiapoptotic gene bcl-2 suppresses apoptosis and induces reversible cell cycle arrest after IR or serum withdrawal and cell senescence after adriamycin treatment. Bcl-2-sustained adriamycin-induced cell senescence requires p38 MAPK, since the knockout of p38 MAPK abrogated anti-apoptotic and senescence-inducing effects of Bcl-2 in adriamycin-treated cells. Moreover, resistance to apoptosis and cell cycle arrest were not observed in p38-/- E1A+ras+bcl-2-transformants following IR or serum deprivation. However, the pro-apoptotic effect of nocodazole in E1A+ras-transformed cells can not be prevented by Bcl-2 overexpression independently of the presence of p38 MAPK. These results allow us to conclude that p38 is necessary for Bcl-2-induced inhibition of apoptosis, induction of cell cycle arrest and accelerated senescence after DNA damage and serum starvation, but not after nocodazole treatment.


[Anti-erythrocyte immunization in the pregnant woman. Apropos of the analysis of 761 cases of alloimmunized women delivered in the Paris area in 1978 and 1979].
Through analysis of 760 cases of allo-immunized women delivered in the Paris area during 1978 and 1979, anti-erythrocyte immunization (ABO excluded) still appears to be a consequent perinatal risk, for the mother as for her fetus. During the considered period, general incidence in the parisian population has been of 3,78 for 1 000 livebirths, one out of four cases being a "non Rh D"immunization. Obviously, anti-D immunoglobulin prophylaxis has not proved to be as efficient as it promised to be, after more than ten years of application. Taking into account cases affecting "non ordinary" residents in the observed area, incidence of anti-D immunizations was of two out of a thousand. Anti-D immunoglobulin actual efficiency cannot be incriminated, for when correctly applied Rhesus immunization prophylaxis has demonstrated its ability to induce a twenty-fold reduction of immunization risk due to pregnancy. It must be pointed out, unfortunately, that most cases of undue immunizations are related to prophylatic omissions after delivery, miscarriage, abortion or fortuitous hetero-Rhesus blood transfusion. On another hand an important increase of "non Rh D" immunizations, which incidence, if one images that unknown cases are as frequent as known cases, could be two out of a thousand deliveries, is perhaps able to neutralize partially the decrease of Rh D immunizations. Though is underlined the absolute necessity to extend systematically anti-erythrocyte antibody screenings to all pregnant women, whatever the blood group is. A great variety of antibodies specificities can be found among "on Rh D" immunizations but anti-Kell and anti-c are by far the most frequently met. In most cases theses immunizations could easily be avoided, assessing that all female subjects aged less than 50 years are only given Kell negative and, if lacking c antigen, CC phenotyped blood.


School nurses: a resource for young worker safety.
On average, 67 youths under age 18 die at work in the United States each year, and many more suffer work-related injuries. In 1998, an estimated 77,000 young workers suffered work injuries that required treatment in hospital emergency rooms. It is estimated that only one third of work-related injuries are seen in emergency departments; therefore, the National Institute for Occupational Safety and Health (NIOSH) estimates that nearly 230,000 youths suffer work-related injuries each year. Through NIOSH's Fatality Assessment and Control Evaluation (FACE) program, NIOSH investigators identified poor knowledge of child labor laws, lack of safety training and supervision, inappropriate job assignment, and lack of employer compliance with labor laws as factors contributing to young worker deaths. School nurses serve as a resource to other professionals, parents, employers, and students and can help foster safer working conditions for youth by providing these groups with young worker safety information.


Downregulated ARID1A by miR-185 Is Associated With Poor Prognosis and Adverse Outcomes in Colon Adenocarcinoma.
AT-rich interaction domain 1A (ARID1A) is a tumor suppressor gene that mutates in several cancer types, including breast cancer, ovarian cancer, and colorectal cancer (CRC). In colon adenocarcinoma (COAD), the low expression of ARID1A was reported but the molecular reason is unclear. We noticed that ARID1A low expression was associated with increased levels of miR-185 in the COAD. Therefore, this study aims to explore ncRNA-dependent mechanism that regulates ARID1A expression in COAD regarding miR-185. The expression of ARID1A was tested in COAD cell line under the effect of miR-185 mimics compared with inhibitor. The molecular features associated with loss of ARID1A and its association with tumor prognosis were analyzed using multi-platform data from The Cancer Genome Atlas (TCGA), and gene set enrichment analysis (GSEA) to identify potential signaling pathways associated with ARID1A alterations in colon cancer. Kaplan-Meier survival curve showed that a low level of ARID1A was closely related to low survival rate in patients with COAD. Results showed that inhibiting miR-185 expression in the COAD cell line significantly restored the expression of ARID1A. Further, the increased expression of ARID1A significantly improved the prolonged overall survival of COAD. We noticed that there is a possible relationship between ARID1A high expression and tumor microenvironment infiltrating immune cells. Furthermore, the increase of ARID1A in tumor cells enhanced the response of inflammatory chemokines. In conclusion, this study demonstrates that ARID1A is a direct target of miR-185 in COAD that regulates the immune modulations in the microenvironment of COAD.


Maternalism and the homeopathic mission in late-Victorian Montreal.
This article examines the interactions between homeopathy and maternal values in the nineteenth century through a case study of Montreal's homeopathic community and the Montreal Homeopathic Hospital, which opened in 1894. Through an analysis of women's diverse roles within the institution, it demonstrates the variety of ways in which maternalism found expression. It argues that the maternal ideology was particularly compatible with homeopathy's self-proclaimed mission to the poor, the emphasis it placed upon inculcating familial values within the homeopathic community, its appeal to women as patients, its claim to reduce child mortality, and the image it cultivated of the special role of the homeopathic mother.


Therapy with transcutaneous administration of imiquimod combined with oral administration of sorafenib suppresses renal cell carcinoma growing in an orthotopic mouse model.
Imiquimod is an imidazoquinoline immune response modifier that is used in antiviral and antiallergic creams. Combination therapy using transcutaneous imiquimod and oral sorafenib was previously demonstrated to reduce the tumor burden of renal cell carcinoma growing cutaneously in a mouse model. In the present study, an orthotopic mouse model was used to investigate whether combined treatment with oral sorafenib and transcutaneous imiquimod inhibited renal cell carcinoma growing in the kidney. Kidneys of female BALB/c mice were orthotopically implanted with RENCA mouse kidney cancer cells, and the mice were transcutaneously treated with cream containing imiquimod and/or with orally administered sorafenib 5 days following cell implantation. Tumor burden and incidence were determined 28 days following the start of therapy. Splenocyte activity was quantified using the 51Cr release assay and the fluorescence-activated cell sorting assay with cluster of differentiation (CD) 4 and CD8 antibodies. Imiquimod, sorafenib and combination therapy were tolerated well. A combination of transcutaneous imiquimod and oral sorafenib inhibited the growth of RENCA tumors in the kidney significantly compared with the control. The 51Cr release assay demonstrated that transcutaneous imiquimod therapy significantly induced the release of 51Cr from RENCA cells compared with the control. The fluorescence-activated cell sorting assay demonstrated that transcutaneous imiquimod therapy induced CD8+ and CD4- splenocytes compared with the control. In summary, the results of the present study demonstrated that combined treatment with transcutaneous imiquimod and oral sorafenib may be a promising strategy for the treatment of patients with renal cell carcinoma.


Bilateral triple concha bullosa: a very rare anatomical variation of intranasal turbinates.
Pneumatization of the intranasal turbinates or concha bullosa is an anatomic variation of the lateral nasal wall. Concha bullosa is defined as the presence of air cells in turbinates. It can be best diagnosed with paranasal sinus computed tomography. Concha bullosa is a possible etiologic factor for recurrent sinusitis due to its negative effect on paranasal sinus ventilation and mucociliary clearance. Concha bullosa is most commonly seen in the middle turbinate and less frequently in the inferior or superior turbinate. Pneumatization of all turbinates is very rare. To our knowledge, there are only two publications about a case with concha bullosa in all turbinates in the current literature. Here, we present a woman with bilateral pneumatization in all three intranasal turbinates.


Influence of prior orchiopexy on stage and prognosis of testicular cancer.
Thirty-four cryptorchid testis cancer cases were studied, of whom 9 patients had prior orchiopexy at the time of cancer diagnosis. Disease stage in this group was: stage I = 4, stage II = 1 and stages III and IV = 4 cases. Seventy-eight percent of these cases (n = 7) had non-seminomas; 4 of these patients died. In the uncorrected cryptorchidism group (n = 25), disease stage was: stage I = 12, stage II = 9 and stages III and IV = 4 cases. Of these cases, 64% (n = 16) had seminomas and 6 patients died. Orchiopexy marginally reduced the symptomatic interval for subsequent cancer and probably decreased the risk of seminoma development. Orchiopexy did not lead to a more favourable disease presentation or prognosis because of the adverse bias of advanced-stage non-seminomas in this group.


Benchmark Study of Density Functional Theory for Neutral Gold Clusters, Aun (n = 2-8).
Neutral gold clusters, Aun (n = 2-8), were optimized using coupled cluster singles and doubles with perturbative triples (CCSD(T)) with a triple-ζ-level basis set to develop reliable reference values for their structural and energy parameters in order to assess the performance of density functionals. The performance of 44 density functional theory (DFT) methods for calculating molecular structures and relative energies is assessed with respect to CCSD(T). In addition, their performance when calculating vertical ionization potentials (vIPs) of Aun (n = 2-8) is also assessed by comparison with experimental values. The revTPSS functional shows good performance for calculating both the structural and energy properties of Aun (n = 2-8), whereas B3P86 shows a remarkable performance in calculating the vIPs. The quadruple-ζ-level valence basis set is necessary for obtaining accurate energy values in CCSD(T) calculations.


PEROMYSCUS LEUCOPUS: AN INTERESTING SUBJECT FOR STUDIES OF SOCIALLY INDUCED STRESS RESPONSES.
White-footed mice, Peromyscus leucopus, possess several characteristics which make them interesting subjects for the experimental study of social interactions and stress physiology: tolerance of very high cage densities among social congeners; marked behavioral intolerance among social strangers; exceptionally large adrenal glands; and adrenal and eosinophil responses sensitive to social disturbance.


Cu(II)-catalyzed domino reaction of 2H-azirines with diazotetramic and diazotetronic acids. Synthesis of 2-substituted 2H-1,2,3-triazoles.
The Cu(II)-catalyzed addition of two molecules of a 3-aryl-2H-azirine to diazotetramic or diazotetronic acids proceeds as a domino reaction with the formation of 1,2,3-triazole derivatives with ortho-fused (pyrrolo[3,4-b]pyrrol or furo[3,4-b]pyrrol) and spiro-cyclic (1-oxa-4,7-diazaspiro[4.4]nonane or 1,7-dioxa-4-azaspiro[4.4]nonane) substituents at the N2 position. The disclosed reaction is a new type of formation of a 1,2,3-triazole ring from (N-N) and (C-C-N) building blocks.


Use of Relibase for retrieving complex three-dimensional interaction patterns including crystallographic packing effects.
Relibase is a database system that has been specially designed to handle protein-ligand data. Included within Relibase is a tool that can be used to systematically analyse protein-ligand interaction patterns specified by three-dimensional (3D) constraints, revealing favorable combinations of interacting functional groups and their preferred interaction geometries. This paper describes the Relibase 3D query tools, including novel extensions (Relibase+) for handling crystallographic packing effects. Examples illustrating the broad range of functionality for defining 3D interaction patterns and the application of such queries in drug design comprise carbonyl-carbonyl interactions, zinc binding site environments, and ligand-ligand interactions in the crystal packing.


The physical properties and ion release of CPP-ACP-modified calcium silicate-based cements.
This study investigated the physical properties and ion release of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)-modified calcium silicate-based cements (CSCs) and compared the properties of a trial mineral trioxide aggregate (MTA) with two commercially available CSCs, Biodentine(™) and Angelus(®) MTA. The setting time, solubility, compressive strength and Vickers surface microhardness of the three CSCs incorporated with 0%, 0.5%, 1.0%, 2.0% and 3.0% (w/w) CPP-ACP were investigated. Release of calcium (Ca(2+) ), phosphate ions (Pi ) and pH of the test cements were measured after 24, 72, 168 and 336 h of storage. The addition of up to 1.0% CPP-ACP into Biodentine(™) and 0.5% into the other cements did not adversely affect their physical properties except for the setting time. The addition of 0.5% CPP-ACP increased Ca(2+) released from Biodentine(™) (after 168 and 336 h), Angelus(®) MTA (after 168 h) and the trial MTA (after 72 h). The addition of 1.0-3.0% CPP-ACP increased Ca(2+) and Pi released from all the cements. Biodentine(™) released more Ca(2+) particularly in the early stages and showed shorter setting time and higher mechanical properties than the other cements. The mechanical properties of Angelus(®) MTA and the trial MTA were similar. All the cements produced highly alkaline storage solutions. Up to 1.0% CPP-ACP in Biodentine(™) improves Ca(2+) and Pi release and 0.5% CPP-ACP in Angelus(®) MTA and the trial MTA improves Ca(2+) release without altering the mechanical properties and solubility. The addition of CPP-ACP into CSCs prolonged the setting time.


Anterior indexing technique for orbital prostheses.
This article describes a straightforward technique for indexing the ocular part of an orbital prosthesis from the anterior aspect. The iris of the ocular portion remains unaffected while using this technique. There is no damage to the moulage as indexing is done from the anterior aspect. This technique provides stability, prevents rotation of the ocular portion, and allows the moulage to be used multiple times. It is cost effective and requires minimal manipulation during processing.


Evaluation of DNA extraction methods for PCR-based detection of Listeria monocytogenes from vegetables.
Epidemiological data indicate that raw vegetables are associated with outbreaks of Listeria monocytogenes. Therefore, there is a demand for the availability of rapid and sensitive methods, such as PCR assays, for the detection and accurate discrimination of L. monocytogenes. However, the efficiency of PCR methods can be negatively affected by inhibitory compounds commonly found in vegetable matrices that may cause false-negative results. Therefore, the sample processing and DNA isolation steps must be carefully evaluated prior to the introduction of such methods into routine practice. In this study, we compared the ability of three column-based and four magnetic bead-based commercial DNA isolation kits to extract DNA of the model micro-organism L. monocytogenes from raw vegetables. The DNA isolation efficiency of all isolation kits was determined using a triplex real-time qPCR assay designed to specifically detect L. monocytogenes. The kit with best performance, the PowerSoil(™) Microbial DNA Isolation Kit, is suitable for the extraction of amplifiable DNA from L. monocytogenes cells in vegetable with efficiencies ranging between 29.6 and 70.3%. Coupled with the triplex real-time qPCR assay, this DNA isolation kit is applicable to the samples with bacterial loads of 10(3) bacterial cells per gram of L. monocytogenes. Several recent outbreaks of Listeria monocytogenes have been associated with the consumption of fruits and vegetables. Real-time PCR assays allow fast detection and accurate quantification of microbes. However, the success of real-time PCR is dependent on the success with which template DNA can be extracted. The results of this study suggest that the PowerSoil(™) Microbial DNA Isolation Kit can be used for the extraction of amplifiable DNA from L. monocytogenes cells in vegetable with efficiencies ranging between 29.6 and 70.3%. This method is applicable to samples with bacterial loads of 10(3) bacterial cells per gram of L. monocytogenes.


Foldable low-cost point-of-care device for testing blood coagulation using smartphones.
Cardiovascular diseases (CVDs) caused by thrombotic events are a significant global health concern, affecting millions of people worldwide. The international normalized ratio (INR) is the most widely used measure of coagulation status, and frequent testing is required to adjust blood-thinning drug dosage, requiring hospital visits and experts to perform the test. Here we present a low-cost and portable smartphone-based device for screening INR levels from whole blood samples at the point of care. Our device uses a 3D printed platform and light-emitting diode backlight modules to create a uniform optical environment, and its foldable design allows for easy transport. Our device also features an algorithm that allows users to acquire and process video of sample flow in a microfluidic channel on their smartphone, providing a cost-effective and convenient option for blood coagulation monitoring at the point of care. We tested the performance of our smartphone-based INR device using both commercially available control samples and clinical human blood samples, demonstrating high accuracy and reliability. Our device has the potential to improve patient outcomes by enabling more frequent monitoring and, as appropriate, dosage adjustments of blood-thinning drugs, providing an affordable and portable option for screening INR levels at the point of care.


Does a social/behavioural gradient in dental health exist among adults? A cross-sectional study.
Objective To explore the potential presence of a social/behavioural gradient in dental health among Italian adults using a cross-sectional study. Methods Caries indices were recorded among 480 subjects (52.9% men, 47.1% women) who also completed a structured self-administered social and behavioural questionnaire. A social/behavioural gradient was generated as the sum of the worst circumstances recorded on the questionnaire (cariogenic diet, smoking, lowest occupational profile, brushing teeth < twice daily, lowest educational level, uneven dental examination attendance). Results Caries figures (DMFT) and the number of filled sound teeth (FS-T) were statistically significantly linked to the social/behavioural gradient (DMFT: χ2(9) = 20.17 p = 0.02, Z = 0.02 p = 0.99; FS-T: χ2(9) = 25.68 p < 0.01, Z = -4.31 p < 0.01). DMFT was statistically significantly associated with gender and with social and behavioural variables. FS-T was higher in women (p = 0.03) and was linked to smoking ( p < 0.01). Conclusions The proposed social/behavioural gradient demonstrated how subjects reporting the worst circumstances on the questionnaire exhibited the worst dental health. The use of the gradient demonstrates that health promotion and prevention cannot be compartmentalized.


Spatial structure of an individual Mn acceptor in GaAs.
The wave function of a hole bound to an individual Mn acceptor in GaAs is spatially mapped by scanning tunneling microscopy at room temperature and an anisotropic, crosslike shape is observed. The spatial structure is compared with that from an envelope-function, effective mass model and from a tight-binding model. This demonstrates that anisotropy arising from the cubic symmetry of the GaAs crystal produces the crosslike shape for the hole wave function. Thus the coupling between Mn dopants in GaMnAs mediated by such holes will be highly anisotropic.


The Process Model of Family Functioning.
The Process Model of Family Functioning differs from the McMaster Model of Family Functioning and their common source, the Family Categories Schema, by its increased emphasis on the dynamic interaction between the major dimensions of family functioning, and by its stress on the interface between intrapsychic subsystems and the interpersonal dimensions of the family system. A model of family process rather than family structure, it defines six universal criteria of family functioning. It describes the processes involved in each along with the content components and the critical aspects of each. A self-report test developed from the model (FAM-III) is being widely used both as a research tool and as a clinical adjunct. Tests to define its validity and reliability continue.


Leptomeningeal cancer in leukemia and solid tumors.
Although some patients with overt leptomeningeal cancer can now be cured, the proportion of patients who survive is very small, and the cost of cure, in terms of neuropsychological and educational morbidity, is substantial. Yet the incidence of central nervous system infiltration of systemic cancer is generally increasing, in most instances because control of systemic cancer has sufficiently prolonged survival to permit leptomeningeal metastases to develop and become symptomatic or detectable. The best chance for prolongation of life and possible cure is early detection and aggressive therapy in those forms of cancer that are amenable to therapy. We review the incidence of the various forms of leptomeningeal metastases, current concepts of pathogenesis and pathophysiology, clinical and laboratory features of leptomeningeal cancer, the available therapies, and the associated toxicities. The various methods that have been used to prevent and treat leptomeningeal cancer are described with an emphasis on childhood acute lymphoblastic leukemia (ALL) because it plays a predominant role in our understanding of meningeal neoplasms in general.


Ultraviolet photodetector based on a MgZnO film grown by radio-frequency magnetron sputtering.
The metal-semiconductor-metal ultraviolet (UV) photodetector was fabricated on the Mg(0.47)Zn(0.53)O layer grown by radio-frequency magnetron cosputtering. The photodetector shows the peak response at 290 nm with a cutoff wavelength at 312 nm. It exhibits a very low dark current of about 3 pA at 5 V bias, and the UV-visible rejection ratio (R = 290 nm/R = 400 nm) is more than 4 orders of magnitude. The transient response for the detector was measured, and it was found that the rise time is 10 ns and the fall time is 30 ns. The reason for the short response time is related to the Schottky structure.


Bulk inhomogeneous phases of anisotropic particles: a fundamental measure functional study of the restricted orientations model.
The phase diagram of prolate and oblate particles in the restricted orientations approximation (Zwanzig model) is calculated. Transitions to different inhomogeneous phases (smectic, columnar, oriented, or plastic solid) are studied through minimization of the fundamental measure functional (FMF) of hard parallelepipeds. The study of parallel hard cubes (PHC's) as a particular case is also included motivated by recent simulations of this system. As a result a rich phase behavior is obtained which include, apart from the usual liquid crystal phases, a very peculiar phase (called here discotic smectic) which was already found in the only existing simulation of the model, and which turns out to be stable because of the restrictions imposed on the orientations. The phase diagram is compared at a qualitative level with simulation results of other anisotropic particle systems.


An in silico ensemble method for lead discovery: decision forest.
Recent progress in combinatorial chemistry and parallel synthesis has radically changed the approach to drug discovery in the pharmaceutical industry. At present, thousands of compounds can be made in a short period, creating a need for fast and effective in silico methods to select the most promising lead candidates. Decision forest is a novel pattern recognition method, which combines the results of multiple distinct but comparable decision tree models to reach a consensus prediction. In this article, a decision forest model was developed using a structurally diverse training data set containing 232 compounds whose estrogen receptor binding activity was tested at the U.S. Food and Drug Administration (FDA)'s National Center for Toxicological Research (NCTR). The model was subsequently validated using a test data set of 463 compounds selected from the literature, and then applied to a large data set with 57,145 compounds as a screening example. The results show that the decision forest method is a fast, reliable and effective in silico approach, which could be useful in drug discovery.


ATP and the autonomy of the contractile vacuole in Amoeba proteus.
Contractile vacuole function in amoebae treated with immobilizing (5 mM) and nonimmobilizing (0.125 mM) concentrations of ATP has been studied. In ATP-immobilized amoebae, most vacuolar parameters are accelerated, especially the rate of output which passes from 30 to 70 micron3/sec. This favors the concept of an autonomous vacuole, fully functional in the absence of any bulk contribution to it from remote points of the cell. A lower concentration of ATP (0.125 mM), which does not inhibit movement, causes a still greater acceleration of vacuolar function. Work is in progress to elucidate the site and mode of action of exogenous ATP on Amoeba.


Ultrasonographic measurement of prenatal fetal liver.
A total of 290 measurements of the size of the fetal liver in utero were made from 19 through 42 weeks of gestation. The right hepatic lobe circumference and area, considered to be the liver size, increased linearly with the advance of gestation. A statistical analysis of these results showed a highly significant correlation between liver size and gestational age (0.87, 0.77: p less than 0.001). The liver size also closely correlated with such growth parameters as biparietal diameter, femur length, and abdominal circumference (0.86, 0.76; 0.85, 0.76; 0.85, 0.73; p less than 0.001). When the liver size of normally grown fetuses was compared with that of growth-retarded fetuses, the liver of the growth-retarded fetuses was found to be significantly smaller (p less than 0.01). We conclude from this study that the measurement of fetal liver size aids in assessing the intrauterine growth of the fetus.


Cutaneous Myoepithelial Neoplasms on Acral Sites Show Distinctive and Reproducible Histopathologic and Immunohistochemical Features.
Cutaneous myoepithelial neoplasms are a heterogenous group of neoplasms with mixed tumors typically affecting the head and myoepitheliomas showing a predilection for the extremities. Their malignant counterparts, myoepithelial carcinoma, and malignant mixed tumor are exceptionally rare in the skin, and the morphologic criteria for malignancy are only poorly defined. The aim of the present study was to characterize the clinicopathologic features of myoepithelial neoplasms presenting on acral skin. The clinical and histopathologic features of 11 tumors were recorded, and follow-up was obtained. Immunohistochemistry was performed for S100, SOX10, glial fibrillary acidic protein, keratins, epithelial membrane antigen, p63, p40, smooth muscle actin, desmin, and PLAG1. The tumors mainly affected the feet of adults (range: 26 to 78 y; median: 47 y) with a predilection for the great toe and a male predominance of 1.8:1. Most tumors (91%) displayed a lobular architecture composed of solid and nested growth of epithelioid cells with plasmacytoid features in a myxoid or angiomatous stroma. Scattered cytologic atypia and rare duct differentiation were frequently noted. Three tumors with confluent cytologic atypia, infiltrative growth, and lymphovascular invasion were classified as malignant. By immunohistochemistry, the tumors were positive for S100, SOX10, keratins AE1/AE3, CK5/6 and CK7, and PLAG1. Local recurrence and bilateral pulmonary metastasis were observed in a patient presenting with a histopathologically benign-appearing tumor. Two patients with malignant tumors experienced local recurrences, and 1 developed metastasis to soft tissue, lung, and mediastinal lymph nodes. All patients are currently alive, all but 1 with no evidence of disease after a median follow-up interval of 96 months (range: 2 to 360 mo). In conclusion, acral myoepithelial neoplasms show distinctive and reproducible histopathologic and immunohistochemical features. They are best regarded as a distinctive subset of mixed tumors with features reminiscent of their salivary gland counterparts. While most tumors pursue a benign disease course, histopathologic features appear to be a poor indicator of prognosis.


[Treatment of Patients With Atrial Fibrillation: the Search for Optimal Solutions].
Atrial fibrillation (AF) - the most common arrhythmia in clinical practice, impair the quality of life significantly increases morbidity and mortality. Current methods of treatment of patients with AF, except anticoagulant therapy hitherto failed to provide significant improvement in cardiovascular events are of limited effectiveness and cause significant side effects. The article presents the current opportunities and challenges for the treatment of patients with atrial fibrillation. Analysis of these data will allow for an informed choice of treatment facilities for individual patients. Appreciates the role of oral anticoagulants and the occluder appendage of the left atrium in the prevention of thromboembolic complications. We consider the current possibilities of improving the efficiency and tolerability of pharmacotherapy AF antiarrhythmics. We discuss the latest achievements of non-pharmacological treatment of AF, including catheter ablation in the left atrium and change the patients lifestyle.


A new clinical test for radial tunnel syndrome--the Rule-of-Nine test: a cadaveric study.
Radial tunnel syndrome refers to pain on the lateral aspect of the forearm as a result of compression of the posterior interosseous nerve within a tunnel with specific anatomical boundaries. Diagnosis of the condition is difficult because of its close association with lateral epicondylitis, which warrants different methods of treatment. Based on a cadaveric study, a new clinical test, the Rule-of-Nine test, is proposed to improve the diagnostic accuracy in radial tunnel syndrome. The test involves constructing 9 equal squares on the anterior aspect of the forearm and noting those squares where tenderness can be elicited. 19 upper limbs were dissected to delineate the path of the posterior interosseous nerve through the radial tunnel, and the relationship of the path of the nerve with the 9 squares. A consistent mapping of the posterior interosseous nerve to the lateral column of 3 squares was observed. The Rule-of-Nine test is proposed as a reliable method of diagnosing radial tunnel syndrome.


Survival in systemic lupus erythematosus, 1995-2010. A prospective study in a Danish community.
The objective of this paper is to investigate survival and causes of death in a Danish lupus population. Two hundred and fifteen SLE patients (94% Caucasians) were followed prospectively for up to 16 years. Thirty-eight patients died. Survival rate and causes of death were analysed. Overall standardized mortality ratio (SMR) was 2.2. Peak values were recorded for patients aged 20-29 (SMR 21.1). Cumulated survival rates at one, five, 10 and 15 years were 98.6%, 93.6%, 86.5% and 73.0%, respectively. The most common causes of death were cardiovascular events (32%), respiratory system disease (16%) and malignancies (13%). Deaths due to infections and active SLE were rare and predominated within the first seven years after diagnosis and before age 40, while cardiovascular deaths prevailed after 20 years' follow-up. This study shows that despite progress in lupus management, including direct access to specialized hospital care and increased use of hydroxychloroquine, mortality in lupus patients is still increased. Main causes of death were active disease and infections among the young and newly diagnosed, while cardiovascular deaths prevailed in longstanding disease.


Absolute position total internal reflection microscopy with an optical tweezer.
A noninvasive, in situ calibration method for total internal reflection microscopy (TIRM) based on optical tweezing is presented, which greatly expands the capabilities of this technique. We show that by making only simple modifications to the basic TIRM sensing setup and procedure, a probe particle's absolute position relative to a dielectric interface may be known with better than 10 nm precision out to a distance greater than 1 μm from the surface. This represents an approximate 10× improvement in error and 3× improvement in measurement range over conventional TIRM methods. The technique's advantage is in the direct measurement of the probe particle's scattering intensity vs. height profile in situ, rather than relying on assumptions, inexact system analogs, or detailed knowledge of system parameters for calibration. To demonstrate the improved versatility of the TIRM method in terms of tunability, precision, and range, we show our results for the hindered near-wall diffusion coefficient for a spherical dielectric particle.


Inhibition of specific NF-κB activity contributes to the tumor suppressor function of 14-3-3σ in breast cancer.
14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.


Delayed low-level calcineurin inhibition promotes allospecific tolerance induction by posttransplantation donor leukocyte infusion.
Donor lymphocytes infused after organ transplantation can have strong immunoregulatory effects. Application of such protocols for transplant tolerance induction in a clinical setting will, however, require combination of specific immunomodulatory strategies with nonspecific immunosuppressive medication for safety reasons. The aim of this study was to analyze the effects of immunosuppressive treatment on tolerance induction protocols by posttransplantation donor lymphocyte infusion. The interaction of postoperative donor leukocyte infusion with different types, dosage, and timing of immunosuppressive drugs were studied in a rat model of heart transplantation. Tolerance could be achieved if donor cell infusion was combined with delayed, but not immediate, low-dose cyclosporine treatment, and this was associated with activation and apoptosis of host lymphocytes. In contrast, combinations with an antibody against the interleukin 2 receptor led to long-term graft survival but severe chronic rejection, and combinations with high-dose cyclosporine or sirolimus led to acute rejection. Postoperative donor leukocyte infusion is a potential way for tolerance induction, but the type, dose, and timing of medication are highly critical for its efficacy.


Extracellular Vesicles of Human Periodontal Ligament Stem Cells Contain MicroRNAs Associated to Proto-Oncogenes: Implications in Cytokinesis.
The human Periodontal Ligament Stem Cells (hPDLSCs) exhibit self-renewal capacity and clonogenicity potential. The Extracellular Vesicles (EVs) secreted by hPDLSCs are particles containing lipids, proteins, mRNAs, and non-coding RNAs, among which microRNAs, that are important in intercellular communication. The purpose of this study was the analysis of the non-coding RNAs contained in the EVs derived from hPDLSCs using Next Generation Sequencing. Moreover, our data were enriched using bioinformatic tools. The analysis highlighted the presence of non-coding RNAs and five microRNAs: MIR24-2, MIR142, MIR335, MIR490, and MIR296. Our results show that these miRNAs target the genes classified in two terms of the Gene Ontology: "Ras protein signal transduction" and "Actin/microtubule cytoskeleton organization." Noteworthy, the in-deep analysis of our EVs highlights that the miRNAs could be implicated in the silencing of proto-oncogenes involved in 12 different types of tumors.


Severe Osteomalacia Related to Long-Term Intravenous Drug Abuse.
Objective. We present the clinical, biochemical, and imaging findings of a woman with vitamin D deficiency and severe osteomalacia related to intravenous heroin addiction. Results. A 54-year-old woman with a medical history significant for long-standing heroin abuse presented with complaints of bone pain, muscle cramping, and a left hip ulcer. She had been bed bound for approximately 1 year secondary to pain of uncertain etiology, and her husband was bringing her both food and drugs. She was admitted to the hospital for debridement of a right ischial ulcer. Further workup revealed osteomyelitis of the left hip and severe vitamin D deficiency. Radiologic evaluation demonstrated diffuse osteopenia with pseudofractures, as well as true fractures. Conclusion. This is the first case reported in the English literature of advanced osteomalacia resulting from a debilitating narcotic dependency. Vitamin D deficiency should be considered in patients with poor nutrition and prolonged sunlight deprivation from any cause.


Comparative Study of Bifunctional Mononuclear and Dinuclear Amidoiridium Complexes with Chiral C-N Chelating Ligands for the Asymmetric Transfer Hydrogenation of Ketones.
A series of new bifunctional C-N chelating Ir complexes possessing a metal/NH group was synthesized by cyclometalation of optically active primary benzylic amines such as O-silylated (S)-2-amino-2-phenylethanols (1 a and 1 a'), (R)-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene (1 b), and (R)-1-phenyl-2,2-dimethylpropylamine (1 c). Although treatment of KOtBu with the amine complexes originating from 1 a and 1 a' afforded amido-bridged dinuclear complexes (3 a and 3 a'), more sterically hindered complexes were solely transformed into the coordinatively unsaturated mononuclear amido complexes (3 b and 3 c), which can serve as real catalyst species in the asymmetric transfer hydrogenation. The structural difference in the C-N chelate framework markedly affected the catalytic performance. Among them, amido complex 3 c showed a pronounced ability to catalyze the transfer hydrogenation of acetophenone in 2-propanol, even at a low temperature of -30 °C. A hydridoiridium complex (4 c) was also identified in the reaction of 3 c in 2-propanol, which provides mechanistic insights into the enantiodiscriminating step in the hydrogen transfer to prochiral ketones.


Vehicle engines produce exhaust nanoparticles even when not fueled.
Vehicle engines produce submicrometer exhaust particles affecting air quality, especially in urban environments. In on-road exhaust studies with a heavy duty diesel vehicle and in laboratory studies with two gasoline-fueled passenger cars, we found that as much as 20-30% of the number of exhaust particles larger than 3 nm may be formed during engine braking conditions-that is, during decelerations and downhill driving while the engine is not fueled. Particles appeared at size ranges extending even below 7 nm and at high number concentrations. Their small size and nonvolatility, coupled with the observation that these particles contain lube-oil-derived metals zinc, phosphorus, and calcium, are suggestive of health risks at least similar to those of exhaust particles observed before. The particles' characteristics indicate that their emissions can be reduced using exhaust after-treatment devices, although these devices have not been mandated for all relevant vehicle types. Altogether, our findings enhance the understanding of the formation vehicle emissions and allow for improved protection of human health in proximity to traffic.


The entire rotator cuff contributes to elevation of the arm.
The function of the infraspinatus, teres minor, and subscapularis during elevation of the arm remains poorly defined. These muscles may generate moments that contribute to abduction of the arm, although they frequently are classified as humeral depressors. The purposes of this study were to measure the contributions to abduction made by the more inferiorly positioned rotator cuff muscles relative to the contributions of the supraspinatus and to determine the range of motion at which the muscles are most effective. Five fresh cadaveric shoulder girdles were mounted in an apparatus designed to simulate contraction of the deltoid and rotator cuff while maintaining the normal relationship between glenohumeral and scapulothoracic motions. The deltoid force required for elevation was measured without simulated contraction of the rotator cuff and with simulated contraction of the entire rotator cuff, of the supraspinatus only, and of the infraspinatus-teres minor and subscapularis only. A significant reduction in deltoid force when other muscle activity was added indicated that the additions contributed significantly to abduction. The deltoid force required with concurrent contraction of the entire rotator cuff averaged 41% less than with the deltoid alone but was not significantly different than with the deltoid and supraspinatus or with the deltoid, infraspinatus-teres minor, and subscapularis. Concurrent application of forces to the supraspinatus or the infraspinatus-teres minor and subscapularis significantly reduced the required deltoid force over the range of motion studied by an average of 28 and 36%, respectively. The contributions of the rotator cuff muscles to abduction of the arm were greatest at low abduction angles (30 and 60 degrees) and were insignificant by 120 degrees. The infraspinatus-teres minor and subscapularis contribute significantly to abduction: their contribution was equal to that of the supraspinatus and, like the supraspinatus, they are most effective during the first 90 degrees of abduction.


Ultrastructure of goat testes: crystalloid in the microbody of Sertoli cells.
During the morphological study of goat spermatogenesis, an electron dense core was noticed in the microbody of the Sertoli cell in adult animals. By means of a goniometer apparatus fitted to the electron microscope, tilting 30 degrees unidirection, the dense core frequently displayed a characteristic checker pattern as a crystalloid or crystal. The size of the lattices in the crystalloid was found to be 6.6 nm lattice rods with 16.7 nm intervals (n = 48). In this report, the structure and function of the crystalloid construction is discussed; and the results suggested, as did former reports, that it may be a kind of peroxisome.


Suspected case of venous air embolism in an infant undergoing hip arthrogram.
An otherwise well ten-week-old girl underwent an air contrast hip arthrogram and application of a hip spica for a developmentally dislocated hip. The child displayed signs consistent with venous air embolism after injection of 5 ml of air into the hip joint. These signs included a decrease in arterial haemoglobin oxygen saturation as measured by pulse oximetry, decreased end-tidal carbon dioxide level and tachycardia. The signs initially resolved, but the patient deteriorated with injection of a further 5 ml of air. The patient responded to cessation of injection and resuscitative measures. The infant remained well postoperatively. The need for the use of air to confirm intra-articular placement of the needle prior to injection of contrast during a hip arthrogram is questioned.


Stability of wheat grain yields over three field seasons in the UK.
Ensuring food security in a changing climate is a major contemporary challenge and requires development of climate-resilient crops that perform well under variable environments. The hypothesis that yield stability in suboptimal conditions is linked to yield penalties in optimal conditions was investigated in field-grown wheat in the UK. The phenotypic responses, rate of wheat crop development, and final grain yield to varying sowing date, rainfall, air temperature, and radiation patterns were studied for a panel of 61 elite commercial wheat cultivars grown in the UK in 2012, 2013, and 2014. Contrasting climatic patterns, particularly rainfall accumulation and distribution over the season, influenced the relative performance of the cultivars affecting the duration of grain development stage and impacting on productivity. Indices for crop productivity, yield stability, and performance under suboptimal conditions revealed four cultivars with a combination of stable and high relative grain yields over the three seasons: Gladiator, Humber, Mercato, and Zebedee. Genetic similarity between cultivars partially explained yield performance in the contrasting seasons. The year of release of the cultivars correlated with grain yield but not with yield stability, supporting the contention that breeding for yield potential does not select for climate resilience and yield stability of crops. Further analysis of the outstanding cultivars may unravel target traits for breeding efforts aimed at increasing wheat yield potential and stability in the changing climate.


Correlation between TGF-beta1 in tears and corneal haze following LASEK and epi-LASIK.
To compare the incidence and degree of corneal haze formation following laser subepithelial keratomileusis (LASEK) and epithelial laser in situ keratomileusis (epi-LASIK), and examine its correlation with tear film transforming growth factor-beta1 (TGF-beta1) levels. This prospective, interventional, clinical trial included 20 eyes (20 patients) randomly assigned to undergo LASEK or epi-LASIK. The level of TGF-beta1 in tear fluid was measured preoperatively and 1, 3, and 5 days postoperatively. Corneal haze was graded at 1 and 3 months after surgery, and the relationship with TGF-beta1 levels was determined. Mean preoperative spherical equivalent refraction was -4.50 +/- 1.44 diopters (D) (range: -1.50 to -6.00 D) for LASEK eyes and -4.90 +/- 1.26 D (range: -1.75 to -6.00 D) for epi-LASIK eyes. Although mean corneal haze scores at 1 month were significantly higher in LASEK-treated eyes than in epi-LASIK treated eyes (P=.031), these scores were similar at 3 months (P=.608). Tear fluid TGF-beta1 levels were similar in LASEK and epi-LASIK eyes before surgery (P=.458) and significantly higher in the LASEK group at 1, 3, and 5 days postoperatively (P=.015, P=.023, and P=.039, respectively). A positive correlation was noted between tear TGF-beta1 levels on the first postoperative day and the degree of corneal haze at 1 month (r=0.501, P=.016). Less corneal haze was noted after epi-LASIK than LASEK. A positive correlation between corneal haze and tear fluid TGF-beta1 levels on the first postoperative day suggest a possible mechanism for the observed difference.


The origin and metabolism of a nascent pre-β high density lipoprotein involved in cellular cholesterol efflux.
The pre-β HDL fraction constitutes a heterogeneous population of discoid nascent HDL particles. They transport from 1 to 25 % of total human plasma apo A-I. Pre-β HDL particles are generated de novo by interaction between ABCA1 transporters and monomolecular lipid-free apo A-I. Most probably, the binding of apo A-I to ABCA1 initiates the generation of the phospholipid-apo A-I complex which induces free cholesterol efflux. The lipid-poor nascent pre-β HDL particle associates with more lipids through exposure to the ABCG1 transporter and apo M. The maturation of pre-β HDL into the spherical α-HDL containing apo A-I is mediated by LCAT, which esterifies free cholesterol and thereby forms a hydrophobic core of the lipoprotein particle. LCAT is also a key factor in promoting the formation of the HDL particle containing apo A-I and apo A-II by fusion of the spherical α-HDL containing apo A-I and the nascent discoid HDL containing apo A-II. The plasma remodelling of mature HDL particles by lipid transfer proteins and hepatic lipase causes the dissociation of lipid-free/lipid-poor apo A-I, which can either interact with ABCA1 transporters and be incorporated back into pre-existing HDL particles, or eventually be catabolized in the kidney. The formation of pre-β HDL and the cycling of apo A-I between the pre-β and α-HDL particles are thought to be crucial mechanisms of reverse cholesterol transport and the expression of ABCA1 in macrophages may play a main role in the protection against atherosclerosis.


Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice.
Myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNFR and TLR families, whose signals are transduced by TNFR-associated factor (TRAF) molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I IFN production, but the in vivo function of TRAF3 in myeloid cells remains unknown. In this article, we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3(-/-)) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyinosinic-polycytidylic acid (a viral mimic), M-TRAF3(-/-) mice exhibited an altered profile of cytokine production. M-TRAF3(-/-) mice immunized with T cell-independent and -dependent Ags displayed elevated T cell-independent IgG3 and T cell-dependent IgG2b responses. Interestingly, 15- to 22-mo-old M-TRAF3(-/-) mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice.


The Effectiveness of Cyrene as a Solvent in Exfoliating 2D TMDs Nanosheets.
The pursuit of environmentally friendly solvents has become an essential research topic in sustainable chemistry and nanomaterial science. With the need to substitute toxic solvents in nanofabrication processes becoming more pressing, the search for alternative solvents has taken on a crucial role in this field. Additionally, the use of toxic, non-economical organic solvents, such as N-methyl-2 pyrrolidone and dimethylformamide, is not suitable for all biomedical applications, even though these solvents are often considered as the best exfoliating agents for nanomaterial fabrication. In this context, the success of producing two-dimensional transition metal dichalcogenides (2D TMDs), such as MoS2 and WS2, with excellent captivating properties is due to the ease of synthesis based on environment-friendly, benign methods with fewer toxic chemicals involved. Herein, we report for the first time on the use of cyrene as an exfoliating agent to fabricate monolayer and few-layered 2D TMDs with a versatile, less time-consuming liquid-phase exfoliation technique. This bio-derived, aprotic, green and eco-friendly solvent produced a stable, surfactant-free, concentrated 2D TMD dispersion with very interesting features, as characterized by UV-visible and Raman spectroscopies. The surface charge and morphology of the fabricated nanoflakes were analyzed using ς-potential and scanning electron microscopy. The study demonstrates that cyrene is a promising green solvent for the exfoliation of 2D TMD nanosheets with potential advantages over traditional organic solvents. The ability to produce smaller-sized-especially in the case of WS2 as compared to MoS2-and mono/few-layered nanostructures with higher negative surface charge values makes cyrene a promising candidate for various biomedical and electronic applications. Overall, the study contributes to the development of sustainable and environmentally friendly methods for the production of 2D nanomaterials for various applications.


Plazomicin for the treatment of multidrug-resistant Klebsiella bacteraemia in a patient with underlying chronic kidney disease and acute renal failure requiring renal replacement therapy.
A 75-year-old man presented with shortness of breath and somnolence and was found to have urosepsis. Blood and urine cultures subsequently grew multidrug-resistant (MDR) Klebsiella pneumoniae (Kp) with the New Delhi metallo-β-lactamase gene. The patient was treated successfully with plazomicin and meropenem/vaborbactam combination therapy. The course was complicated by acute kidney injury temporarily requiring haemodialysis, gastrointestinal bleed requiring multiple transfusions and hospital readmission with blood cultures again positive with MDR Kp. Plazomicin drug levels were persistently high during treatment, suggesting that therapeutic drug monitoring may be needed to safely use this drug in patients with severe renal dysfunction. This case marks the first use of plazomicin for bacteraemia in the literature outside of a clinical trial and demonstrates its safe and effective use in a patient with advanced renal disease, and provides important insights about dosing and therapeutic drug monitoring considerations in this patient population.


Expression of intermediate filaments and desmoplakin in vertebrate olfactory mucosa.
The expression of intermediate filaments (IF) and desmoplakin was investigated in frog, bovine, and human (fetal) olfactory mucosa. IF are tissue-specific molecular cytoskeletal markers; desmoplakin is the major desmosomal protein. Positive immunoreactivity was observed in the epithelium and in the subepithelial Bowman's glands to keratin and to desmoplakin, indicating the epithelial nature of this tissue. Desmin, neurofilaments, and glial fibrillary acidic protein (GFAP) were not detected in the mucosa. The absence of neurofilaments and GFAP in the tissue containing sensory neurons and glia-like supporting cells is a unique feature and may be related to the fact that the chemosensory neurons are situated in a bonafide epithelium and are known to undergo continuous turnover. In view of the controversy regarding the expression of vimentin in the olfactory neurons, three independently derived antibodies to vimentin were used; weak or no labeling was found in the epithelium, whereas mesenchymal cells in the lamina propia were labeled with all three antibodies. Olfactory nerve fascicles in the lamina propia were heterogenously labeled: VIM 13.2 gave very weak labeling; aVimAS showed mild labeling and SBV-21 showed intensive labeling in the nerve fascicle. This heterogenous labeling pattern may suggest that olfactory vimentin is distinct in reacting only with some of the antivimentin antibodies.


High-Sensitivity Troponin: A Review on Characteristics, Assessment, and Clinical Implications.
The use of high-sensitivity cardiac troponin (hs-cTn) assays has become part of the daily practice in most of the laboratories worldwide in the initial evaluation of the typical chest pain. Due to their early surge, the use of hs-cTn may reduce the time needed to recognise myocardial infarctions (MI), which is vital for the patients presenting in the emergency departments for chest pain. The latest European Society of Cardiology Guidelines did not only recognise their central role in the diagnosis algorithm but also recommended their use for rapid rule-in/rule-out of MI. High-sensitivity cardiac troponins are also powerful prognostic markers for long-term events and mortality, not only in a wide spectrum of other cardiovascular diseases (CVD) but also in several non-CVD pathologies. Moreover, these biomarkers became a powerful tool in special populations, such as paediatric patients and, most recently, COVID-19 patients. Although highly investigated, the assessment and interpretation of the hs-cTn changes are still challenging in the patients with basal elevation such as CKD or critically ill patients. Moreover, there are still various analytical characteristics not completely understood, such as circadian or sex variability, with major clinical implications. In this context, the present review focuses on summarizing the most recent research in the current use of hs-cTn, with a main consideration for its role in the diagnosis of MI but also its prognostic value. We have also carefully selected the most important studies regarding the challenges faced by clinicians from different specialties in the correct interpretation of this biomarker. Moreover, future perspectives have been proposed and analysed, as more research and cross-disciplinary collaboration are necessary to improve their performance.


Dietary patterns and changes in cardiovascular risk factors in apparently healthy Chinese women: a longitudinal study.
Little is known of the relationships between dietary patterns and cardiovascular risk factors in China. We therefore designed a 3-year longitudinal study to evaluate the impacts of dietary patterns on changes in these factors among Chinese women. A total of 1,028 subjects who received health examination in 2011 and 2014 were recruited. Three major dietary patterns ("vegetable pattern", "meat pattern", and "animal offal-dessert-and-alcohol pattern") were derived by principal component analysis based on validated food frequency questionnaires. Cardiovascular risk factors were standardized to create within-cohort z-scores and the changes in them were calculated as the differences between 2011 and 2014. Relationships between dietary patterns and changes in cardiovascular risk factors were assessed using general linear model. After adjustment for potential confounders, changes in total cholesterol and fasting blood glucose decreased across the tertiles of vegetable pattern (p for trend = 0.01 and 0.04, respectively). While, changes in diastolic blood pressure, total cholesterol and low density lipoprotein cholesterol increased across the tertiles of animal offal-dessert-and-alcohol pattern (p for trend = 0.02, 0.01, and 0.02, respectively). The findings suggest that vegetable pattern was beneficially related to cardiovascular risk factors, whereas animal offal-dessert-and-alcohol pattern was detrimental related to these factors among apparently healthy Chinese women.


[Fistula-producing giant coronary aneurysm in a 62-year-old woman].
Giant coronary aneurysms (GCA with a diameter > 20 mm) are rare with a prevalence < 0.02%. A 62-year-old woman with no history of ischaemic heart disease was admitted to hospital with acute chest pain. A coronary angiography revealed a left an-terior descendent-associated GCA. A cardiac computed tomo-g-raphy demonstrated a "snake-pit"-like fistula connecting the GCA and the pulmonary artery. Atherosclerosis, connective tissue dis-orders, and previous coronary intervention will predispose to GCA. No evidence-based treatment regimen exists, but coiling, excision or a conservative approach, as in this case, is possible strategies.


The Presence of a Transporter-Induced Protein Binding Shift: A New Explanation for Protein-Facilitated Uptake and Improvement for In Vitro-In Vivo Extrapolation.
Accurately predicting hepatic clearance is an integral part of the drug-development process, and yet current in vitro to in vivo (IVIVE) extrapolation methods yield poor predictions, particularly for highly protein-bound transporter substrates. Explanations for error include inaccuracies in protein-binding measurements and the lack of recognition of protein-facilitated uptake, where both unbound and bound drug may be cleared, violating the principles of the widely accepted free drug theory. A new explanation for protein-facilitated uptake is proposed here, called a transporter-induced protein binding shift High-affinity binding to cell-membrane proteins may change the equilibrium of the nonspecific binding between drugs and plasma proteins, leading to greater cellular uptake and clearance than currently predicted. The uptake of two lower protein-binding organic anion transporting polypeptide substrates (pravastatin and rosuvastatin) and two higher binding substrates (atorvastatin and pitavastatin) were measured in rat hepatocytes in incubations with protein-free buffer versus 100% plasma. Decreased unbound K m values and increased intrinsic clearance values were seen in the plasma incubations for the highly bound compounds, supporting the new hypothesis and mitigating the IVIVE underprediction previously seen for highly bound transporter substrates.


Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis.
This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.


Classification of Multiple Sclerosis Clinical Profiles via Graph Convolutional Neural Networks.
Recent advances in image acquisition and processing techniques, along with the success of novel deep learning architectures, have given the opportunity to develop innovative algorithms capable to provide a better characterization of neurological related diseases. In this work, we introduce a neural network based approach to classify Multiple Sclerosis (MS) patients into four clinical profiles. Starting from their structural connectivity information, obtained by diffusion tensor imaging and represented as a graph, we evaluate the classification performances using unweighted and weighted connectivity matrices. Furthermore, we investigate the role of graph-based features for a better characterization and classification of the pathology. Ninety MS patients (12 clinically isolated syndrome, 30 relapsing-remitting, 28 secondary-progressive, and 20 primary-progressive) along with 24 healthy controls, were considered in this study. This work shows the great performances achieved by neural networks methods in the classification of the clinical profiles. Furthermore, it shows local graph metrics do not improve the classification results suggesting that the latent features created by the neural network in its layers have a much important informative content. Finally, we observe that graph weights representation of brain connections preserve important information to discriminate between clinical forms.


Group of Quantum Bits Acting as a Bit Using a Single-Domain Ferromagnet of Uniaxial Magnetic Ions.
Read/write operations with individual quantum bits (i.e., qbits) are a challenging problem to solve in quantum computing. To alleviate this difficulty, we considered the possibility of using a group of qbits that act collectively as a bit (hereafter, a group bit or a gbit, in short). A promising candidate for a gbit is a single-domain ferromagnet (SDF) independent of its size, which can be prepared as a magnet of well-separated uniaxial magnetic ions (UMIs) at sites of no electric dipole moment with their uniaxial axes aligned along one common direction. When magnetized, the UMIs of such a magnet have a ferromagnetic (FM) arrangement and the resulting SDF becomes a gbit with its two opposite moment orientations representing the |0⟩ and |1⟩ states of a bit. We probed the requirements for such magnets and identified several 2H-perovskites as materials satisfying these requirements.