Trial Watch: Anticancer radioimmunotherapy.
Radiotherapy has extensively been employed as a curative or palliative intervention against cancer throughout the last century, with a varying degree of success. For a long time, the antineoplastic activity of X- and γ-rays was entirely ascribed to their capacity of damaging macromolecules, in particular DNA, and hence triggering the (apoptotic) demise of malignant cells. However, accumulating evidence indicates that (at least part of) the clinical potential of radiotherapy stems from cancer cell-extrinsic mechanisms, including the normalization of tumor vasculature as well as short- and long-range bystander effects. Local bystander effects involve either the direct transmission of lethal signals between cells connected by gap junctions or the production of diffusible cytotoxic mediators, including reactive oxygen species, nitric oxide and cytokines. Conversely, long-range bystander effects, also known as out-of-field or abscopal effects, presumably reflect the elicitation of tumor-specific adaptive immune responses. Ionizing rays have indeed been shown to promote the immunogenic demise of malignant cells, a process that relies on the spatiotemporally defined emanation of specific damage-associated molecular patterns (DAMPs). Thus, irradiation reportedly improves the clinical efficacy of other treatment modalities such as surgery (both in neo-adjuvant and adjuvant settings) or chemotherapy. Moreover, at least under some circumstances, radiotherapy may potentiate anticancer immune responses as elicited by various immunotherapeutic agents, including (but presumably not limited to) immunomodulatory monoclonal antibodies, cancer-specific vaccines, dendritic cell-based interventions and Toll-like receptor agonists. Here, we review the rationale of using radiotherapy, alone or combined with immunomodulatory agents, as a means to elicit or boost anticancer immune responses, and present recent clinical trials investigating the therapeutic potential of this approach in cancer patients.


(&mgr;-2, 6-Bis
The binuclear cation of the title compound, [Ni(2)(C(33)H(29)N(4)O(3))(H(2)O)(4)]C(2)H(3)O(2).C(3)H(7)NO.0. 75H(2)O, was synthesized as a model for the active site of urease. Two tridentate halves of the symmetrical 2, 6-bis[(2-hydroxyphenyl)(2-pyridylmethyl)amino]methyl-4-methylphenol ate (BPPMP(3-)) ligand are arranged in a meridional fashion around the two Ni(II) ions, with the phenoxo O atom bridging the Ni(II) ions. The cation has an approximate twofold rotation axis running through the C-O bond of the bridging phenolate group. Four water molecules complete the octahedral environment of each Ni(II) ion.


Influences of solution chemistry and polymeric natural organic matter on the removal of aquatic pharmaceutical residuals by nanofiltration.
This study demonstrates the removal efficiency and the permeate flux behavior during cross-flow nanofiltration (NF) of aqueous solutions of five pharmaceutically active compounds (PhACs). Cephalexin, tetracycline, acetaminophen, indomethacin and amoxicillin were used as models of PhACs, and alginate was selected as model of natural organic matter (NOM). Two commercial composite NF membranes (SR2 and SR3) with different characteristics were used. The highest rejection was observed for tetracycline, i.e., 75-95% for membrane SR 2 and 95-100% for membrane SR 3, while the rejection was least for acetaminophen (32-36% for SR2 and 52-59% for SR3). As the pH of acetaminophen solution was increased (from 6 to 9) the rejection would increase. Changes of ionic content (from 10 to 20mM) lead to increase (from 89 to 93% for SR 3) or decrease (from 100 to 91% for SR2) of cephalexin rejection depending on the membrane used. The permeate flux would decrease with decreasing the pH solution and increasing ionic strength. The addition of alginate in the feed stream decreased the permeate flux, with lower reduction for SR3, and increased the PhAC rejection except for acetaminophen and amoxicillin. Both size and Donnan exclusions seemed to occur, and the effect of Donnan exclusion was more pronounced for the NF membrane having larger effective pore size (SR2).


Prepandemic Antivaccination Websites' COVID-19 Vaccine Behavior: Content Analysis of Archived Websites.
The onset of the COVID-19 pandemic and the concurrent development of vaccines offered a rare and somewhat unprecedented opportunity to study antivaccination behavior as it formed over time via the use of archived versions of websites. This study aims to assess how existing antivaccination websites modified their content to address COVID-19 vaccines and pandemic restrictions. Using a preexisting collection of 25 antivaccination websites curated by the IvyPlus Web Collection Program prior to the pandemic and crawled every 6 months via Archive-It, we conducted a content analysis to see how these websites acknowledged or ignored COVID-19 vaccines and pandemic restrictions. Websites were assessed for financial behaviors such as having storefronts, mention of COVID-19 vaccines in general or by manufacturer name, references to personal freedom such as masking, safety concerns like side effects, and skepticism of science. The majority of websites addressed COVID-19 vaccines in a negative fashion, with more websites making appeals to personal freedom or expressing skepticism of science than questioning safety. This can potentially be attributed to the lack of available safety data about the vaccines at the time of data collection. Many of the antivaccination websites we evaluated actively sought donations and had a membership option, evidencing these websites have financial motivations and actively build a community around these issues. The content analysis also offered the opportunity to test the viability of archived websites for use in scholarly research. The archived versions of the websites had significant shortcomings, particularly in search functionality, and required supplementation with the live websites. For web archiving to be a viable source of stand-alone content for research, the technology needs to make significant improvements in its capture abilities. In summary, we found antivaccination websites existing prior to the COVID-19 pandemic largely adapted their messaging to address COVID-19 vaccines with very few sites ignoring the pandemic altogether. This study also demonstrated the timely and significant need for more robust web archiving capabilities as web-based environments become more ephemeral and unstable.


Clinical Characteristics of Suicidal Youths and Adults: A One-Year Retrospective Study.
Suicide is a major mental health problem, particularly during youth, when it is the second leading cause of death. Since young people at risk of suicide are often cared for by the adult health system, we sought to identify the specificities and similarities between suicidal youths and adults in order to further inform the potential need for adaptations in taking care of suicidal youths. For this study, we used the following data: mental disorders, treatments, previous hospitalization, and reasons for current hospitalization, that were collected from November 2016 to October 2017 among people hospitalized for a suicidal crisis in a specialized psychiatric unit. First, we compared the data from the youth group with those from the adult group, and then we tried to determine if there were any associations between variables. Analyses showed that youths were more similar to adults than expected. In particular, we found comparable rates of personality disorders (especially borderline) and relapse, and similar profiles of reasons for hospitalization in suicidal crisis. Remarkably, among youth, neuroleptics appeared to be associated with fewer hospitalizations for behavioral than ideational reasons, but with more relapses. Results of this study suggest that young people could benefit from brief psychotherapeutic interventions implemented for adults.


Improved method for estimating the minimum length of modal filters fabricated for stellar interferometry.
We present an improved theoretical model to estimate the minimum fiber length required for achieving a desired degree of wavefront filtering in stellar interferometry. The proposed model is based on modal analysis of the fiber and is compared with numerical results obtained through the beam propagation method as well as with reported experimental observations. We also study the effect of introducing a spatial filter at the output end of the fiber and show that the required fiber length can be reduced significantly by introducing a circular aperture of optimum radius after the fiber.


The Use of Virtual Reality Technologies in the Treatment of Duchenne Muscular Dystrophy: Systematic Review.
Duchenne muscular dystrophy is a serious and progressive disease affecting one in 3500-6000 live male births. The use of new virtual reality technologies has revolutionized the world of youth rehabilitation. We performed a systematic review to study the effectiveness of the use of virtual reality systems applied in the rehabilitation of the upper limbs of individuals with Duchenne muscular dystrophy. Between June 2018 and September 2019, we carried out a series of searches in 5 scientific databases: (1) PubMed, (2) Web of Science, (3) Scopus, (4) The Cochrane Library, and (5) MEDLINE via EBSCO. Two evaluators independently conducted the searches following the PRISMA recommendations for systematic reviews for articles. Two independent evaluators collated the results. Article quality was determined using the PEDro scale. A total of 7 clinical trials were included in the final review. These studies used new technologies as tools for physiotherapeutic rehabilitation of the upper limbs of patients with Duchenne muscular dystrophy. Collectively, the studies showed improvement in functionality, quality of life, and motivation with the use of virtual reality technologies in the rehabilitation of upper limbs of individuals with Duchenne muscular dystrophy. The treatment of neuromuscular diseases has changed in recent years, from palliative symptom management to preventive methods for capacity building. The use of virtual reality is beginning to be necessary in the treatment of progressive diseases involving movement difficulties, as it provides freedom and facilitates the improvement of results in capacity training. Given that new technologies are increasingly accessible, rehabilitation and physiotherapy programs can use these technologies more frequently, and virtual reality environments can be used to improve task performance, which is essential for people with disabilities. Ultimately, virtual reality can be a great tool for physiotherapy and can be used for Duchenne muscular dystrophy rehabilitation programs to improve patient performance during training. PROSPERO International Prospective Register of Systematic Reviews CRD42018102548; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=102548.


Earlier Treatment Yields Superior Outcomes in Competitive Athletes Undergoing Primary Hip Arthroscopy.
To report minimum 2-year patient-reported outcome scores (PROs) and return to sport (RTS) for competitive athletes undergoing primary hip arthroscopy for femoroacetabular impingement syndrome within 1 year of symptom onset and to compare these results with a propensity-matched control group of competitive athletes with symptoms for over 1 year. Data on professional, collegiate, high-school, and organized amateur athletes who underwent primary hip arthroscopy within 1 year of symptom onset between April 2008 and November 2017 were collected. RTS and minimum 2-year PROs were collected for the modified Harris Hip Score (mHHS), Non-arthritic Hip Score (NAHS), Hip Outcome Score-Sport Specific Subscale (HOS-SSS), International Hip Outcome Tool (iHOT-12), and visual analog pain scale (VAS). Rates of achieving minimal clinically important difference (MCID) were also evaluated. These patients were propensity-matched to a control group of competitive athletes with symptoms for over one year for comparison. Fifty competitive athletes (51 hips, 54.9% female) were included in the study group with a mean follow-up of 70.9 ± 29.1 months and age of 23.6 ± 11.3 years. They demonstrated significant improvement from preoperative to latest follow-up for all recorded PROs (P < .001) and RTS at a rate of 72.9%. When outcomes were compared to the control group, the study group demonstrated similar preoperative scores for all PROs but significantly better minimum 2-year postoperative scores for NAHS (93.8 vs 85.1, P = .0001), HOS-SSS (89.1 vs 77.2, P = .001), iHOT-12 (87.7 vs 76.4, P = 0.011), and VAS (1.5 vs 2.4, P = 0.027). Rates of achieving MCID for HOS-SSS and mHHS were comparable between groups. Further, RTS rates were similar between groups (P = .301). Competitive athletes undergoing primary hip arthroscopy with symptoms for less than 1 year demonstrated superior 2-year PROs compared to a propensity-matched control group with symptoms for over 1 year, but the rates achieving MCID and RTS were similar between groups. Level III, retrospective comparative study.


Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic.
Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with (67)Ga. EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with (67)Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of (67)Ga. Cellular and nuclei uptake of (67)Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of (67)Ga-EDTA, (67)Ga-NOTA-BSA and (67)Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. (67)Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of (67)Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific (67)Ga-NOTA-BSA and (67)Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to (67)Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of (67)Ga. These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters.


Sex differences in immunocompetence differ between two Peromyscus species.
Males generally exhibit reduced immunocompetence and greater susceptibility to disease than females. The explanations for why males may be more susceptible to disease than females fall into two categories: 1) the proximate mechanisms mediating immunity, such as hormonal mechanisms, and 2) variation in reproductive success between the sexes. The present study examined the extent to which these factors contribute to sex differences in cell-mediated immune function in polygynous Peromyscus maniculatus and monogamous Peromyscus californicus. Prevailing hypotheses suggest that, because variation in male and female reproductive success is greater among polygynous than monogamous species, sex differences in immunocompetence should be greater among polygynous than monogamous species as well. In contrast to these predictions, sex differences in cell-mediated immunity and body mass were only observed among monogamous P. californicus, in which females exhibited higher splenocyte proliferation in response to the T cell mitogen, concanavalin A, and weighed less than male conspecifics. Male P. maniculatus had higher serum testosterone concentrations than male P. californicus, but females of the two species did not differ in circulating estradiol concentrations. Sex steroid concentrations were not correlated with either immunocompetence or body mass; however, large P. californicus males exhibited reduced immune responses. Taken together, these results do not support the hypothesis that sex differences in immunocompetence are more pronounced among polygynous compared with monogamous species. Furthermore, these data suggest that circulating testosterone does not mediate sex differences in immuno-competence or body mass in P. californicus.


[Neuropsychiatric disorders in insulinoma].
The case of a young female presenting severe mental problems and episodic neurological symptoms is described. Obsessive-compulsive disorder was diagnosed upon psychiatric treatment for eight months. No neurological condition was found. Hypoglycaemia was observed during an episode of long-lasting somnolescence and the patient referred for endocrinological examination. Reactive hypoglycaemia was ruled out in an oral glucose tolerance test. A test of prolonged starvation revealed hypoglycaemia associated with neuropsychiatric symptoms. Glucose abolished this condition, suggesting an insulinoma as the basis of the spontaneous hypoglycaemia. Subsequently, two insulinomas were resected from the tail of the pancreas. The patient has recovered completely after her surgery, with no signs of mental or neurological disease and blood glucose within normal limits. As insulinoma is often associated to the MEN1-syndrome, the patient and her relatives are now being investigated for this condition.


Endocrine and haemodynamic stress responses to an arithmetic cognitive challenge.
We aimed at developing and validating a simple, highly repeatable computer-based tool, which could be employed to simulate the effects of an acute mental stress on endocrine and haemodynamic stress responses. Fifteen subjects underwent a mental cognitive challenge, employing an ad hoc designed web tool (available at http://bagame.altervista.org) that proposed a series of random arithmetic operations (addictions or subtractions) between one- to three-digit numbers for 10 minutes. We measured plasma epinephrine, norepinephrine, cortisol, and ACTH, in addition to heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure throughout the test. The arithmetic mental challenge promptly activated the sympatho-adrenomedullary axis (epinephrine +112±24%, p<0.05; norepinephrine +37±13%, p<0.004) and the hypothalamic-pituitary-adrenocortical axis (cortisol +25±7%, p<0.008; ACTH +97±44%, p<0.008), which in turn exerted stimulatory effects on the cardiovascular system (HR +18±4%, p<0.05; SBP +112±24%, p<0.05; DBP +34±8%, p<0.05) in all subjects, without any symptoms and regardless of the individuals' mental arithmetic ability. We developed and validated a computer-based tool that is effective for simulating endocrine and haemodynamic responses to an acute mental stress. This novel tool is easy-to-use, freely-accessible, and it can be employed to further investigate stress-related pathophysiological mechanisms and their role in cardiovascular diseases.


An Efficient Single Phase Method for the Extraction of Plasma Lipids.
Lipidomic approaches are now widely used to investigate the relationship between lipid metabolism, health and disease. Large-scale lipidomics studies typically aim to quantify hundreds to thousands of lipid molecular species in a large number of samples. Consequently, high throughput methodology that can efficiently extract a wide range of lipids from biological samples is required. Current methods often rely on extraction in chloroform:methanol with or without two phase partitioning or other solvents, which are often incompatible with liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI-MS/MS). Here, we present a fast, simple extraction method that is suitable for high throughput LC ESI-MS/MS. Plasma (10 μL) was mixed with 100 μL 1-butanol:methanol (1:1 v/v) containing internal standards resulting in efficient extraction of all major lipid classes (including sterols, glycerolipids, glycerophospholipids and sphingolipids). Lipids were quantified using positive-ion mode LC ESI-MS/MS. The method showed high recovery (>90%) and reproducibility (%CV < 20%). It showed a strong correlation of all lipid measures with an established chloroform:methanol extraction method (R2 = 0.976). This method uses non-halogenated solvents, requires no drying or reconstitution steps and is suitable for large-scale LC ESI-MS/MS-based lipidomic analyses in research and clinical laboratories.


False positive Lyme serology due to syphilis: report of 6 cases and review of the literature.
A 44-year-old man presented with visual field defects. Ophthalmoscopy revealed papilloedema of the left eye. Neuroborreliosis was suspected and serum was positively being tested using VIDAS* Lyme screen II (bioMerieux Vitek Inc). However, confirmatory testing using the Borrelia VlsE C6 titre was negative. Western Blotting on serum and cerebrospinal fluid could not confirm the possible diagnosis of neuroborreliosis. VDRL and TPPA testing was positive, and finally, the diagnosis of neurosyphilis was established. We subsequently screened our database on patients with positive VIDAS Lyme screening and negative confirmatory testing by Western blot, and found another 5 cases in which Lyme screening was false positive due to cross-reactivity with Treponema pallidum antibodies. Our data show that in patients with positive Lyme screening and negative confirmatory testing, performance of lues serology should be considered.


Prophylactic bladder neck incision in the treatment of small benign prostatic hyperplasia.
From May 1986 to January 1989, a total of 178 patients with small prostate (less than 20 grams) received transurethral resection for benign prostatic hyperplasia. Twenty-two patients (12.4%) developed bladder neck contracture with an average interval of 247 days. The prophylactic bladder neck incision was performed concomitantly with transurethral resection of the prostate on 72 patients. Although smaller adenoma (average weight: 11.4 grams) was resected in this group, the bladder neck contracture occurred in 4 patients (5.6%), compared to 18 contractures in 106 patients (16.9%) who underwent transurethral resection of the prostate alone for larger adenoma (14 grams), P value less than 0.05. The operation time, peri-operative morbidity and hospital stay were similar in these two groups. It appeared that prophylactic bladder neck incision could protect against the formation of bladder neck contracture in patients with small obstructing prostatic adenoma.


Direct interaction of proliferating cell nuclear antigen with the small subunit of DNA polymerase delta.
The interaction between proliferating cell nuclear antigen (PCNA) and DNA polymerase delta is essential for processive DNA synthesis during DNA replication/repair; however, the identity of the subunit of DNA polymerase delta that directly interacts with PCNA has not been resolved until now. In the present study we have used reciprocal co-immunoprecipitation experiments to determine which of the two subunits of core DNA polymerase delta, the 125-kDa catalytic subunit or the 50-kDa small subunit, directly interacts with PCNA. We found that PCNA co-immunoprecipitated with human p50, as well as calf thymus DNA polymerase delta heterodimer, but not with p125 alone, suggesting that PCNA directly interacts with p50 but not with p125. A PCNA-binding motif, similar to the sliding clamp-binding motif of bacteriophage RB69 DNA polymerase, was identified in the N terminus of p50. A 22-amino acid oligopeptide containing this sequence (MRPFL) was shown to bind PCNA by far Western analysis and to compete with p50 for binding to PCNA in co-immunoprecipitation experiments. The binding of p50 to PCNA was inhibited by p21, suggesting that the two proteins compete for the same binding site on PCNA. These results establish that the interaction of PCNA with DNA polymerase delta is mediated through the small subunit of the enzyme.


Resveratrol and its analogs suppress HIV replication, oxidative stress, and inflammation in macrophages.
HIV suppression in brain viral reservoirs, especially macrophages, and microglia is critical to suppress HIV neuropathogenesis and subsequently HIV-associated neurocognitive disorders (HAND). Since most antiretroviral therapy (ART) drugs do not achieve optimal therapeutic concentrations in the brain and can cause neurotoxicity, an alternative/adjuvant therapy is needed to suppress HIV neuropathogenesis. In this study, our objectives were to examine the anti-HIV, antioxidant, and anti-inflammatory potential of resveratrol (RES) and its synthetic analogs 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) and 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD) in HIV-infected macrophages. We used HIV replication (viral load), oxidative stress (reactive oxygen species and antioxidant enzymes), and inflammatory response (pro- and anti-inflammatory cytokines/chemokines) assays to achieve the objectives of the study. Our results showed that RES and its analogs HPIMBD and TIMBD at 25 µM concentration significantly decrease HIV replication in both primary monocyte-derived macrophages and U1-differentiated macrophages. Moreover, RES and its analogs do not induce any cytotoxicity for up to 3 days in these cells. Further, treatment with RES and TIMBD (25 µM) also reduced the levels of reactive oxygen species without affecting the expression of antioxidant enzymes, SOD1, and catalase in U1 macrophages. Besides, RES and HPIMBD treatment inhibited the proinflammatory cytokines and chemokines in U1 macrophages, which was associated with decreased levels of anti-inflammatory cytokines. Importantly, our western blot experiments show that RES also decreases cellular proinflammatory cytokine IL-1β, which is usually elevated in both myeloid and neuronal cells upon HIV infection. Taken together, our results suggest that RES and/or its analogs are important adjuvants that may be used not only to suppress HIV but also oxidative stress and inflammation in brain viral reservoirs.


The role of RhoA in the germinal vesicle breakdown of mouse oocytes.
We have investigated a new role of RhoA in the germinal vesicle breakdown (GVBD) of mouse oocytes. First, RhoA was identified by immunostaining and ADP-ribosylation in germinal vesicle (GV) stage-oocytes. RhoA was mainly localized in the ooplasmic area, but rarely detected in germinal vesicle. Incubation of oocyte extract with C3 transferase induced a strong ADP-ribosylation at about 25 kDa. Incubation of GV-stage oocytes in culture medium induced the spontaneous maturation to GVBD by about 78 and 87% of total oocytes at 1 and 3 h, respectively. However, microinjection of C3 transferase into GV-stage oocytes significantly inhibited GVBD at 1 (GVBD = 29%) and 3 h (GVBD = 49%). To study the role of reactive oxygen species (ROS) in the oocyte maturation, the level of intra-oocyte ROS was measured using a ROS-specific fluorescent dye H(2)DCFDA during the oocyte maturation. Spontaneous maturation of GV-stage oocytes induced a significant increase of ROS at 3 h by about twofold over the control level and then the increased level was maintained until 6 h. However, microinjection of C3 transferase inhibited the production of intra-oocyte ROS. Incubation with ROS scavengers, N-acetyl-l-cysteine and catalase, blocked the ROS increase. The ROS scavengers also significantly inhibited GVBD, as did C3 transferase. Thus, it was proposed that RhoA was involved in the GVBD, possibly by the production of ROS in mouse oocytes.


Water mold infection but not paternity induces selective filial cannibalism in a goby.
Many animals heavily invest in parental care but still reject at least some of their offspring. Although seemingly paradoxical, selection can favor parents to neglect offspring of particularly low reproductive value, for example, because of small survival chances. We here assess whether filial cannibalism (FC), where parents routinely eat some of their own young, is selective in response to individual offspring reproductive value. We performed two independent laboratory experiments in the common goby (Pomatoschistus microps) to test whether caring fathers preferentially cannibalize eggs of a given infection history and paternity. While males did not discriminate kin from nonkin eggs, they consumed significantly more eggs previously exposed to water mold compared to uninfected eggs. Our findings clearly show that parents differentiate between eggs based on differences in egg condition, and thus complement the prevailing view that FC arises for energetic reasons. By preventing the spread of microbial infections, the removal of molded eggs can constitute an important component of parental care and may represent a key driver of selective FC in a wide array of parental fish.


The tropics: cradle, museum or casino? A dynamic null model for latitudinal gradients of species diversity.
Several ecological and evolutionary hypotheses have been proposed to explain the latitudinal diversity gradient (LDG), but a general model for this conspicuous pattern remains elusive. Mid-domain effect (MDE) models generate gradients of species diversity by randomly placing the geographic ranges of species in one- or two-dimensional spaces, thus excluding both evolutionary processes and the effect of contemporary climate. Traditional MDE models are statistical and static because they determine the size of ranges either randomly or based on empirical frequency distributions. Here we present a simple dynamic null model for the LDG that simulates stochastic processes of range shifts, extinction and speciation. The model predicts higher species diversity and higher extinction and speciation rates in the tropics, and a strong influence of range movements in shaping the LDG. These null expectations should be taken into consideration in studies aimed at understanding the many factors that generate latitudinal diversity gradients.


Highly anisotropic metasurface: a polarized beam splitter and hologram.
Two-dimensional metasurface structures have recently been proposed to reduce the challenges of fabrication of traditional plasmonic metamaterials. However, complex designs and sophisticated fabrication procedures are still required. Here, we present a unique one-dimensional (1-D) metasurface based on bilayered metallic nanowire gratings, which behaves as an ideal polarized beam splitter, producing strong negative reflection for transverse-magnetic (TM) light and efficient reflection for transverse-electric (TE) light. The large anisotropy resulting from this TE-metal-like/TM-dielectric-like feature can be explained by the dispersion curve based on the Bloch theory of periodic metal-insulator-metal waveguides. The results indicate that this photon manipulation mechanism is fundamentally different from those previously proposed for 2-D or 3-D metastructures. Based on this new material platform, a novel form of metasurface holography is proposed and demonstrated, in which an image can only be reconstructed by using a TM light beam. By reducing the metamaterial structures to 1-D, our metasurface beam splitter exhibits the qualities of cost-efficient fabrication, robust performance, and high tunability, in addition to its applicability over a wide range of working wavelengths and incident angles. This development paves a foundation for metasurface structure designs towards practical metamaterial applications.


Mental health service provision in low and middle-income countries: recent developments.
The study discusses key issues and concepts of how to provide basic mental health services for people with mental disorders in low and middle-income countries (LAMICs). In the last years a considerable gap between mental healthcare needs and available services in LAMICs has been documented. The transformation of hospital-based to community-based mental health and the building of accessible services in low-resource settings require mental health training of primary care providers, task-sharing/task-shifting models, involvement of families and peers and basic models of community rehabilitation. Several international initiatives have been set up to increase the evidence base and test the feasibility, acceptability, and effectiveness of these approaches which are not new but which have been implemented in only a small amount of LAMICs. A combination of interventions on different levels (governance, legislation, providers, and community) is necessary. It remains to be shown how the recent global mental health movement, beyond increasing international financial resources, will be helpful in finding locally and culturally sensitive solutions to reduce the mental health gap in LAMICs. Although concepts of a well designed mix of services are available, solutions to reduce implementation barriers must be local, and implementation strategies may vary considerably and still lack a sufficient evidence base.


Egomotion estimation of a range camera using the space envelope.
In this paper we present a method to compute the egomotion of a range camera using the space envelope. The space envelope is a geometric model that provides more information than a simple segmentation for correspondences and motion estimation. We describe a novel variation of the maximal matching algorithm that matches surface normals to find correspondences. These correspondences are used to compute rotation and translation estimates of the egomotion. We demonstrate our methods on two image sequences containing 70 images. We also discuss the cases where our methods fail, and additional possible methods for exploiting the space envelope.


Co-Design of a Computer-Assisted Medical Decision Support System to Manage Antibiotic Prescription in an ICU Ward.
About 37 thousand people die per year in Europe due to infections by resistant bacteria. Fighting antimicrobial resistances (AR) is a top priority to save lives and reduce costs. AR is triggered mostly by uncritical antibiotic prescription. This paper presents HAITool, a decision-making information system to support antibiotic prescription. The system was co-developed together with health professionals using Design Science Research Methodology, empowered with innovative data visualization techniques to improve AR management. HAITool includes integrated visualizations of patient, microbiology, and pharmacy data, facilitating clinical decision support, antibiotic prescriptions quality and antibiotic-resistant bacteria monitoring. It also includes an alert module that monitors conformance of antibiotic prescriptions with norms and guidelines. HAITool is evaluated using both the Österle principles and interviews with physicians and infection control team from three participant hospitals.


FISH mapping of two putative keratin gene clusters on cat (Felis catus) chromosomes.
Genes encoding keratins are evolutionary highly conserved and clustered in two linkage groups in mammalian genomes. Canine keratin 9 (K-9) and keratin 2e (K-2) cosmid-derived gene probes were used to localize the acidic and basic-neutral keratin gene clusters to cat chromosomes E1q12 and B4q15, respectively. The status of the physical map of the cat genome is discussed.


The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy.
Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy. The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840-50. ©2015 AACR.


SIRT5 regulation of ammonia-induced autophagy and mitophagy.
In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. However, while SIRT5 is ubiquitously expressed, urea cycle and CPS1 are only present in the liver and, to a minor extent, in the kidney. To address the possibility that SIRT5 is involved in ammonia production also in nonliver cells, clones of human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12, overexpressing or silenced for SIRT5 were produced. Our results show that ammonia production increased in SIRT5-silenced and decreased in SIRT5-overexpressing cells. We also obtained the same ammonia increase when using a new specific inhibitor of SIRT5 called MC3482. SIRT5 regulates ammonia production by controlling glutamine metabolism. In fact, in the mitochondria, glutamine is transformed in glutamate by the enzyme glutaminase, a reaction producing ammonia. We found that SIRT5 and glutaminase coimmunoprecipitated and that SIRT5 inhibition resulted in an increased succinylation of glutaminase. We next determined that autophagy and mitophagy were increased by ammonia by measuring autophagic proteolysis of long-lived proteins, increase of autophagy markers MAP1LC3B, GABARAP, and GABARAPL2, mitophagy markers BNIP3 and the PINK1-PARK2 system as well as mitochondrial morphology and dynamics. We observed that autophagy and mitophagy increased in SIRT5-silenced cells and in WT cells treated with MC3482 and decreased in SIRT5-overexpressing cells. Moreover, glutaminase inhibition or glutamine withdrawal completely prevented autophagy. In conclusion we propose that the role of SIRT5 in nonliver cells is to regulate ammonia production and ammonia-induced autophagy by regulating glutamine metabolism.


Ecstasy analogues found in cacti.
Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs."


Quality of spirometry tests performed by 9893 adults in 14 countries: the BOLD Study.
to determine the ability of participants in the Burden of Obstructive Lung Disease (BOLD) study to meet quality goals for spirometry test session quality and to assess factors contributing to good quality. Following 2 days of centralized training, spirometry was performed pre- and post-bronchodilator (BD) at 14 international sites, in random population-based samples of persons aged ≥40 years, following a standardized protocol. The quality of each test session was evaluated by the spirometer software and an expert reading center. Descriptive statistics were calculated for key maneuver acceptability variables. A logistic regression model identified the predictors of acceptable quality test sessions. About 96% of test sessions met our quality goals for a low back-extrapolated volume (BEV), time to peak flow (PEFT), and end-of-test volume (EOTV). The mean forced expiratory time (FET) was 10.4 s. Ninety percent of the maneuvers with the highest FVC had a forced expiratory time (FET) > 6.8 s. About 90% of test sessions had FEV(1) and FVC which were repeatable within 150 mL. Test quality was slightly better for post-BD test sessions when compared to pre-BD. Independent predictors of adequate test quality included female sex, younger age, higher education, lack of dyspnea, higher pre-BD FEV(1), less BD responsiveness, and study site. Quality goals for spirometry tests were met about 90% of the time in these population-based samples of adults from several countries.


A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone.
Endocrine disrupting chemicals (e.g., estrogens, androgens and their mimics) are known to affect reproduction in fish. 17α-ethynylestradiol is a synthetic estrogen used in birth control pills. 17β-trenbolone is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter in livestock. Both 17α-ethynylestradiol and 17β-trenbolone have been found in the aquatic environment and affect fish reproduction. In this study, we developed a physiologically-based computational model for female fathead minnows (FHM, Pimephales promelas), a small fish species used in ecotoxicology, to simulate how estrogens (i.e., 17α-ethynylestradiol) or androgens (i.e., 17β-trenbolone) affect reproductive endpoints such as plasma concentrations of steroid hormones (e.g., 17β-estradiol and testosterone) and vitellogenin (a precursor to egg yolk proteins). Using Markov Chain Monte Carlo simulations, the model was calibrated with data from unexposed, 17α-ethynylestradiol-exposed, and 17β-trenbolone-exposed FHMs. Four Markov chains were simulated, and the chains for each calibrated model parameter (26 in total) converged within 20,000 iterations. With the converged parameter values, we evaluated the model's predictive ability by simulating a variety of independent experimental data. The model predictions agreed with the experimental data well. The physiologically-based computational model represents the hypothalamic-pituitary-gonadal axis in adult female FHM robustly. The model is useful to estimate how estrogens (e.g., 17α-ethynylestradiol) or androgens (e.g., 17β-trenbolone) affect plasma concentrations of 17β-estradiol, testosterone and vitellogenin, which are important determinants of fecundity in fish.


Automated airway quantification associates with mortality in idiopathic pulmonary fibrosis.
The study examined whether quantified airway metrics associate with mortality in idiopathic pulmonary fibrosis (IPF). In an observational cohort study (n = 90) of IPF patients from Ege University Hospital, an airway analysis tool AirQuant calculated median airway intersegmental tapering and segmental tortuosity across the 2nd to 6th airway generations. Intersegmental tapering measures the difference in median diameter between adjacent airway segments. Tortuosity evaluates the ratio of measured segmental length against direct end-to-end segmental length. Univariable linear regression analyses examined relationships between AirQuant variables, clinical variables, and lung function tests. Univariable and multivariable Cox proportional hazards models estimated mortality risk with the latter adjusted for patient age, gender, smoking status, antifibrotic use, CT usual interstitial pneumonia (UIP) pattern, and either forced vital capacity (FVC) or diffusion capacity of carbon monoxide (DLco) if obtained within 3 months of the CT. No significant collinearity existed between AirQuant variables and clinical or functional variables. On univariable Cox analyses, male gender, smoking history, no antifibrotic use, reduced DLco, reduced intersegmental tapering, and increased segmental tortuosity associated with increased risk of death. On multivariable Cox analyses (adjusted using FVC), intersegmental tapering (hazard ratio (HR) = 0.75, 95% CI = 0.66-0.85, p < 0.001) and segmental tortuosity (HR = 1.74, 95% CI = 1.22-2.47, p = 0.002) independently associated with mortality. Results were maintained with adjustment using DLco. AirQuant generated measures of intersegmental tapering and segmental tortuosity independently associate with mortality in IPF patients. Abnormalities in proximal airway generations, which are not typically considered to be abnormal in IPF, have prognostic value. Quantitative measurements of intersegmental tapering and segmental tortuosity, in proximal (second to sixth) generation airway segments, independently associate with mortality in IPF. Automated airway analysis can estimate disease severity, which in IPF is not restricted to the distal airway tree. • AirQuant generates measures of intersegmental tapering and segmental tortuosity. • Automated airway quantification associates with mortality in IPF independent of established measures of disease severity. • Automated airway analysis could be used to refine patient selection for therapeutic trials in IPF.


Immunity to Salmonella infections.
The results of current investigations regarding the mechanisms of immunity to Salmonella infections and the use of vaccines are presented. Since chemical suppression of the humoral immune response in chickens does not jeopardise immunization with a live vaccine and immunized guinea-pigs exhibit distinct inhibition of macrophage migration, it is concluded that cellular immunity is a prominent factor in protection. Data is presented to show that the mice and calves can be equally well immunized with either live or inactivated S. typhimurium and S. dublin vaccines and the practical advantages of inactivated vaccines are discussed.


Detection of interferon-gamma-inducible chemokines in human milk.
To assess the immunological role of human milk by analysing the concentrations of interferon-gamma-inducible protein of 10 kda (IP-10) and monokine induced by interferon-gamma (MIG) in human milk from mothers of preterm and term infants. IP-10 and MIG levels of colostrum, early milk, mature milk and sera were measured by enzyme-linked immunosorbent assay (ELISA). IP-10 and MIG mRNA expression levels in cellular components of human milk were determined by RT-PCR. IP-10 and MIG protein expression in mammary gland tissues was analysed by immunohistochemistry. Significant amounts of IP-10 and MIG were detected in human milk. The concentrations of IP-10 and MIG in colostrum and early milk were significantly higher than those of sera from healthy controls or lactating mothers. These chemokine concentrations in colostrum and early milk were significantly higher than those of mature milk. Premature delivery or pregnancy complications of mothers had no significant correlation with these chemokine concentrations in breast milk. There were significant correlations between MIG and interferon-gamma (IFN-gamma) or IP-10 levels (p < 0.001) in human milk. Expression of IP-10 and MIG genes and proteins in the milk cells as well as in mammary gland epithelial tissues was detected by RT-PCR and immunohistochemistry. IP-10 and MIG in human milk, probably derived from milk cells and mammary gland epithelial cells, may contribute to the migration and activation of intestinal T lymphocytes to enhance mucosal immunity during the early neonatal period.


HEALTH SURVEY OF FREE-RANGING RACCOONS (PROCYON LOTOR) IN CENTRAL PARK, NEW YORK, NEW YORK, USA: IMPLICATIONS FOR HUMAN AND DOMESTIC ANIMAL HEALTH.
We conducted health assessments on 113 free-ranging raccoons ( Procyon lotor ) in Central Park, New York City, US, in February 2010, September 2010, and November 2011 in conjunction with a trap-vaccinate-release program to control a raccoon rabies epizootic. Five individuals were sampled at two time points for 118 raccoon examinations in total. We tested 13 of 13 and 8 of 13 euthanized raccoons for rabies and canine distemper virus (CDV), respectively, by antigen testing on brain tissue; all were negative for both viruses. Endoparasitism was the most common necropsy finding, with definitive identification of Baylisascaris procyonis in six of eight (75%) necropsied raccoons. Multiple intestinal parasites were detected in feces of living raccoons, including ascarid-type ova in 25 of 80 (31%) raccoons, with B. procyonis confirmed in one sample. Median blood lead level was 7.3 μg/dL (n=104). Rabies virus neutralizing antibody titer was ≥0.5 IU/mL in 9 of 88 (10%) raccoons naive to rabies vaccination and in 13 of 20 (65%) previously vaccinated raccoons. The majority of raccoons we tested were seropositive for canine parvovirus-2 (54/59, 92%) and Toxoplasma gondii (39/60, 65%). Fewer were seropositive for Rickettsia rickettsii (3/30, 10%). None were seropositive for CDV (n=108), canine adenovirus-1 (n=60), or Borrelia burgdorferi (n=30). Ectoparasites found during 16 of 118 (13.6%) physical examinations included Ixodes texanus ticks (15/118, 12.7%) and Trichodectes octomaculatus lice (1/118, 0.8%). We detected Campylobacter jejuni in 5 of 79 (6%) fecal samples. We detected 11 Salmonella enterica serotypes in 70 of 111 (63.1%) enteric cultures, the most common of which were Salmonella Newport (20/70, 29%) and Salmonella Oranienburg (20/70, 29%). These results indicate that raccoons in Central Park likely are involved in the environmental occurrence and potential disease transmission of a variety of infectious and noninfectious diseases of concern for human, wildlife, and domestic animal health.


Prognostic significance of the number of leads with ST depression during an anginal attack in high risk patients with unstable angina.
We examined the prognostic significance of electrocardiographic predictors (number of leads with ST depression, maximal ST depression, QT dispersion), C-reactive protein, fibrinogen, myosin light chain 1 and creatine kinase MB fraction in 62 patients with unstable angina showing ST depression during an anginal attack. During the 90-day follow-up period, 15 patients (24%) exhibited new cardiac events (death, myocardial infarction or urgent revascularization). Using multivariate analysis, the number of leads with ST depression [relative risk 6.305 (95% confidence intervals 1.831-21.71), p<0.01] during an anginal attack was found to be an independent risk factor to predict cardiac events. Other predictors did not have prognostic significance. The number of leads with ST depression during an anginal attack is an independent risk predictor for new cardiac events in high risk patients with unstable angina.


[A case of rhabdomyolysis after status epilepticus without stroke-like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes].
A 24-year-old man was referred to our hospital emergency department due to a sudden onset of convulsions after drinking. On arrival he presented status epilepticus and was managed by artificial ventilation. He had no brainstem signs or meningeal irritation. Head MRI showed an old infarction-like lesion in the left occipital lobe, but no abnormal signals on diffusion-weighted images. The patient showed acute rhabdomyolysis (CK 18,000 IU/l) and renal failure, and hemodialysis was started. On 18 day after admission, he was transferred to our department with mild proximal limb muscle weakness and bilateral sensorineural hearing impairment. Electroencephalography demonstrated diffuse intermittent slow wave activities. We suspected a mitochondrial disease because of a significant increase in the lactate/pyruvate ratio (24.1) in the spinal fluid, and identified A3243G mutations in mitochondrial DNA (heteroplasmy 20%) in peripheral white blood cells. We diagnosed his illness as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This is a rare case presenting an acute onset of rhabdomyolysis following alcohol intake related to A3243G mitochondrial mutation without preceding stroke-like episodes.


The effect of meal frequency in a reduced-energy regimen on the gastrointestinal and appetite hormones in patients with type 2 diabetes: A randomised crossover study.
Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.


Design, synthesis and antiproliferative effect of 17β-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics.
A series of 17β-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17β-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17β-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t1/2β=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC0-tmin=2068.20±315.74μgmL-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t1/2β=22.28min) with a t1/2β of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.


Learning building layouts with non-geometric visual information: the effects of visual impairment and age.
Previous studies suggest that humans rely on geometric visual information (hallway structure) rather than non-geometric visual information (eg doors, signs, and lighting) for acquiring cognitive maps of novel indoor layouts. In this study we asked whether visual impairment and age affect reliance on non-geometric visual information for layout learning. We tested three groups of participants-younger (<50 years of age) normally sighted; older (50-70 years of age) normally sighted; and low-vision (people with heterogeneous forms of visual impairment ranging in age from 18 to 67 years). Participants learned target locations in building layouts using four presentation modes: a desktop virtual environment (VE) displaying only geometric cues (sparse VE); a VE displaying both geometric and non-geometric cues (photorealistic VE); a map; and a real building. Layout knowledge was assessed by map drawing and by asking participants to walk to specified targets in the real space. Results indicate that low-vision and older normally sighted participants relied on additional non-geometric information to accurately learn layouts. In conclusion, visual impairment and age may result in reduced perceptual and/or memory processing that makes it difficult to learn layouts without non-geometric visual information.


Cancer stem cells: the development of new cancer therapeutics.
Cancer stem cells (CSCs) are a subpopulation of tumor cells with indefinite proliferative potential that drive the growth of tumors. CSCs seem to provide a suitable explanation for several intriguing aspects of cancer pathophysiology. An explosion of therapeutic options for cancer treatment that selectively target CSCs has been recorded in the recent years. These include the targeting of cell-surface proteins, various activated signalling pathways, different molecules of the stem cell niche and various drug resistance mechanisms. Importantly, approaching cancer research by investigating the pathogenesis of these intriguing cancer cells is increasing the knowledge of the pathophysiology of the disease, emphasizing certain molecular mechanisms that have been partially neglected. The characterization of the molecular phenotype of these cancer stem-like cells, associated with an accurate definition of their typical derangement in cell differentiation, can represent a fundamental advance in terms of diagnosis and therapy of cancer. Preliminary results seem to be promising but further studies are required to define the therapeutic index of this new anticancer treatment. Moreover, understanding the pathogenetic mechanisms of CSCs can expand the therapeutic applications of normal adult stem cells by reducing the risk of uncontrolled tumorigenic stem cell differentiation.


Telmisartan reduces mortality and left ventricular hypertrophy with sympathoinhibition in rats with hypertension and heart failure.
Angiotensin II type 1 receptor (AT1R) blockers have various benefits on hypertension and/or heart failure. We demonstrated that telmisartan (TLM), an AT1R blocker, causes sympathoinhibition by reduction of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) of stroke-prone spontaneously hypertensive rats (SHRSPs). The aim of this study was to determine whether TLM improves survival in rats with hypertension and heart failure. Angiotensin II-infused and salt-loaded SHRSPs were divided into TLM-treated, candesartan cilexetil (CAN)-treated, and control groups. We determined the dose of TLM or CAN with similar depressor effects. We examined survival, urinary norepinephrine excretion (uNE) as a parameter of sympathoexcitation, ROS in the RVLM, and left ventricular (LV) end-diastolic pressure (LVEDP). LV hypertrophy (LVH) was assessed by echocardiography and heart/body weight. Compared with the control group, TLM improved survival to a greater extent than CAN. At 4 weeks after treatment, ROS in the RVLM and uNE were significantly lower in the TLM-treated group than in the CAN-treated group, despite the similar depressor effects. At 8 weeks after the treatments, LVH and LVEDP were attenuated in the TLM-treated group compared with the CAN-treated group. Our results suggest that TLM has the potential to reduce mortality, LVH, and LVEDP and that enhanced sympathoinhibition by reduction of ROS in the RVLM might be one of the mechanisms contributing to the beneficial actions of TLM in a model of rats with severe hypertension and heart failure.


Extracranial carotid stenosis: evidence based review.
Extracranial cerebrovascular disease is one of the most important causes of death and disability worldwide and its treatment is based on clinical and surgical strategies, the latter being performed by conventional or endovascular techniques. The management of stenosis of the carotid bifurcation is mainly aimed at preventing stroke and has been the subject of extensive investigation. The role of clinical treatment has been re-emphasized, but carotid endarterectomy remains the first-line treatment for symptomatic patients with 50% to 99% stenosis and for asymptomatic patients with 60% to 99% stenosis. Stent angioplasty is reserved for symptomatic patients with stenosis of 50% to 99% and at high risk for open surgery due to anatomical or clinical reasons. Currently, the endovascular procedure is not recommended for asymptomatic patients who are able to undergo conventional surgical treatment. Brazil presents a trend similar to that of other countries in North America and Europe, keeping endarterectomy as the main indication for the treatment of carotid stenosis and reserving the endovascular procedure for cases in which there are contraindications for the first intervention. However, we must improve our results by reducing complications, notably the overall mortality rate.


Investigating Viewership of Season 3 of "13 Reasons Why" and the Mental Wellness of Adolescents: Partially Randomized Preference Trial.
A conflicting body of research suggests that additional investigation is needed to understand how globally watched television shows featuring social and mental health issues, such as 13 Reasons Why, might affect adolescents' mental wellness. This study aims to investigate adolescents' viewership of the third season of the Netflix drama 13 Reasons Why (13RW-3) and their engagement with show-related content, paying special attention to mental health outcomes and conversational partners. A panel-based research platform operated by the National Opinion Research Center at the University of Chicago recruited 157 adolescents aged 13 to 17 years from its nationally representative pool of participants. Participants answered questions about how they discussed and learned about social and mental health issues portrayed in 13RW-3 (eg, masculine role pressure and sexual assault) and questions about mental wellness (eg, mental health self-efficacy and depression). After the participants completed the survey (T1), they were directed to either watch 13RW-3 as it aired for the first time (intervention group) or not watch 13RW-3 (control group). Approximately one month later (T2), all the participants were asked to complete the postsurvey. Additional survey questions about conversational partners, information seeking because of watching the show, and use of show-related content were included in the intervention postsurvey. Our sample (N=157) was 52.2% (n=82) female and 54.8% (n=86) White, with a mean age of 14.99 (SD 1.4) years. At T2, viewers of 13RW-3 spoke about suicide significantly more frequently than nonviewers (P=.007). From T1 to T2, viewers increasingly discussed issues explored by 13RW-3 (P=.002), especially suicide, mental health, and bullying. Adolescent viewers were most likely to speak with friends, and parents were the second most commonly named. Two variables emerged as consistent moderators of conversational choices-having depressive symptoms and being impacted by sexual assault. There was no association between conversational frequency and information seeking around social and mental health issues, and neither mental health self-efficacy scores nor masculine role pressure scores significantly differed between viewers and nonviewers at T2. Viewing 13RW-3, a globally watched television show featuring social and mental health issues, led to adolescent conversations and information searches about topics explored by the show. Depressive symptoms and the impact of sexual assault moderated several relationships, guiding participants toward engaging with certain issues and seeking out specific conversational partners. As 13RW-3's stories drove conversations-and story-driven conversations can raise awareness, reduce stigma, shift attitudes, normalize certain behaviors, and strengthen supportive relationships-potential wellness implications for television shows featuring social and mental health issues are considerable.


Characteristics of primary care consultations for musculoskeletal foot and ankle problems in the UK.
Foot and ankle problems are highly prevalent in the general population; however, little is known about the characteristics of those seeking medical assessment for these problems. The objective of this study was to explore the extent and types of musculoskeletal foot and ankle problems in primary care. Consultation data related to musculoskeletal foot and ankle problems in 2006 were extracted from the Consultations in Primary Care Archive (CiPCA), which covers consultations in 12 general practices in North Staffordshire. Data were cross-tabulated by age and gender, and annual consultation prevalence per 10,000 registered persons was calculated. Of the 55,033 musculoskeletal consultations documented in CiPCA in 2006, 4500 (8%) related to foot and ankle problems. The most commonly documented Read term was 'foot pain' (1281 consultations; 28%), followed by 'ankle pain' [451 (10%)]. Most consultations [3538 (79%)] involved non-traumatic conditions. Females accounted for slightly more consultations than males (55 vs 45%), and the highest proportion of consultations involved people aged 45-64 years (36%). The number of consultations per patient ranged from 1 to 11. Annual consultation prevalence was 290 per 10,000 registered persons and increased with age, reaching a peak in the 65- to 74-year age group (411 per 10,000 registered persons). Foot and ankle problems account for a substantial number of consultations in primary care, and most frequently involve non-traumatic conditions. Further research is required to evaluate the factors that influence consultation for foot problems and strategies that general practitioners use to manage these conditions.


Electrochemical label-free methods for ultrasensitive multiplex protein profiling of infectious diseases.
Electrochemical detection methods are the more appropriate detection methods when it comes to the sensitive and specific determination of biomarkers. Biomarkers are the biological targets for disease diagnosis and monitoring. This review focuses on recent advances in label-free detection of biomarkers for infectious disease diagnosis. The current state of the art for rapid detection of infectious diseases and their clinical applications and challenges were discussed. Label-free electroanalytical methods are probably the most promising means to achieve this. We are currently in the early stages of the emerging technology of using label-free electrochemistry of proteins to develop biosensors. To date, antibody-based biosensors have been intensively developed, although many improvements in reproducibility and sensitivity are still needed. Moreover, there is no doubt that a growing number of aptamers and hopefully label-free biosensors based on nanomaterials will soon be used for disease diagnosis and therapy monitoring. And also here in this review article, we have discussed recent developments in the diagnosis of bacterial and viral infections, as well as the current status of the use of label-free electrochemical methods for monitoring inflammatory diseases.


Winners and losers in a world where the high seas is closed to fishing.
Fishing takes place in the high seas and Exclusive Economic Zones (EEZs) of maritime countries. Closing the former to fishing has recently been proposed in the literature and is currently an issue of debate in various international fora. We determine the degree of overlap between fish caught in these two areas of the ocean, examine how global catch might change if catches of straddling species or taxon groups increase within EEZs as a result of protection of adjacent high seas; and identify countries that are likely to gain or lose in total catch quantity and value following high-seas closure. We find that <0.01% of the quantity and value of commercial fish taxa are obtained from catch taken exclusively in the high seas, and if the catch of straddling taxa increases by 18% on average following closure because of spillover, there would be no loss in global catch. The Gini coefficient, which measures income inequality, would decrease from 0.66 to 0.33. Thus, closing the high seas could be catch-neutral while inequality in the distribution of fisheries benefits among the world's maritime countries could be reduced by 50%.


A-type Lamins Form Distinct Filamentous Networks with Differential Nuclear Pore Complex Associations.
The nuclear lamina is a universal feature of metazoan nuclear envelopes (NEs) [1]. In mammalian cells, it appears as a 10-30 nm filamentous layer at the nuclear face of the inner nuclear membrane (INM) and is composed primarily of A- and B-type lamins, members of the intermediate filament family [2]. While providing structural integrity to the NE, the lamina also represents an important signaling and regulatory platform [3]. Two A-type lamin isoforms, lamins A and C (LaA and LaC), are expressed in most adult human cells. Encoded by a single gene, these proteins are largely identical, diverging only in their C-terminal tail domains. By contrast with that of LaC, the unique LaA tail undergoes extensive processing, including farnesylation and endo-proteolysis [4, 5]. However, functional differences between LaA and LaC are still unclear. Compounding this uncertainty, the structure of the lamina remains ill defined. In this study, we used BioID, an in vivo proximity-labeling method to identify differential interactors of A-type lamins [6]. One of these, Tpr, a nuclear pore complex (NPC) protein, is highlighted by its selective association with LaC. By employing superresolution microscopy, we demonstrate that this Tpr association is mirrored in enhanced interaction of LaC with NPCs. Further superresolution studies visualizing both endogenous A- and B-type lamins have allowed us to construct a nanometer-scale model of the mammalian nuclear lamina. Our data indicate that different A- and B-type lamin species assemble into separate filament networks that together form an extended composite structure at the nuclear periphery providing attachment sites for NPCs, thereby regulating their distribution.


A novel small-molecule thienoquinolin urea transporter inhibitor acts as a potential diuretic.
Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small-molecule library for inhibitors of UT-facilitated urea transport. A novel class of thienoquinolin UT-B inhibitors were identified, of which PU-14 had potent inhibition activity on human, rabbit, rat, and mouse UT-B. The half-maximal inhibitory concentration of PU-14 on rat UT-B-mediated urea transport was ∼0.8 μmol/l, and it did not affect urea transport in mouse erythrocytes lacking UT-B but inhibited UT-A-type urea transporters, with 36% inhibition at 4 μmol/l. PU-14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 μmol/l. Subcutaneous delivery of PU-14 (at 12.5, 50, and 100 mg/kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU-14 has a diuretic effect by urea-selective diuresis. Thus, PU-14 or its analogs might be developed as a new diuretic to increase renal fluid clearance in diseases associated with water retention without causing electrolyte imbalance. PU-14 may establish 'chemical knockout' animal models to study the physiological functions of UTs.


The time course of nerve growth factor content in different neuropsychiatric diseases--a unifying hypothesis.
Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradely transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate approach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.


Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study.
Clostridium difficile infection (CDI) is the most frequent cause of health care-associated infectious diarrhea in industrialized countries. The only previous report describing the incidence of health care-associated CDI (HA CDI) in Canada was conducted in 1997 by the Canadian Nosocomial Infection Surveillance Program. We re-examined the incidence of HA CDI with an emphasis on patient outcomes. A prospective surveillance was conducted from 1 November 2004 through 30 April 2005. Basic demographic data were collected, including age, sex, type of patient ward where the patient was hospitalized on the day HA CDI was identified, and patient comorbidities. Data regarding severe outcome were collected 30 days after the diagnosis of HA CDI; severe outcome was defined as an admission to the intensive care unit because of complications of CDI, colectomy due to CDI, and/or death attributable to CDI. A total of 1430 adults with HA CDI were identified in 29 hospitals during the 6-month surveillance period. The overall incidence rate of HA CDI for adult patients admitted to these hospitals was 4.6 cases per 1000 patient admissions and 65 per 100,000 patient-days. At 30 days after onset of HA CDI, 233 patients (16.3%) had died from all causes; 31 deaths (2.2%) were a direct result of CDI, and 51 deaths (3.6%) were indirectly related to CDI, for a total attributable mortality rate of 5.7%. The rates are remarkably similar to those found in our previous study; although we found wide variations in HA CDI among the participating hospitals. However, the attributable mortality increased almost 4-fold (5.7% vs. 1.5%; P<.001).


Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.
DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and isolated and familial forms of conotruncal cardiac defects have been associated with deletions of chromosomal region 22q11.2. This report describes the identification, cloning, and characterization of the human TBX1 gene, which maps to the center of the DiGeorge chromosomal region. Further, we have extended the mouse cDNA sequence to permit comparisons between human and mouse Tbx1. TBX1 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes are transcription factors involved in the regulation of developmental processes. There is 98% amino acid identity between human and mouse TBX1 proteins overall, and within the T-box domain, the proteins are identical except for two amino acids. Expression of human TBX1 in adult and fetal tissues, as determined by Northern blot analysis, is similar to that found in the mouse. Additionally, using 3 'RACE, we obtained a differentially spliced message in adult skeletal muscle. Mouse Tbx1 has been previously shown to be expressed during early embryogenesis in the pharyngeal arches, pouches, and otic vesicle. Later in development, expression is seen in the vertebral column and tooth bud. Thus, human TBX1 is a candidate for some of the features seen in the 22q11 deletion syndrome.


Superior Performance of Teaching and Transplant Hospitals in the Management of Hepatic Encephalopathy from 2007 to 2014.
Background and Aims: Hepatic encephalopathy is a liver disease complication with significant mortality and costs. The aim of this study was to evaluate the relative performance of facilities based on their teaching status and transplant capability by correlating their connections to mortality, cost, and length of stay from 2007 to 2014. Methods: The Nationwide Inpatient Sample database was utilized to collect information on (USA) American patients admitted with a primary diagnosis of hepatic encephalopathy from 2007-2014. Hospitals were placed into one of four categories using their teaching and transplant status. Using regression analysis, mortality, length of stay and cost adjusted rate ratios were calculated. Results: The study revealed that teaching transplant centers had a mortality risk ratio of 0.783 (95% confidence interval (CI): 0.750-0.819, p < 0.001). Blacks had the highest mortality risk ratio, of 1.273 (95%CI: 1.217-1.331, p < 0.001). Furthermore, teaching transplant hospitals had a cost rate ratio of 1.226 (95%CI: 1.214-1.238, p < 0.001) and a length of stay rate ratio of 1.104 (95%CI: 1.093-1.115, p < 0.001). Conclusions: It appears that admission to transplant facilities for hepatic encephalopathy is associated with reduced mortality but increased costs and longer stay independent of transplantation. Moreover, factors impacting black mortality should also be examined more closely.


Influence of Early Enteral Nutrition on Clinical Outcomes in Neurocritical Care Patients With Intracerebral Hemorrhage.
Objective: Early enteral nutrition (EEN) represents the current standard of care for patients treated in general intensive care units (ICU). Specific nutritional recommendations for patients receiving dedicated neurocritical care are not established. This study investigated associations of EEN with clinical outcomes for patients suffering from intracerebral hemorrhage treated at a neurological ICU (NICU). Methods: This retrospective cohort study included patients admitted to the NICU with atraumatic ICH over a 4-year period. Nutritional data, demographic, clinical, radiological, and laboratory characteristics were assessed. EEN was defined as any enteral nutrition within 48 hours after admission. Comparisons were undertaken for patients with EEN vs. those without, further propensity score (PS) matching (caliper 0.2; one: many) was used to account for baseline imbalances. Primary outcome was the modified Rankin Scale (0-3 = favorable, 4-6 = unfavorable) at 12 months, secondary outcomes comprised perihemorrhagic edema (PHE) volume, infectious complications during the hospital stay, and mRS at 3 months, as well as mortality rates at 3 and 12 months. Results: Of 166 ICH-patients treated at the NICU, 51 (30.7%) patients received EEN, and 115 (69.3%) patients received no EEN (nEEN). After propensity score matching, calories delivered from enteral nutrition (EEN 161.4 [106.4-192.3] kcal/day vs. nEEN 0.0 [0.0-0.0], P < 0.001) and the total calories (EEN 190.0 [126.0-357.0] kcal/day vs. nEEN 33.6 [0.0-190.0] kcal/day, P < 0.001) were significantly different during the first 48 h admitted in NICU. Functional outcome at 12 months (mRS 4-6, EEN 33/43 [76.7%] vs. nEEN, 49/64 [76. 6%]; P = 1.00) was similar in the two groups. There were neither differences in mRS at 3 months, nor in mortality rates at 3 and 12 months between the two groups. EEN did not affect incidence of infective complications or gastrointestinal adverse events during the hospital stay; however, EEN was associated with significantly less extent of PHE evolution [maximum absolute PHE (OR 0.822, 95% CI 0.706-0.957, P = 0.012); maximum relative PHE (OR 0.784, 95% CI 0.646-0.952, P = 0.014)]. Conclusion: In our study, EEN was associated with reduced PHE in ICH-patients treated at a NICU. However, this observation did not translate into improved survival or functional outcome at 3 and 12 months.


Effect of simulated weightlessness on the response characteristics of human brain.
In order to systematically investigate the effects of simulated weightlessness on the function state of human brain, 15 degrees head-down tilt (HDT) was used to simulate weightlessness, and the response changes of event-related EEG power spectra, medium-frequency synchronous potentials and slow-waves were examined in the present study. It was found that HDT had characteristic effects on the above EEG responses, suggesting that the effects mainly occurred in the brain's regulatory system, therefore, resulting in changes of the brain function state.


Model of the active site in the blue oxidases based on the ceruloplasmin-plastocyanin homology.
Available sequence information (a total of 650 residues out of about 1,050) of human ceruloplasmin, a blue copper-containing oxidase, has been examined for internal homologies and relationships to other blue proteins. The peptide chain has an evident 3-fold repeat of about 340 residues, and weak evidence for a 6-fold repeat of 170 residues exists. When another method was used to compare the longer sequence with the sequences of small blue proteins, azurins and plastocyanins, a 109-residue-long sequence at the COOH terminus of ceruloplasmin was found to be homologous to the plastocyanins. The alignment obtained was used to construct, on a graphic display, a three-dimensional model of this part of ceruloplasmin by using the coordinates for popular plastocyanin. Deletions and insertions could be accommodated in turns and kinks in the essentially eight-stranded pleated sheet molecule wherein each of the hydrophobic core residues was conserved or conservatively replaced. Eight of the 12 histidine side chains were clustered at or close to the binding site for the blue (type 1) copper. On the assumption that these are copper ligands, a model for the active site of ceruloplasmin containing four copper ions could be constructed in a manner consistent with known spectroscopic and kinetic data. In particular, two of the coppers are close enough (3 A) to form a binuclear center. The positions of the two additional coppers (the fifth and the sixth) in ceruloplasmin are suggested on the basis of the internal homologies.


In Search of the Global East: Thinking between North and South.
Carving up the world into Global North and Global South has become an established way of thinking about global difference since the end of the Cold War. This binary, however, erases what this paper calls the Global East - those countries and societies that occupy an interstitial position between North and South. This paper problematises the geopolitics of knowledge that has resulted in the exclusion of the Global East, not just from the Global North and South, but from notions of globality in general. It argues that we need to adopt a strategic essentialism to recover the Global East for scholarship. To that end, it traces the global relations of IKEA's bevelled drinking glass to demonstrate the urgency of rethinking the Global East at the heart of global connections, rather than separate from them. Thinking of such a Global East as a liminal space complicates the notions of North and South towards more inclusive but also more uncertain theorising.


A machine learning-based linguistic battery for diagnosing mild cognitive impairment due to Alzheimer's disease.
There is a limited evaluation of an independent linguistic battery for early diagnosis of Mild Cognitive Impairment due to Alzheimer's disease (MCI-AD). We hypothesized that an independent linguistic battery comprising of only the language components or subtests of popular test batteries could give a better clinical diagnosis for MCI-AD compared to using an exhaustive battery of tests. As such, we combined multiple clinical datasets and performed Exploratory Factor Analysis (EFA) to extract the underlying linguistic constructs from a combination of the Consortium to Establish a Registry for Alzheimer's disease (CERAD), Wechsler Memory Scale (WMS) Logical Memory (LM) I and II, and the Boston Naming Test. Furthermore, we trained a machine-learning algorithm that validates the clinical relevance of the independent linguistic battery for differentiating between patients with MCI-AD and cognitive healthy control individuals. Our EFA identified ten linguistic variables with distinct underlying linguistic constructs that show Cronbach's alpha of 0.74 on the MCI-AD group and 0.87 on the healthy control group. Our machine learning evaluation showed a robust AUC of 0.97 when controlled for age, sex, race, and education, and a clinically reliable AUC of 0.88 without controlling for age, sex, race, and education. Overall, the linguistic battery showed a better diagnostic result compared to the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and a combination of MMSE and CDR.


Isolated intestinal transplantation for intestinal failure.
Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving. This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center. The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed post-transplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated. Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.


Occupational exposure to pesticides and risk of adult brain tumors.
The authors examined incident glioma and meningioma risk associated with occupational exposure to insecticides and herbicides in a hospital-based, case-control study of brain cancer. Cases were 462 glioma and 195 meningioma patients diagnosed between 1994 and 1998 in three US hospitals. Controls were 765 patients admitted to the same hospitals for nonmalignant conditions. Occupational histories were collected during personal interviews. Exposure to pesticides was estimated by use of a questionnaire, combined with pesticide measurement data abstracted from published sources. Using logistic regression models, the authors found no association between insecticide and herbicide exposures and risk for glioma and meningioma. There was no association between glioma and exposure to insecticides or herbicides, in men or women. Women who reported ever using herbicides had a significantly increased risk for meningioma compared with women who never used herbicides (odds ratio = 2.4, 95% confidence interval: 1.4, 4.3), and there were significant trends of increasing risk with increasing years of herbicide exposure (p = 0.01) and increasing cumulative exposure (p = 0.01). There was no association between meningioma and herbicide or insecticide exposure among men. These findings highlight the need to go beyond job title to elucidate potential carcinogenic exposures within different occupations.


Enzymatic resolution of racemic amines in a continuous reactor in organic solvents.
An enzymatic process has been developed for the continuous production of the pharmaceutically important intermediate (R)-1-aminoindan and of the chiral resolving agent (R)-1-(1-naphthyl)ethylamine. The process consists of the subtilisin catalyzed stereoselective aminolysis of the racemic primary amine with an active ester in organic solvent. The competing nonenzymatic reaction has been suppressed by appropriate choice of solvent and reactant's concentration and by minimizing the time of contact between the amine and the active ester. Subtilisin was immobilized on glass beads and the reaction carried out in a continuous-flow column bioreactor. By using a 450-mL column bioreactor containing 5.7 g of subtilisin immobilized on 570 g of glass beads, 1.6 kg of racemic 1-(1-naphthyl)ethylamine was resolved after 320 h of continuous operation with only a slight loss of the enzymatic activity. During the whole process, the optical purity of the chiral amine eluting from the column was higher than 90%. A facile procedure was developed for separating the unreacted (R)-amine from the (S)-amide and for the recycling of the solvent 3-methyl-3-pentanol and the active ester 2,2,2-trifluoroethyl butyrate.


Anxiety in neurosurgical patients undergoing nonurgent surgery during the COVID-19 pandemic.
The COVID-19 pandemic has forced many countries into lockdown and has led to the postponement of nonurgent neurosurgical procedures. Although stress has been investigated during this pandemic, there are no reports on anxiety in neurosurgical patients undergoing nonurgent surgical procedures. Neurosurgical patients admitted to hospitals in eastern Lombardy for nonurgent surgery after the lockdown prospectively completed a pre- and postoperative structured questionnaire. Recorded data included demographics, pathology, time on surgical waiting list, anxiety related to COVID-19, primary pathology and surgery, safety perception during hospital admission before and after surgery, and surgical outcomes. Anxiety was measured with the State-Trait Anxiety Inventory. Descriptive statistics were computed on the different variables and data were stratified according to pathology (oncological vs nononcological). Three different models were used to investigate which variables had the greatest impact on anxiety, oncological patients, and safety perception, respectively. Because the variables (Xs) were of a different nature (qualitative and quantitative), mostly asymmetrical, and related to outcome (Y) by nonlinear relationships, a machine learning approach composed of three steps (1, random forest growing; 2, relative variable importance measure; and 3, partial dependence plots) was chosen. One hundred twenty-three patients from 10 different hospitals were included in the study. None of the patients developed COVID-19 after surgery. State and trait anxiety were reported by 30.3% and 18.9% of patients, respectively. Higher values of state anxiety were documented in oncological compared to nononcological patients (46.7% vs 25%; p = 0.055). Anxiety was strongly associated with worry about primary pathology, surgery, disease worsening, and with stress during waiting time, as expected. Worry about positivity to SARS-CoV-2, however, was the strongest factor associated with anxiety, even though none of the patients were infected. Neuro-oncological disease was associated with state anxiety and with worry about surgery and COVID-19. Increased bed distance and availability of hand sanitizer were associated with a feeling of safety. These data underline the importance of psychological support, especially for neuro-oncological patients, during a pandemic.


[Isolation and purification of restriction endonuclease BpeI from Bordetella pertussis].
New restriction endonuclease has been isolated from Bordetella pertussis vaccine strain 305 and purified in 1 stage on Sepharose covalently bound with blue dextran. The isolated restrictase has been found capable of breaking down lambda-phag DNA into 7 fragments. According to its specificity, Bpe I is the isoschizomer of Hind III obtained from Haemophilus influenzae strain Rd.


Male-male competition leads to less abundant but more attractive sperm.
Males employ complex strategies to optimize their reproductive success when faced with male-male competition; for instance, they can adjust the ejaculate characteristics. In copulating species, a male may also strategically adjust his ejaculate expenditure according to female quality. Quantifying the relative contribution of ejaculate plasticity in male reproductive success is often difficult, especially when females exert postcopulatory cryptic choice. One way to quantify the functional significance of ejaculate plasticity is offered by mating systems in which the reproductive partners do not meet each other during insemination. In the collembolan Orchesella cincta, males deposit their ejaculates (spermatophores) irrespective of the presence of females. We tested whether Orchesella males adjust spermatophore number when exposed to the presence of another male and whether changes in spermatophore production influence female choice. We found that Orchesella males display plasticity in spermatophore allocation. Males decreased the spermatophore number when exposed to a rival male. Moreover, females preferentially took up spermatophores of males that were exposed to a competitor. The reduction in spermatophore number suggests, besides an adaptive response to the risk of ejaculate removal by rival males, an optimization strategy owing to the costs of more attractive spermatophores.