A study to investigate the relationship between difficult intubation and prediction criterion of difficult intubation in patients with obstructive sleep apnea syndrome.
Obstructive sleep apnea (OSA) syndrome is predisposed to the development of upper airway obstruction during sleep, and it poses considerable problem for anesthetic management. Difficult intubation (DI) is an important problem for management of anesthesia. In this clinical research, we aim to investigate the relationship between DI and prediction criteria of DI in cases with OSA. We studied 40 [OSA (Group O, n = 20) and non-OSA, (Group C, n = 20)] ASA I-II, adult patients scheduled tonsillectomy under general anesthesia. Same anesthetic protocol was used in two groups. Intubation difficulties were assessed by Mallampati grading, Wilson sum score, Laryngoscopic grading (Cormack and Lehane), a line joining the angle of the mouth and tragus of the ear with the horizontal, sternomental distance, and tyromental distance. Demographic properties, time-dependent hemodynamic variables, doses of reversal agent, anesthesia and operation times, and recovery parameters were recorded. Significant difference was detected between groups in terms of BMI, Mallampati grading, Wilson weight scores, Laryngoscopic grading, sternomental distance, tyromental distance, doses of reversal agent, and recovery parameters. OSA patient's DI ratio is higher than that of non-OSA patients. BMI Mallampati grading, Wilson weight scores, Laryngoscopic grading, sternomental distance, and tyromental distance evaluation might be predictors for DI in patients with OSA.


Short-course chemotherapy for extrapulmonary tuberculosis. Nine years' experience.
Short-course chemotherapy with isoniazid and rifampin is well established for pulmonary tuberculosis but not yet for extrapulmonary disease. We report our 9-year experience with short-course chemotherapy in treating 350 patients; 402 extrapulmonary sites were involved. Therapy was largely self-administered with careful monitoring by local public health nurses. Administration of drugs was directly supervised in less than 2% of patients. Short-course chemotherapy with isoniazid and rifampin for 9 months was successful in 95% of patients, equivalent to conventional therapy with two to three drugs for 18 to 24 months. It was found that early drainage and complete debridement of necrotic material in bone lesions enhances healing. Short-course chemotherapy has excellent patient acceptance, short duration, fewer doses, and modest toxicity. Our largely twice-weekly regimen has the additional advantages of reduced cost, fewer doses, and ease of supervision when needed.


Feasibility of pooling annotated corpora for clinical concept extraction.
Availability of annotated corpora has facilitated application of machine learning algorithms to concept extraction from clinical notes. However, it is expensive to prepare annotated corpora in individual institutions, and pooling of annotated corpora from other institutions is a potential solution. In this paper we investigate whether pooling of corpora from two different sources, can improve performance and portability of resultant machine learning taggers for medical problem detection. Specifically, we pool corpora from 2010 i2b2/VA NLP challenge and Mayo Clinic Rochester, to evaluate taggers for recognition of medical problems. Contrary to our expectations, pooling of corpora is found to decrease the F1-score. We examine the annotation guidelines to identify factors for incompatibility of the corpora and suggest development of a standard annotation guideline by the clinical NLP community to allow compatibility of annotated corpora.


Immunohistochemical staining and enzyme activity measurements show myo-inositol-1-phosphate synthase to be localized in the vasculature of brain.
Rabbit anti-bovine myo-inositol-1-phosphate synthase was used to examine the distribution of that enzyme in perfused and immersion-fixed bovine brain and testis. In brain, intense and specific staining was found in the walls of all the vascular elements including cerebral capillaries. The remainder of brain parenchyma exhibited only low levels of background staining. In testis, an organ rich in the enzyme, blood vessels showed no specific staining. Instead, the enzyme was found in the seminiferous epithelium of the seminiferous tubules, perhaps localized in spermatozoa. To confirm the brain finding, the activity of myo-inositol-1-phosphate synthase was measured in bovine brain microvessel preparations and brain pial vessels. In these preparations the activity of the enzyme was found on average to be 7 and 22 times enriched over that in whole brain, respectively. The activities of two other enzymes of inositol metabolism, myo-inosose reductase and myo-inositol-1-phosphatase, were also examined for their distribution in brain. Those enzymes were found to be generally distributed. The surprising finding of a vascular localization of myo-inositol-1-phosphate synthase in brain raises new questions about the mechanism by which myo-inositol is concentrated to such high cellular levels in the principal substance of that organ.


Photodegradation of 4-chloronitrobenzene in the presence of aqueous titania suspensions in different gas atmospheres.
The photocatalytic degradation of 4-chloronitrobenzene (4-CNB) was carried out using Degussa P25 TiO(2) as photocatalyst in three different gas atmospheres: nitrogen, oxygen, and ozone. The total organic carbon (TOC) and inorganic anions including chloride, nitrite, and nitrate anions were measured to monitor the mineralization processes, while the degradation of 4-CNB and the formation of intermediates were followed by liquid chromatography-mass spectrometry (LC/MS). Results showed that the photocatalytic efficiency followed the order of TiO(2)/UV/N(2) < TiO(2)/UV/O(2) < TiO(2)/UV/O(3), which was further proved by evaluating the reaction activities using electron paramagnetic resonance (EPR) spin trapping technique. Chlorine atom, nitro group and hydrogen atom of the benzene ring could be displaced by hydroxyl radical (•OH) leading to the formation of chloride, nitrite (III) anions and a variety of phenols, then the nitrite (III) anions were further oxidized to nitrate (V) anions. 4-Nitrophenol and 5-chloro-2-nitrophenol were identified and quantified in both of the TiO(2)/UV/N(2) and TiO(2)/UV/O(2) processes while no aromatic intermediates were monitored in the process of TiO(2)/UV/O(3).


Trichodermin (12,13-ep-oxy-trichethec-9-en-4β-yl 4-fluoro-benzoate).
IN THE TITLE TRICHODERMIN COMPOUND (SYSTEMATIC NAME: 12,13-ep-oxy-trichothec-9-en-4β-yl 4-fluoro-benzoate), C(22)H(25)FO(4), the five-membered ring displays an envelope conformation, whereas the two six-membered rings show the different conformations, viz. chair and half-chair. As for the seven-membered ring, the dihedral angle between the mean planes formed by the four C atoms of the envelope unit and the three C and one O atoms of the six-membered chair is 68.67 (2)°; these two mean planes are nearly perpendicular to the ep-oxy ring with angles of 87.97 (2)and 88.14 (2)°, respectively.


Dynamics of elastic rods in perfect friction contact.
One of the most challenging and basic problems in elastic rod dynamics is a description of rods in contact that prevents any unphysical self-intersections. Most previous works addressed this issue through the introduction of short-range potentials. We study the dynamics of elastic rods with perfect rolling contact which is physically relevant for rods with a rough surface. Such dynamics cannot be described by the introduction of any kind of potential. We show that, surprisingly, the presence of rolling contact in rod dynamics leads to highly complex behavior even for the evolution of small disturbances.


Total synthesis of norzoanthamine.
Norzoanthamine, an alkaloid isolated from Zoanthus sp., can suppress the loss of bone weight and strength in ovariectomized mice. Norzoanthamine derivatives can also strongly inhibit the growth of P-388 murine leukemia cell lines and human platelet aggregation. However, norzoanthamine's densely functionalized complex stereostructure and scarce availability from natural sources have proved a synthetic challenge. We report the stereoselective total synthesis of norzoanthamine in 41 steps, with an overall yield of 3.5% (an average of 92% yield each step).


Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells.
Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD-deleted adenovirus driven by the Oct-3/4 promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer.


TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies.
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular complications, but the molecular mechanism of action is unknown. We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA. Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two tumour necrosis factor alpha (TNFα) transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly up-regulated leading to increased vascular oxLDL uptake and NFκB-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNFα treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients. Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL, and Arg2 levels.


Therapeutic potential of placenta-derived stem cells for liver diseases: current status and perspectives.
Over the last decade, there has been a growing interest in the human placenta as a unique source of stem cells. The placenta is a fetal organ that is normally discarded following delivery. Therefore, it is readily available as a source of cells without the ethical concerns normally associated with embryonic stem cells. These cells also carry less risk for age- and environmental-related DNA damage. In addition to these practical advantages of placenta-derived cells, amniotic epithelial cells possess unique stem cell-like biological characteristics. In contrast to other parts of the placenta, cells from the amniotic epithelium are derived from pluripotent epiblasts and possess the ability to differentiate into all three germ layers. From a translational perspective, amnion-derived stem cells are very attractive candidates for clinical application. These cells are genetically stable and do not demonstrate tumorigenicity upon transplantation, and may be endowed with immunomodulatory and/or anti-inflammatory properties. These unique characteristics have made amniotic epithelial cells attractive for use as stem cell-based therapies for liver disease. Human and rodent amniotic epithelial cells have already demonstrated their therapeutic efficacy in multiple animal models. Although the detailed mechanism by which the transplanted cells generate a therapeutic effect is not yet totally understood, these dramatic results have generated significant interest for consideration of these amnion-derived stem cells for clinical applications. This review covers recent findings of the therapeutic potential of amnion-derived stem cells for liver diseases, and provides perspectives for future developments.


A -D-fructofuranosidase from Claviceps purpurea.
Evidence suggests that sucrose is the main carbon source for growth of Claviceps spp. in the parasitic condition. The sucrose acts as substrate for an active beta-fructofuranosidase, produced by the fungus, which in the first instance converts the disaccharide into glucose and an oligofructoside. In this way, 50% of the glucose, supplied as sucrose, is made available to the parasite for assimilation. Subsequent action of the enzyme on both sucrose and the oligofructoside leads to the release of more glucose and the formation of additional oligosaccharides. The structures of the main oligosaccharides formed have been elucidated and the interactions of each compound studied. In experiments with purified enzyme in vitro the interaction of the oligosaccharides is rapid but in culture they are assimilated only slowly; in each case some free fructose is liberated. Free fructose is not assimilated in the presence of glucose and, further, inhibits growth at concentrations which might be expected to occur in the parasitic condition. A dual role has been suggested for the enzyme, with sucrose as substrate, in which glucose is made available to the growing parasite, while at the same time transfer of the fructose to form oligosaccharides prevents it from accumulating at inhibitory concentrations. Ultimately, when glucose becomes limiting, the fungus will adapt to fructose assimilation.


The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature.
trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster. Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour.


Bioequivalence requirements in the European Union: critical discussion.
The aim of the present paper is to summarize the revised European Union (EU) Guideline on the Investigation of Bioequivalence and to discuss critically with respect to previous European requirements and present US Food and Drug Administration guidelines its more relevant novelties such as the following: in order to facilitate the development of generic medicinal products, the EU guideline includes the eligibility for Biopharmaceutics Classification System (BCS)-based biowaivers not only for BCS class I drugs but also for class III drugs with tighter requirements for dissolution and excipient composition. The permeability criterion of BCS classification has been substituted with human absorbability, as per the Biopharmaceutical Drug Disposition Classification System. The widening of the acceptance range for C (max) is possible only for highly variable reference products with an additional clinical justification. This scaled widening is carried out with a proportionality constant of 0.760 which is more conservative than the FDA approach and maintains the consumer risk at a 5% level when the intra-subject CV is close to 30%, due to the smooth transition between the scaled and the constant criteria. The guideline allows for the possibility of two-stage designs to obtain the necessary information on formulation differences and variability from interim analyses as a part of the pivotal bioequivalence study, instead of undertaking pilot studies. The guideline also specifies that the statistical analyses should be performed considering all factors as fixed, which has implications in the case of replicate designs.


Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphoma in vitro and in vivo.
Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC50 value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50-200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.


Antibodies to the ciliary membrane of Paramecium tetraurelia alter membrane excitability.
Immobilization of Paramecium followed the binding of antibodies to the major proteins of the ciliary membrane (the immobilization antigens, i-antigens, approximately 250,000 mol wt). Immunoelectron microscopy showed this binding to be serotype-specific and to occur over the entire cell surface. Antibody binding also reduced the current through the Ca-channel of the excitable ciliary membrane as monitored using a voltage-clamp. The residual Ca-current appeared normal in its voltage sensitivity and kinetics. As a secondary consequence of antibody binding, the Ca-induced K-current was also reduced. The resting membrane characteristics and other activatable currents, however, were not significantly altered by the antibody treatment. Since monovalent fragments of the antibodies also reduced the current but did not immobilize the cell, the electrophysiological effects were not the secondary consequences of immobilization. Antibodies against the second most abundant family of proteins (42,000-45,000 mol wt) had similar electrophysiological effects as revealed by experiments in which the Paramecia and the serum were heterologous with respect to the i-antigen but homologous with respect to the 42,000-45,000-mol-wt proteins. Protease treatment, shown to remove the surface antigen, also caused a reduction of the Ca-inward current. The loss of the inward Ca-current does not seem to be due to a drop in the driving force for Ca++ entry since increasing the external Ca++ or reducing the internal Ca++ (through EGTA injection) did not restore the current. Here we discuss the possibilities that (a) the major proteins define the functional environment of the Ca-channel and that (b) the Ca-channel is more susceptible to certain general changes in the membrane.


Phenotypic Variability in a Coinfection With Three Independent Candida parapsilosis Lineages.
The human pathogenic yeast Candida parapsilosis has gained significant importance over the past decades as one of the principal causes of fungal bloodstream infections. Isolates of C. parapsilosis are known to be able to switch between several different colony morphologies in vitro, which are correlated with different cell shapes, altered cell surface properties, and thus different capacities to form biofilms on indwelling medical devices. In a set of six clinical specimens from a single surgery patient yielding stable smooth- as well as crepe-morphology isolates, we investigated the differences between five of them on a phenotypic and genomic level. In contrast to the initial assumption that they were switched forms of a clonal strain, karyotyping and genome sequencing showed that the patient was colonized by at least three distinct linages. Statistical analysis placed these groups distantly across the population of C. parapsilosis. Interestingly the single blood culture isolate was of smooth morphology and matched with an isolate from the patient's nose of similar morphology. Strong variation between the isolates was seen in adhesin-encoding genes, where repeat regions showed significant variation in length and repeat-numbers, most strikingly in HWP1 of the smooth isolates. Although no differences in drug susceptibility were evident, the high phylogenetic distance separating the individual strains highlights the need for testing of multiple colonies in routine practice. The absence of biofilm formation in the blood stream isolate indicates a lack of respective adhesins in the cell wall, in turn pointing toward lack of adhesion as a positively contributing factor for dissemination.


A phase II study of bromocriptine in patients with androgen-independent prostate cancer.
Prolactin is an important physiological regulator of prostate development and growth in preclinical models. In prostate cancer there is strong evidence that prolactin exerts a trophic effect independent of testosterone. In addition, patients with prostate cancer that have an elevated prolactin level correlated with a poorer prognosis. Based on these data, we evaluated the clinical effect of prolactin suppression using bromocriptine in patients with androgen-independent prostate cancer. We conducted an open-label phase II trial of bromocriptine in patients with progressive metastatic prostate cancer. Basal and thyrotropin releasing hormone (TRH)-stimulated prolactin levels were utilized as biological endpoints for determining the dose of bromocriptine. All patients continued to receive complete androgen blockade. Thirteen patients were enrolled (median age 69.5 years). There were no complete or partial responses associated with bromocriptine in 11 of the evaluable patients. The mean duration of bromocriptine treatment was 8.2 weeks (2-14 weeks). One patient had a clinically insignificant decrease in prostate-specific antigen (PSA) and another patient had a 19.9% decrease in PSA with progression of a soft tissue mass. The vast majority of patients (10 of 11) had suppression of prolactin with a bromocriptine dose of 2.5 mg three times a day. One patient required a dose adjustment due to inadequate suppression, with a final maintenance dose of bromocriptine 12.5 mg per day resulting in complete suppression. No serious treatment-related toxicities were observed. The most common complications noted were nausea, headaches, dizziness, and fatigue. Our data showed that 2.5 mg three times per day of bromocriptine suppressed prolactin in 90% of the patients. Furthermore, this dose appears to be well tolerated.


Coping-related variables associated with individual differences in adjustment to cancer.
This study examined relationships between emotional adjustment and a number of coping styles and strategies in people with cancer. Two-hundred eighty-three adults completed measures of positive and negative emotions, subjective ratings of cancer-related symptoms and functional impairment, coping strategies, hope, benefit finding, emotional approach/avoidance, and cancer-related social support. Among the coping strategies, self-blame and behavioral disengagement were consistently associated with poor adjustment, while acceptance and humor were consistently associated with good adjustment. Among the broader measures of coping style, there were associations between poor adjustment and emotional processing, and between good adjustment and hope, benefit finding, and cancer-related social support.


Characterization of OpuA, a glycine-betaine uptake system of Lactococcus lactis.
A Lactococcus lactis glycine-betaine transport system was identified by functional complementation of an Escherichia coli proP proU mutant with a gene library from L. lactis sbsp. cremoris. The cloned locus forms an operon highly homologous to opuA, encoding a glycine-betaine uptake system of Bacillus subtilis. Disruption of opuA in L. lactis abolished protection by glycine-betaine against elevated osmolarity. OpuA belongs to the so-called "ABC transporters" family, which comprise an extracellularly localized substrate-binding protein. In B. subtilis OpuA system, this binding protein is a lipoprotein, attached to the external face of the cytoplasmic membrane by its lipidic moiety. In contrast, in the L. lactis opuA operon, and in other gram-positive homologues as well, a fusion between the gene encoding the integral membrane protein and the substrate-binding protein components gave rise to a hybrid protein presumably attaching the substrate-binding protein to the surface of the cell via its covalent link to the integral membrane component. Mapping of L. lactis opuA transcription start identified one mRNA, more abundant in cells grown at elevated osmolarity. Construction of an opuA-gusA fusion confirmed that opuA transcription is directed by a promoter osmotically inducible in L. lactis. When recombined upstream from a lac transcriptional fusion in the chromosome of E. coli, the opuA promoter appeared as very strong, and only poorly stimulated by elevated osmotic pressure, suggesting the existence of a specific machinery involved in the osmotic signal transduction in L. lactis.


Marsupial anti-Mullerian hormone gene structure, regulatory elements, and expression.
During male sexual development in reptiles, birds, and mammals, anti-Müllerian hormone (AMH) induces the regression of the Müllerian ducts that normally form the primordia of the female reproductive tract. Whereas Müllerian duct regression occurs during fetal development in eutherian mammals, in marsupial mammals this process occurs after birth. To investigate AMH in a marsupial, we isolated an orthologue from the tammar wallaby (Macropus eugenii) and characterized its expression in the testes and ovaries during development. The wallaby AMH gene is highly conserved with the eutherian orthologues that have been studied, particularly within the encoded C-terminal mature domain. The N-terminus of marsupial AMH is divergent and larger than that of eutherian species. It is located on chromosome 3/4, consistent with its autosomal localization in other species. The wallaby 5' regulatory region, like eutherian AMH genes, contains binding sites for SF1, SOX9, and GATA factors but also contains a putative SRY-binding site. AMH expression in the developing testis begins at the time of seminiferous cord formation at 2 days post partum, and Müllerian duct regression begins shortly afterward. In the developing testis, AMH is localized in the cytoplasm of the Sertoli cells but is lost by adulthood. In the developing ovary, there is no detectable AMH expression, but in adults it is produced by the granulosa cells of primary and secondary follicles. It is not detectable in atretic follicles. Collectively, these studies suggest that AMH expression has been conserved during mammalian evolution and is intimately linked to upstream sex determination mechanisms.


Structure comparison of human glioma pathogenesis-related protein GliPR and the plant pathogenesis-related protein P14a indicates a functional link between the human immune system and a plant defense system.
The human glioma pathogenesis-related protein (GliPR) is highly expressed in the brain tumor glioblastoma multiforme and exhibits 35% amino acid sequence identity with the tomato pathogenesis-related (PR) protein P14a, which has an important role for the plant defense system. A molecular model of GliPR was computed with the distance geometry program DIANA on the basis of a P14a-GliPR sequence alignment and a set of 1,200 experimental NMR conformational constraints collected with P14a. The GliPR structure is represented by a group of 20 conformers with small residual DIANA target function values, low AMBER-energies after restrained energy-minimization with the program OPAL, and an average rms deviation relative to the mean of 1.6 A for the backbone heavy atoms. Comparison of the GliPR model with the P14a structure lead to the identification of a common partially solvent-exposed spatial cluster of four amino acid residues, His-69, Glu-88, Glu-110, and His-127 in the GliPR numeration. This cluster is conserved in all known plant PR proteins of class 1, indicating a common putative active site for GliPR and PR-1 proteins and thus a functional link between the human immune system and a plant defense system.


The stereoscopic anisotropy: individual differences and underlying mechanisms.
Observers are more sensitive to variations in the depth of stereoscopic surfaces in a vertical than in a horizontal direction; however, there are large individual differences in this anisotropy. The authors measured discrimination thresholds for surfaces slanted about a vertical axis or inclined about a horizontal axis for 50 observers. Orientation and spatial frequency discrimination thresholds were also measured. For most observers, thresholds were lower for inclination than for slant and lower for orientation than for spatial frequency. There was a positive correlation between the 2 anisotropies, resulting from positive correlations between (a) orientation and inclination thresholds and (b) spatial frequency and slant thresholds. These results support the notion that surface inclination and slant perception is in part limited by the sensitivity of orientation and spatial frequency mechanisms.


In vitro methods for CFTR biogenesis.
Cell-free expression systems provide unique tools for understanding CFTR biogenesis because they reconstitute the cellular folding environment and are readily amenable to biochemical and pharmacological manipulation. The most common system for this purpose is rabbit reticulocyte lysate (RRL), supplemented with either canine pancreatic microsomes or semi-permeabilized cells, which has yielded important insights into the folding of CFTR and its individual domains. A common problem in such studies, however, is that biogenesis of large proteins such as CFTR is often inefficient due to low translation processivity, ribosome stalling, and/or premature termination. The first part of this chapter therefore describes parameters that affect in vitro translation of CFTR in RRL. We have found that CFTR expression is uniquely dependent upon 5'- and 3'-untranslated regions (UTRs) of the mRNA. Full-length CFTR expression can be markedly increased using mRNA lacking a 5'-cap analog (G(5')ppp(5')G), whereas the reverse usually holds for smaller proteins and individual CFTR domains. In the context of the full-length mRNA, translation was further stimulated by the presence of a long 3'-UTR. The second part of this chapter describes CFTR translation in lysates derived from cultured mammalian cells including human bronchial epithelial cells. Unfortunately, mammalian cell-derived lysates showed limited ability to sustain full-length CFTR synthesis. However, they provide a unique opportunity to examine specific CFTR domains (i.e., nucleotide-binding domain 1 and transmembrane domain 1) under conditions that more closely resemble the native folding environment.


Gender, ageing, and injustice: social and political contexts of bioethics.
There has been considerable work in bioethics addressing injustice and gender oppression in the provision of healthcare services, in the interaction between client and healthcare professional, and in allocation of healthcare services within a particular hospital or health service. There remain several sites of continued injustice that can only be addressed adequately from a broader analytical perspective, one that attends to the social and political contexts framing healthcare policy and practice. Feminist bioethicists have a strong track record in providing this kind of analysis. Using current Australian aged care and welfare policy this paper demonstrates some of the ways in which issues of gender, age, and social inequity shape bioethical debate, policy, and practice in the areas of aged care and welfare provision. The author develops an argument that demonstrates the gender injustice underlying health care and welfare policy. This argument recognises the inevitability of human dependency relations, and questions the adequacy of current political theories to address the requirements for full and equal citizenship. The author shows that an adequate analysis of the ethics of aged healthcare depends on sufficient consideration of the social and political context within which healthcare policy is framed and an adequate understanding of human dependency.


Influence of UV exposure time and simulated marine environment on different microplastic degradation.
This study investigated the influence of environmental factors (UV radiation and salinity) in the degradative process of microplastics (MPs). MPs derived from polypropylene (PP), polystyrene (PS), and ethylene-vinyl acetate (EVA) were subjected to accelerated photodegradation while being submerged in distilled water or artificial seawater. Depending on the polymer, changes in surface properties, new functional chemical group formation and oxidative index, and thermal characteristics of samples were observed. After photodegradation experiments, EVA-MPs samples showed an increase in their thermal resistance, besides the changes in their surface. PP-MPs crystallinity index increased upon exposure to UV radiation. PS samples showed a higher carbonyl and hydroxyl index after 30 h of UV exposure. The methodology exploited applies to any location in the world and can be comparable once considering the total ultraviolet index (UVI). The saline medium increases the crystallinity index of PP and EVA-MPs samples and intensifies the formation of new carbonyl and hydroxyl bonds in EVA-MPs samples. The results showed that several environmental factors should be considered in interpreting MPs photodegradation.


Electrochemotherapy of cutaneous metastases of melanoma--a case series study and systematic review of the evidence.
Electrochemotherapy (ECT) is a novel therapeutic option for the treatment of cutaneous and subcutaneous metastases of malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver nonpermeant or poorly permeant chemotherapeutic agents into the cells, increasing local cytotoxicity of anticancer drugs. We compared the clinical effectiveness of ECT as an alternative palliative treatment option for unresectable metastatic lesions of malignant melanoma with a systematic review of reported outcomes. One hundred fifty-eight cutaneous and subcutaneous metastases of nine patients were treated with ECT. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 195 days. In our case series, complete response rate was 23%, and partial response rate was 39%. We observed no change in 30% and progressive disease in 8% of cases. ECT is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma with minimal side effects. Our results provide further data for the growing body of evidence in recently published studies that ECT used for palliation has clinical benefit. The authors have indicated no significant interest with commercial supporters.


Consensus evidence-based guidelines for insulin therapy in patients with type 1 diabetes mellitus as per Indian clinical practice.
Type 1 diabetes mellitus (T1DM) is a chronic disease characterised by auto-immune destruction of insulin producing beta cells of the pancreas. Most cases of T1DM are diagnosed during childhood and adolescence, and it remains the predominant form of the disease in this population. Early identification and treatment of T1DM is important in reducing complications of this form of disease. Because individuals with T1DM lack endogenous insulin production, the current consensus guideline recommends administration of rapid-acting and long-acting analogues for all patients with T1DM to achieve glycaemic goals and reduce insulin-induced side effects like weight gain and hypoglycaemia. It also emphasises that effective use of insulin requires an understanding of various insulin treatment and regimens, sick-day management regarding insulin use, and ability to manage insulin-induced hypoglycaemia to achieve the individualised treatment goals established between the patient, family and diabetes care team. The current consensus guideline has been developed by a panel of experts based on the existing guidelines which aims to provide better clinical practice in the Indian scenario for the management of T1DM.


Efficient in vivo gene transfection by stable DNA/PEI complexes coated by hyaluronic acid.
Plasmid DNA was mixed with polyethyleneimine (PEI) and hyaluronic acid (HA) to afford ternary complexes with negative surface charge regardless of the mixing order. They showed reduced non-specific interactions with blood components. When DNA and PEI were mixed at a high concentration such as that used in in vivo experiments, they soon aggregated, and large particles were formed. On the other hand, pre-addition of HA to DNA prior to PEI effectively diminished the aggregation, and 10% (in volume) of the complexes remained as small particles with a diameter below 80 nm. Those negatively charged small ternary complexes induced a much stronger extra-gene expression in tumor than binary DNA/PEI complex after intratumoral or intravenous injection into the mice bearing B16 cells.


Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice.
Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer's disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.


NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications.
The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.


Coronary artery bypass surgery in women.
Coronary artery disease remains a predominant cause of morbidity and mortality in women. Some studies indicate that there exists a degree of gender bias in the distribution of surgical therapy for coronary artery disease. Numerous studies have demonstrated that female patients have a higher operative mortality rate when undergoing coronary artery bypass surgery. The reasons for this appear to be many including an increased number of comorbid factors in female patients, instability at the time of surgery, and smaller coronary artery size resulting in more technical difficulties and greater risk of incomplete revascularization. Once past the perioperative time period, however, female patients have survival and functional benefits from surgery equivalent to those of men. Increased awareness of clinical manifestations of coronary artery disease in women and careful selection of patients for surgical therapy is warranted.


Hypertrophy of stellate ganglion cells in hypertensive, but not hyperactive, rats.
The dendritic complexity of peripheral autonomic neurons is positively matched with the size of the target they innervate, apparently by trophic interactions with the target (D. Purves, W. D. Snider, and J. T. Voyvodic. Nature Lond. 336: 123-128, 1988). We have asked whether the vascular hypertrophy associated with hypertension is accompanied by dendritic hypertrophy of sympathetic ganglion cells. To do this, we examined the morphology of stellate ganglion cells in the spontaneously hypertensive rat (SHR), its normotensive control Wistar-Kyoto rat (WKY), and two new strains derived from the SHR that independently express the hypertensive phenotype of the SHR (WKHT) and the behavioral hyperactivity present in the SHR (WKHA). Cells were examined by intracellular staining with horseradish peroxidase in in vitro preparations of the ganglia. Carotid arterial wall size was also examined. Significant hypertrophy of both the carotid arterial wall and stellate ganglion cell dendrites was observed in the two hypertensive strains (SHR and WKHT) but not in either of the normotensive strains (WKY and WKHA). This increased total dendritic length of stellate ganglion cells associated with hypertension provides a greater target area for preganglionic innervation that may result in hyperinnervation of these cells.


[Pain syndrome in patients with spastic torticollis before and after the treatment with dysport].
53 patients with the syndrome of spastic torticollis (ST) were examined to assess the nature and dynamics of pain syndrome during the treatment with dysport. The patient's condition assessment was examined before and 1 month after injection of dysport using Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The TWSTRS scale includes 3 subscales (severity of torticollis, disability and pain), each of which consists of the attributes estimated for scores. Observations showed that 1 month after injection of dysport with doses ranging from 500 to 1000 units in the affected muscles of the neck pain intensity decreased by an average of 55%, which has averaged 6,2 points of the TWSTRS pain subscale (p<0,01). Observation confirmed that pain is one of the leading complaints in patients with ST. Pathogenetic basis of the pain formation in this disease and prospects of botulinum toxin therapy in pain syndrome correction were discussed.


Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon.
Mesenchymal stem (progenitor; stromal) cell (MSC) therapy has gained popularity for the treatment of equine tendon injuries but without reports of long-term follow-up. To evaluate the safety and reinjury rate of racehorses after intralesional MSC injection in a large study of naturally occurring superficial digital flexor tendinopathy and to compare these data with those published for other treatments. Safety was assessed clinically, ultrasonographically, scintigraphically and histologically in a cohort of treated cases: 141 client-owned treated racehorses followed-up for a minimum of 2 years after return to full work. Reinjury percentages were compared to 2 published studies of other treatments with similar selection criteria and follow-up. The number of race starts, discipline, age, number of MSCs injected and interval between injury and treatment were analysed. There were no adverse effects of the treatment with no aberrant tissue on histological examination. The reinjury percentage of all racehorses with follow-up (n = 113) undergoing MSC treatment was 27.4%, with the rate for flat (n = 8) and National Hunt (n = 105) racehorses being 50 and 25.7%, respectively. This was significantly less than published for National Hunt racehorses treated in other ways. No relationship between outcome and age, discipline, number of MSCs injected or injury to implantation interval was found. Whilst recognising the limitations of historical controls, this study has shown that MPC implantation is safe and appears to reduce the reinjury rate after superficial digital flexor tendinopathy, especially in National Hunt racehorses. This study has provided evidence for the long-term efficacy of MSC treatment for tendinopathy in racehorses and provides support for translation to human tendon injuries.


An assessment of state level sexual assault prevalence estimates.
The purpose of our research is to compare sexual violence prevalence rates from three sources of state level data. Public health officials, legislators and other policymakers often require state-level sexual assault prevalence estimates to justify funding and rationalize both new and ongoing sexual violence prevention programs, as well as programs for victims. We compared survey design and resulting prevalence rates of the three surveys frequently used at the state level: the Behavioral Risk Factor Surveillance System (BRFSS), the National Violence Against Women Survey (NVAWS) extrapolations, and replications of the NVAWS. Although the specificity of the questions used in the NVAWS provides a clearer picture of the prevalence of sexual assault than the BRFSS questions, the sexual violence module on the BRFSS survey has the advantage that it is used regularly by some states. Currently available female sexual assault prevalence estimates differ widely at the state level but can be used when interpreted with informed caution. The new National Intimate Partner and Sexual Violence Surveillance System holds promise for providing better estimates in the future.


Pancreatic lesions in acute experimental Chagas' disease.
Chagas' disease is an endemic tropical affliction found from southern United States to Argentina. The acute phase of this disease is difficult to study in man because the symptoms are non-specific and most cases require no medical assistance. Experimental models have been developed for sequential studies, and intense parasitism in all organs and tissues, including the pancreas, have been detected in the acute phase. To evaluate the involvement of the pancreas in acute experimental Chagas' disease in a mouse model by histopathological characterization. Ten BALBc mice, about 20 g, injected i.p. with 100 000 forms of the Y strain of Trypanosoma cruzi were used. The animals were sacrificed after 14 days of infection. Fragments of pancreas were processed by conventional paraffin embedding and hematoxylin-eosin staining. Ruptured pseudocysts and release of parasites to the extracellular medium caused by necrosis of acinar and duct cells and foci of fat were the most striking histopathological features of acute Chagasic pancreatitis. Parasitism is the main cause of acute pancreatitis in Chagas' disease.


Spatial distribution and partitioning of polychlorinated biphenyls in Tokyo Bay, Japan.
Spatial distributions and partitioning of polychlorinated biphenyls (PCBs) in Tokyo Bay, Japan, were evaluated by measuring the concentrations of all 209 PCB congeners in surface and bottom waters and bottom sediment at 10 locations. The dissolved + particulate summed congener concentrations (SigmaPCB [sum of the concentrations of all 209 PCB congeners]) in surface and bottom waters ranged from 120 to 1100 pg L(-1) (median 250 pg L(-1)) and from 83 to 910 pg L(-1) (median 230 pg L(-1)), respectively. The concentrations did not statistically differ between the two layers, possibly because of vertical mixing of the water column. SigmaPCB concentrations in sediment ranged from 2.7 to 110 ng g(-1)-dry weight. The highest SigmaPCB concentrations in both water and sediment were found at stations in the northern bay. Logarithms of field-observed organic carbon-normalized partition coefficients (K(OC)) increased linearly as the log octanol-water partition coefficients (K(OW)) increased, up to a log K(OW) of about 6.5, and then decreased for log K(OW) > 6.5 (mostly hexa- and hepta-chlorinated biphenyls). Furthermore, log K(OC) values of congeners having log K(OW) < 6.5 were higher by about 1 than values predicted by a published empirically derived equation, suggesting that application of K(OC) values determined in laboratory experiments with soil or sediment samples to fate prediction models may result in overestimation by about one order of magnitude of the concentrations of PCBs with log K(OW) < 6.5 in the dissolved phase in the water column.


Antibody to hepatitis C is common among patients with alcoholic liver disease with and without risk factors.
Thirty-seven patients with clinically suspected alcoholic liver disease were retrospectively studied for the prevalence of antibody to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. Twenty-four had biopsy-proven cirrhosis. Nineteen had identifiable risk factors for non-A, non-B viral hepatitis, and 18 did not. Five of 19 high-risk (26%) and 6 of 18 low-risk (33%) patients had positive antibody, compared with two of 179 healthy blood donors (p less than 0.01 for either group of alcoholics compared with blood donors). Nine of 11 ELISA-positive patients were also either positive or indeterminable by immunoblot testing. Histologic scores for parameters commonly associated with chronic viral hepatitis were numerically worse among anti-HCV-positive patients, but none reached statistical significance. Clinically, seven of 11 (64%) of anti-HCV-positive patients versus 14 of 26 (54%) anti-HCV-negative patients were Child's class C. Among the 21 Child's class C patients, seven (33%) were anti-HCV-positive versus four of 16 (25%) of Child's class A/B patients. A weak correlation between IgG and ELISA optical density was observed (r = 0.52). We conclude that antibody to hepatitis C by ELISA and immunoblot is common among alcoholics with liver disease even in the absence of known or suspected risk factors for viral hepatitis. Although hepatitis C-positive patients tended to have more severe histologic disease, neither histologic parameters nor clinical findings were adequate to predict antibody seropositivity.


External contamination of antineoplastic drug vials: an occupational risk to consider.
Risk management for workers involved in the handling and preparation of cytotoxic drugs is challenging. This study aims to investigate drug contamination of the exterior surfaces of cytotoxic drug vials. Two batches of commercially available cytotoxic drugs in unprotected vials (ifosfamide, etoposide phosphate and cyclophosphamide) and plastic shrink wrap vials (doxorubicin, cytarabine and busulfan) were tested without removing the flip-off cap or the plastic wrap, and without prewashing. The results showed significant trace amounts of cytotoxic drugs on the exterior surfaces in both unprotected (eg, cyclophosphamide, ifosfamide) and protected plastic shrink wrap vials (eg, cytarabine), indicating that the secondary packaging of protected vials does not systematically prevent exposure to the handlers. These results focus on the need for guidelines to prevent cytotoxic vial contamination and safety recommendations for staff in the handling and storage of these vials.


Validated liquid chromatography separation methods for identification and quantification of anthocyanins in fruit and vegetables: A systematic review.
Food composition data are challenged by data availability and quality. Anthocyanins are the bright colored pigments found in fruits and vegetables with growing evidence for health benefits. For the estimation of anthocyanin content in the foods, it is imperative to find an ideal analytical method. To quantify anthocyanin components, liquid chromatography-based methods are commonly used. This review addresses the variability of liquid chromatography (LC) mass spectrometry (MS) methods for the identification and quantification of anthocyanins. Published studies for all years until February 2020 reporting LC methods for anthocyanins in fruits and vegetables were screened from 7660 studies. Only 29 studies met the eligibility criteria of method type and of these, only 13 studies reported a validated LC method. A wide range of validation parameters were identified including specificity, calibration, stability, and limits of detection. Differences in the sampling amounts for extraction were observed in all of the included studies. The quantification of multiple anthocyanin types without their corresponding analytical standards was observed in eight studies. The included 13 studies used reverse phase liquid chromatography separation with C18 type or similar stationary phases and acidified aqueous or acidified aqueous: organic (usually methanol or acetonitrile) binary gradient mobile phases. Although all of the studies used mass spectrometry for identification, ultraviolet absorbance quantification was often used in conjunction with a photo-diode array (DAD/PDA) detector using reference standards where available. Extraction and preparation of samples remains the key concern for analysis as the oxidative stability of anthocyanins are a major impediment for accurate quantification of the components in foods. This review provides a summary of validated LC methods to assist analysts and nutritionists in the quantification of anthocyanin food components as the nutrient profiles of foods are challenged by the variability of the analytical methods.


Modeling antibiotic resistance to project future rates: quinolone resistance in Escherichia coli.
While the development of resistance to a new antibiotic is expected, the time course and degree of resistance that will develop are uncertain. Some best projections of the future extent of resistance can be highly impactful for activities, such as antimicrobial development, that require significant lead time. We focus on the surge among hospital isolates in fluoroquinolone-resistant Escherichia coli and use data on resistance and consumption to explore and quantify trends in increasing resistance and their relationship to antibiotic use from 2001 to 2007. A mixed-effects logistic regression model produced a good fit to the observed resistance rates during this period in the United States and Europe. The model contained significant effects of time, consumption, and country on developing fluoroquinolone resistance in E. coli. There was a larger projected increase in resistance for high fluoroquinolone-consuming countries projected to 2013: 45% (95% confidence interval [CI]: 38%, 53%) for high consumers vs. 33% (95% CI: 25%, 41%) for low consumers. The model was also used to obtain regional projections of resistance that can be used by local prescribers. In order to better understand and predict trends in antimicrobial resistance, it is vital to implement and expand current surveillance systems.


Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy.
Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab 32 days (range 1-192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1-93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3-99), at the onset of irAE 49.5 mg/L (range 0.3-251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3-18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9-18.8) and median overall survival was not reached. Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.


Simultaneous analysis of the behavioural phenotype, physical factors, and parenting stress in people with Cornelia de Lange syndrome.
Studies into the phenotype of rare genetic syndromes largely rely on bivariate analysis. The aim of this study was to describe the phenotype of Cornelia de Lange syndrome (CdLS) in depth by examining a large number of variables with varying measurement levels. Virtually the only suitable multivariate technique for this is categorical principal component analysis. The characteristics of the CdLS phenotype measured were also analysed in relation to parenting stress. Data for 37 children and adults with CdLS were collected. The type of gene mutation and relevant medical characteristics were measured. Information on adaptive functioning, behavioural problems, the presence of the autistic disorder and parenting stress were obtained through questionnaires and semi-structured interviews with the parents. Chronological age and gender were also included in the analysis. All characteristics measured, except gender, were highly interrelated and there was much variability in the CdLS phenotype. Parents perceived more stress when their children were older, were lower functioning, had more behavioural problems, and if the autistic disorder was present. A new perspective was acquired on the relation between the gene mutation type and medical and behavioural characteristics. In contrast with earlier research the severity of medical characteristics did not appear a strong prognostic factor for the level of development. Categorical principal component analysis proved particularly valuable for the description of this small group of participants given the large number of variables with different measurement levels. The success of the technique in the present study suggests that a similar approach to the characterisation of other rare genetic syndromes could prove extremely valuable. Given the high variability and interrelatedness of characteristics in CdLS persons, parents should be informed about this differentiated perspective.


Coxsackievirus B3-induced cellular protrusions: structural characteristics and functional competence.
Virus-induced alterations in cell morphology play important roles in the viral life cycle. To examine the intracellular events of coxsackievirus B3 (CVB3) infection, green monkey kidney (GMK) cells were either inoculated with the virus or transfected with the viral RNA. Various microscopic and flow cytometric approaches demonstrated the emergence of CVB3 capsid proteins at 8 h posttransfection, followed by morphological transformation of the cells. The morphological changes included formation of membranous protrusions containing viral capsids, together with microtubules and actin. Translocation of viral capsids into these protrusions was sensitive to cytochalasin D, suggesting the importance of actin in the process. Three-dimensional (3D) live-cell imaging demonstrated frequent contacts between cellular protrusions and adjacent cells. Markedly, in spite of an increase in the cellular viral protein content starting 8 h postinfection, no significant decrease in cell viability or increase in the amount of early apoptotic markers was observed by flow cytometry by 28 h postinfection. Comicroinjection of viral RNA and fluorescent dextran in the presence of neutralizing virus antibody suggested that these protrusions mediated the spread of infection from one cell to another prior to virus-induced cell lysis. Altogether, the CVB3-induced cellular protrusions could function as a hitherto-unknown nonlytic mechanism of cell-to-cell transmission exploited by enteroviruses.


Ignorance is not probability.
The distinction between ignorance about a parameter and knowing only a probability distribution for that parameter is of fundamental importance in risk assessment. Brief dialogs between a hypothetical decisionmaker and a risk assessor illustrate this point, showing that the distinction has real consequences. These dialogs are followed by a short exposition that places risk analysis in a decision-theoretic framework, describes the important elements of that framework, and uses these to shed light on Terje Aven's criticism of nonprobabilistic purely "objective" methods. Suggestions are offered concerning a more effective approach to evaluating those methods.


Diagnostic utility of cerebrospinal fluid immunocytochemistry for diagnosis of feline infectious peritonitis manifesting in the central nervous system.
Objectives The aim of the study was to evaluate whether an ante-mortem diagnosis of central nervous system (CNS) feline infectious peritonitis (FIP) is possible via immunocytochemical staining (ICC) of feline coronavirus antigen (FCoV) within macrophages of cerebrospinal fluid (CSF). Methods Prospectively, CSF samples of 41 cats were investigated, including cats with histopathologically confirmed FIP and neurological signs (n = 10), cats with confirmed FIP without CNS involvement (n = 11), cats with neurological signs but another confirmed CNS disease (n = 17), and cats without neurological signs and a disease other than FIP (n = 3). ICC staining of CSF macrophages was performed in all cats. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of CSF ICC were calculated. Results Of 10 samples from cats with CNS FIP, eight had detectable CSF macrophages, seven of which were positive for FCoV. Ten of 11 samples from cats with confirmed FIP without neurological signs had macrophages in the CSF, with all 10 being ICC-positive. In cats with other CNS disorders, 11/17 had macrophages, two of which stained positively. In cats with diseases other than FIP and without neurological disorders, 2/3 revealed macrophages, with one cat showing positive ICC staining. Diagnosis of FIP via CSF ICC had a sensitivity of 85.0% and a specificity of 83.3%. PPV and NPV were 85.0% and 83.3%. Conclusions and relevance CSF ICC is a highly sensitive test for ante-mortem diagnosis of FIP manifesting in the CNS. However, CNS ICC specificity is too low to confirm FIP and the method should only be applied in conjunction with other features such as CSF cytology. CNS ICC could be helpful to discover pre-neurological stages of CNS FIP.


Drought as a trigger of the rapid rise of professional skateboarding in 1970s Southern California.
In 1977 California, authorities responded to an extreme drought with an unprecedented state order to drastically reduce domestic water usage and leave countless newly built swimming pools empty. These curved pools became "playgrounds" for inspired surfers to develop professional vertical skateboarding in the Los Angeles area. Industrial production of polyurethane, and the advent of digital photography, laser printing, and high gloss mass media further contributed to the explosive popularization of skateboarding, creating a global subculture and multibillion-dollar industry that still impacts music, fashion, and lifestyle worldwide. Our interdisciplinary investigation demonstrates that neither the timing nor the location of the origin of professional skateboarding was random. This modern case study highlights how environmental changes can affect human behavior, transform culture, and engender technical innovation in the Anthropocene.


Effect of honeycomb-patterned surface topography on the function of mesenteric adipocytes.
Excessive accumulation of visceral adipose tissue, particularly mesenteric adipose tissue, is one of the most important factors in the pathogenesis of the metabolic syndrome. We previously developed a system for physiologically differentiating rat mesenteric-stromal vascular cells (mSVCs) to mesenteric-visceral adipocytes (mVACs) and are currently implementing various approaches to elucidate the details of the pathophysiology of mVACs. However, there is a critical problem to overcome, namely, that mature mVACs detach from the culture dishes and lose their function after approx. 10 days in culture. Therefore, we examined a culture of mSVCs on self-organized honeycomb-patterned films (honeycomb films) in order to establish a long-term culture for mVACs. The honeycomb films with highly regular porous structures can be prepared under humid casting conditions. These films can be prepared with ease, at a low cost and without any limitations pertaining to the availability of materials for the scaffold. As a result, mSVCs differentiated to mVACs and maintained their function for the secretion of adiponectin on the honeycomb films for at least 40 days. In addition, we investigated the influence of the pore size of the honeycomb films on mVAC behavior. We found that a honeycomb film with a pore size of 20 μm showed the highest mVAC function and optimum size for the long-term culture of mVACs. Thus, we established a long-term culture system for mVACs using the honeycomb films. We believe that this culture system will contribute to the understanding of the pathophysiology of mVACs and to the evaluation of drug candidates for the metabolic syndrome.


Evaluation of the in vitro and in vivo performance of two sustained-release lithium carbonate matrix tablets. Effect of different diets on the bioavailability.
Two sustained-release (SR) lithium carbonate (Li) matrix tablets, which use a hydrophilic (HP) matrix of hydroxypropylmethylcellulose (Methocel 4K MP) and a lipid (L) matrix of hydrogenated castor oil (Cutina HR) as sustaining agents, have been studied. In vitro performance through dissolution tests in different media was established. The L and HP formulations were affected by the composition of the dissolution media, and liberation was complete in 8 hr using a variable-pH medium that simulates the gastrointestinal (Gl) pH. Liberation was better described by the diffusional model of the square root of time for the L matrix and by zero-order kinetics for the HP matrix. Absolute bioavailability (BA) and food-induced changes on BA of both formulations were studied. The in vivo study design was a 4 x 4 Latin square involving 12 subjects who received two tablets of a 300-mg dose of SR formulations while fasting or with a standardized normal, high-fat, or high-fat/high-protein meal. The results for both formulations showed no differences in the disposition parameters and mean residence time when the tablets were administered with any type of diet. Changes in rate of absorption were found when both types of tablets were administered with any class of diet. The analysis of the ratio Cmax/AUC (area under the curve) evidenced that changes in Cmax were attributable to a higher rate of absorption for the HP matrix and to a higher amount absorbed for the L matrix. In the last, high-fat and high-fat/high-protein diets produced higher AUCs than under fasting condition. The SR Li tablets formulated with hydrogenated castor oil were affected more by high-fat food, probably because of the increase of pancreatic and biliary secretions promoted by the meal, which would affect the matrix itself. The HP matrix was also affected, but to a lesser extent. The magnitude of the change in Cmax observed with this matrix probably is not important from a clinical point of view. Absolute BA was very low for the lipid matrix; in addition, since it is more seriously affected by food, probably it is not a good choice for a drug such as lithium. The in vivo behavior of the HP matrix makes it advisable to invest in efforts to achieve increased BA. Comparing in vitro and in vivo results, the focus should be achieving sustained, but complete, in vitro liberation in not more than 3 hr, with simulation of the transit time through the stomach and small bowel since lithium ion is only absorbed to this point.


[Cell therapy of critical lower limb ischemia (problems and prospects)].
Critical limb ischemia is a syndrome that combines several peripheral artery diseases with different ethiology and pathogenesis but with similar prognosis, high morbidity and mortality. Possibility of surgical and conservative treatment of critical limb ischemia almost completely exhausted. Some hopes have arisen due to progress in cell technology. The article provides a critical analysis of pathogenic prerequisites of stem/progenitor cells for the treatment of patients with a critical limb ischemia in detail the basic results of preclinical and clinical studies on the safety and efficacy of cell technology. Unsolved problems and prospects of practical application are also discussed.


Solution structure of Eps15's third EH domain reveals coincident Phe-Trp and Asn-Pro-Phe binding sites.
Eps15 homology (EH) domains interact with proteins involved in endocytosis and signal transduction. EH domains bind to Asn-Pro-Phe (NPF) consensus motifs of target proteins. A few EH domains, such as the third EH domain (EH(3)) of human Eps15, prefer to bind Phe-Trp (FW) sequences. The structure of EH(3) has been solved by nuclear magnetic resonance (NMR) spectroscopy and is the first of an FW- and NPF-binding EH domain. Both FW and NPF sequences bind in the same hydrophobic pocket as shown by heteronuclear chemical shift mapping. EH(3) contains the dual EF-hand fold characteristic of the EH domain family, but it binds calcium with high affinity in the first EF-hand rather than the usual coordination in the second EF-hand. Point mutations were designed based on differences in the EH(3) and the second EH domain (EH(2)) of human Eps15 that alter the affinity of the domains for FW or NPF motif peptides. Peptides that mimic binding sites in the potential EH(3) targets Rab, synaptojanin, and the cation-dependent mannose 6-phosphate receptor were used to explore wild-type and mutant affinities. Characterization of the structure and binding properties of an FW- and NPF-binding EH domain and comparison to an NPF-specific EH domain provide important insights into the mechanisms of EH domain ligand recognition.


Recycling of the dense-core vesicle membrane protein phogrin in Min6 beta-cells.
Phogrin (IA2-beta) is an integral membrane protein of dense-core vesicles in neuroendocrine cells. We have examined the recycling of endogenous phogrin following exocytosis in insulin secreting Min6 beta-cells by monitoring stimulus dependent-uptake of antibodies directed against the lumenal domain of the protein. While low levels of internalized phogrin accumulated in LAMP1-positive lysosomes, more than 35% of internalized phogrin recycled back to an insulin-positive compartment and could return to the cell surface during a second exocytic stimulation. The recycling phogrin transited a syntaxin 6-positive compartment but did not appear to go through the TGN38-positive trans Golgi network. The results suggest a model in which secretory membrane components can recycle from the endosomal system to immature secretory granules without interaction with the major portion of the TGN.


The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.
We conducted a systematic examination of the experience of delirium in a sample of 154 hospitalized patients with cancer. Patients all met DSM-IV criteria for delirium and were rated with the Memorial Delirium Assessment Scale as a measure of delirium severity, phenomenology, and resolution. Of the 154 patients assessed, 101 had complete resolution of their delirium and were administered the Delirium Experience Questionnaire (DEQ-a face-valid measure that assesses delirium recall and distress related to the delirium episode). Spouse/caregivers and primary nurses were also administered the DEQ to assess distress related to caring for a delirious patient. Fifty-four (53.5%) patients recalled their delirium experience. Logistic-regression analysis demonstrated that short-term memory impairment (odds ratio [OR] = 38.4), delirium severity (OR = 11.3), and the presence of perceptual disturbances (OR = 6.9) were significant predictors of delirium recall. Mean delirium-related distress levels (on a 0-4 numerical rating scale of the DEQ) were 3.2 for patients who recalled delirium, 3.75 for spouses/caregivers, and 3.09 for nurses. Logistic-regression analysis demonstrated that the presence of delusions (OR = 7.9) was the most significant predictor of patient distress. Patients with "hypoactive" delirium were just as distressed as patients with "hyperactive" delirium. Karnofsky Performance Status (OR = 9.1) was the most significant predictor of spouse/caregiver distress. Delirium severity (OR =5.2) and the presence of perceptual disturbances (OR =3.6) were the most significant predictors of nurse distress. In conclusion, a majority of patients with delirium recall their delirium as highly distressing. Delirium is also a highly distressing experience for spouses/caregivers and nurses who are caring for delirious patients. Prompt recognition and treatment of delirium is critically important to reduce suffering and distress.


Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists.
As crucial members of the G-protein coupled receptor (GPCR) superfamily, alpha (1)-adrenergic receptors (alpha(1)-ARs) are recognized to intervene the actions of endogenous catecholamines such as norepinephrine and epinephrine. So far three distinct alpha(1)-AR subtypes, alpha(1A), alpha(1B) and alpha(1D), have been characterized by functional analysis, radio-ligand binding and molecular biology studies. The alpha(1)-ARs are of therapeutic interest because of their distinct and critical roles in many physiological processes, containing hypertension, benign prostatic hyperplasia, smooth muscle contraction, myocardial inotropy and chronotropy, and hepatic glucose metabolism. Accordingly, designing subtype-selective antagonists for each of the three alpha(1)-AR subtypes has been an enthusiastic region of medicinal research. Even though a large number of studies on GPCRs have been conducted, understanding of how known antagonists bind to alpha(1)-ARs still remains sketchy and has been a serious impediment to search for potent and subtype-selective alpha(1)-AR antagonists because of the lack of detailed experimental structural knowledge. This review deliberates the simulation of alpha(1)-ARs and their interactions with antagonists by using ligand-based (pharmacophore identification and QSAR modeling) and structure-based (comparative modeling and molecular docking) approaches. Combined with experimental data, these computational attempts could improve our understanding of the structural basis of antagonist binding and the molecular basis of receptor activation, thus offering a more reasonable approach in the design of drugs targeting alpha(1)-ARs.


Using genomics to guide seed-sourcing at the right taxonomical level for ecological restoration projects: The complex case of Carex bigelowii s.lat. in Norway.
There is a growing demand for ecological restoration using suitable seeds following international standards or national legal demands for local seed-sourcing. However, before selecting the appropriate geographic origin of seeds, it is vital to explore taxonomic complexity related to the focal taxa. We used ddRAD-seq to screen genomic diversity within Carex bigelowii s.lat. focussing on Norway. This species complex is considered a candidate for seeding, but presents considerable morphological, ecological, and genetic variation. The genetic structure of 132 individuals of C. bigelowii s.lat., including Carex nigra as an outgroup, was explored using ordinations, clustering analyses, and a genetic barrier algorithm. Two highly divergent clusters were evident, supporting the recognition of two taxonomic units "C. dacica" and C. bigelowii "subsp. bigelowii". Previously defined seed-sourcing regions for C. bigelowii s.lat. did not consider the known taxonomic complexity, and therefore interpreted the overall genetic structure as seed-sourcing regions, not taxa. We estimated genetic neighborhood sizes within each taxon to be 100-150 km and 300 km, respectively, indicating species-specific delimitations of local seed-sourcing regions. Frequent hybrids, local genetic distinctiveness, and suggested ecotypes add complexity to the discussed seed-sourcing regions. Our results show how genomic screening of diversity and structure in a species complex can alleviate the taxonomic impediment, inform practical questions, and legal requirements related to seed-sourcing, and together with traditional taxonomic work provide necessary information for a sound management of biodiversity.


The suitability of FISH chromosome painting and ESR-spectroscopy of tooth enamel assays for retrospective dose reconstruction.
A comparative analysis of two groups of highly irradiated victims was carried out in order to evaluate the suitability of two assays for retrospective dose assessment: late translocations and electron spin resonance (ESR) dosimetry. The first group comprised 24 subjects who exhibited acute radiation syndrome (ARS) due to overexposure as a result of nuclear submarine accidents during the period 1961-1985. Their grades of ARS and individual doses were ascertained by Navy physicians who carried out primary examinations and treatment of the exposed seamen. Cytogenetic analyses were made 16-40 y after their accidents. During medical treatment seven tooth samples were collected for ESR analysis from this group. The second group consisted of ten highly irradiated men from the Chernobyl accident. Comparison was made between estimates of their average whole-body penetrating radiation doses derived from several biological parameters. In three cases ESR measurements on tooth enamel from this group were also made. Retrospective dosimetry using FISH translocations was attempted 10-13 y later. Yields of late translocations were in good agreement with initially estimated doses and with doses obtained by ESR spectroscopy analysis of tooth enamel long after exposure. It was concluded that both persisting stable translocations and ESR spectroscopy signals are suitable with similar efficiencies for retrospective biodosimetry after acute whole-body exposure.


Engineering the synthesis of silica-gold nano-urchin particles using continuous synthesis.
Compared to freestanding nanoparticles, supported nanostructures typically show better mechanical stability as well as ease of handling. Unique shapes such as core-shells, raspberries and crescents have been developed on supported materials to gain improved chemical and optical properties along with versatility and tunability. We report the formation of hyper-branched gold structures on silica particles, silica-gold nano-urchin (SGNU) particles. Kinetic control of crystallization, fast mass transfer as well as a bumped surface morphology of the silica particles are important factors for the growth of gold branches on the silica support. Using a microfluidic platform, continuous synthesis of SGNUs is achieved with increased reaction rate (less than 12 min of residence time), better controllability and reproducibility than that obtained in batch synthesis. The hyper-branched gold structures display surface-enhanced Raman scattering (SERS).


Pilot Study of Patient-Reported Outcomes in Patients With Esophageal Cancer After Esophagectomy.
Patient-reported outcomes (PROs) are critical measures of patient well-being after esophagectomy. In this pilot study, we assessed PROs before and after esophagectomy using the Patient Reported Outcomes Measurement Information System (PROMIS) to assess patient recovery after surgery. We prospectively collected PROMIS dyspnea severity, physical function, and pain interference measures from patients with esophageal cancer undergoing esophagectomy (2017-2020). We merged these data with our institutional Society of Thoracic Surgery esophagectomy database. We used linear mixed-effect multivariable models to assess changes in PROMIS scores (least square mean [LSM] differences) preoperatively and postoperatively at 1 and 6 months. The study included 112 patients undergoing esophagectomy. Pain interference, physical function, and dyspnea severity scores were significantly worse 1 month after surgery. While physical function and dyspnea severity scores returned to baseline 6 months after surgery, pain interference scores remained persistently worse (LSM difference, 2.7 ± 2.5; P = .036). PROMIS scores were further assessed among patients undergoing transhiatal esophagectomy compared with transthoracic esophagectomy. Physical function and dyspnea severity scores were similar between the groups at each assessment. However, pain interference scores were persistently better among patients undergoing THE at both 1 month (LSM difference, 6.5 ± 5.1; P = .013) and 6 months after surgery (LSM difference, 5.2 ± 3.9; P = .008). This pilot study assessing PROMIS scores after esophagectomy for cancer reveals that pain is a persistently reported symptom up to 6 months after surgery, particularly among patients receiving transthoracic esophagectomy.


Exploring the Contribution of Proprioceptive Reflexes to Balance Control in Perturbed Standing.
Humans control balance using different feedback loops involving the vestibular system, the visual system, and proprioception. In this article, we focus on proprioception and explore the contribution of reflexes based on force and length feedback to standing balance. In particular, we address the questions of how much proprioception alone could explain balance control, and whether one modality, force or length feedback, is more important than the other. A sagittal plane neuro-musculoskeletal model was developed with six degrees of freedom and nine muscles in each leg. A controller was designed using proprioceptive reflexes and a dead zone. No feedback control was applied inside the dead zone. Reflexes were active once the center of mass moved outside the dead zone. Controller parameters were found by solving an optimization problem, where effort was minimized while the neuro-musculoskeletal model should remain standing upright on a perturbed platform. The ground was perturbed with random square pulses in the sagittal plane with different amplitudes and durations. The optimization was solved for three controllers: using force and length feedback (base model), using only force feedback, and using only length feedback. Simulations were compared to human data from previous work, where an experiment with the same perturbation signal was performed. The optimized controller yielded a similar posture, since average joint angles were within 5 degrees of the experimental average joint angles. The joint angles of the base model, the length only model, and the force only model correlated weakly (ankle) to moderately with the experimental joint angles. The ankle moment correlated weakly to moderately with the experimental ankle moment, while the hip and knee moment were only weakly correlated, or not at all. The time series of the joint angles showed that the length feedback model was better able to explain the experimental joint angles than the force feedback model. Changes in time delay affected the correlation of the joint angles and joint moments. The objective of effort minimization yielded lower joint moments than in the experiment, suggesting that other objectives are also important in balance control, which cause an increase in effort and thus larger joint moments.


Communications: Electron polarization critically stabilizes the Mg2+ complex in the catalytic core domain of HIV-1 integrase.
In this paper, we present a detailed dynamics study of the catalytic core domain (CCD) of HIV-1 integrase using both polarized and nonpolarized force fields. The numerical results reveal the critical role of protein polarization in stabilizing Mg(2+) coordination complex in CCD. Specifically, when nonpolarized force field is used, a remarkable drift of the Mg(2+) complex away from its equilibrium position is observed, which causes the binding site blocked by the Mg(2+) complex. In contrast, when polarized force field is employed in MD simulation, HIV-1 integrase CCD structure is stabilized and both the position of the Mg(2+) complex and the binding site are well preserved. The detailed analysis shows the transition of alpha-helix to 3(10)-helix adjacent to the catalytic loop (residues 139-147), which correlates with the dislocation of the Mg(2+) complex. The current study demonstrates the importance of electronic polarization of protein in stabilizing the metal complex in the catalytic core domain of HIV-1 integrase.


Grief as a predictor of long-term risk for suicidal ideation and attempts of parentally bereaved children and adolescents.
Although children who experience the death of a parent have a heightened risk of suicidality, the long-term associations between grief and suicidality among bereaved youth have yet to be examined. Research is needed to test the specific aspects of grief associated with suicidality, after controlling for other risk factors, in this population. Grief and covariates, including age, gender, parental cause of death, time since parental death, depression, anxiety, internalizing problems, posttraumatic stress symptoms, and child treatment involvement, were assessed at baseline, 6-year, and 15-year follow-ups in a sample of 244 parentally bereaved youth aged 8-16 years. Utilizing multiple grief measures, a bifactor approach was used to identify a general factor and two uncorrelated specific factors: Intrusive Grief Thoughts and Social Detachment/Insecurity. Suicidal thoughts and attempts were assessed at both follow-ups. The Intrusive Grief Thoughts specific factor had a prospective nonlinear association with suicidality at both follow-ups after controlling for all baseline covariates. The nonlinear relation consisted of a large effect, OR > 73 (using the rescaled scores), on the increased risk of suicidality from low to moderate levels of intrusive grief, with no association from moderate to high levels. At 6-year follow-up, the specific Social Detachment/Insecurity factor was significantly associated with suicidality after controlling for covariates. Specific grief factors assessed at different points were associated with suicidal thoughts or attempts among parentally bereaved youth. These findings highlight the significance of specific aspects of child and adolescent grief that have implications for the development of upstream suicide prevention services.


Factors Influencing Married Immigrant Women's Perceived Health Status: The National Survey of Multicultural Families 2012.
The purpose of this study was to investigate factors that influence married female immigrants' perceived health status. This study was a retrospective review of dataset from the 2012 National Multicultural Family Survey in Korea. Data were analyzed using descriptive statistics, t-tests, an analysis of variance (ANOVA), Pearson correlation analysis, and multiple regression with the data of 3,014 married female immigrants. Multiple regression analysis showed that demographic factors (age, education level, nationality, period of residency in Korea, and residential area), socio-economical factors (monthly family income, employment, support from the government for basic living, and Medicaid), social support factors (marital conflict, satisfaction with family relationships, some one to talk about self or family matters, meeting with homeland friend, and participation in community meeting), and immigration factors (life satisfaction, experience of social discrimination, and difficulties with living and using medical care) were associated with perceived health status. It is important to pay closer attention to immigrant women who have low economic status, less social support, experience difficulties with living in Korea and using medical care. An effective support system for this population should be developed in order to help them successfully transition.


Assessment of Female Medical Students' Interest in Careers in Cardiothoracic Surgery.
Although over half of medical students are females, women comprise only 21% of cardiothoracic (CT) surgery residency applicants and 5% of the CT workforce. We sought to gain insight into female medical students' perceptions of CT surgery and identify targets to increase interest. A 33-question survey queried career selection factors, perceptions of CT surgery, and ways to increase interest in the field. Responses were stratified by sex and preclinical versus clinical years. Women at 13 US medical schools were compared to men at a Midwest medical school. Surveys were distributed to approximately 4400 women and were completed by 372 (8.5%) women. Comparison surveys were distributed to approximately 170 preclinical men and were completed by 98 (57.6%) men. Preclinical woman had broad interests, whereas clinical women were more interested in primary care (p = 0.0124). Intellectual interest and lifestyle were important in specialty selection for men and women (91% versus 90%; 78% versus 86%). Although preclinical men valued perceived prestige and salary significantly more than preclinical women (39% versus 20%, p = 0.0014; 64% versus 48%, p = 0.0173), preclinical women valued caring for specific ethnicities and addressing health disparities significantly more than preclinical men (26% versus 15%, p = 0.0173; 53% versus 33%, p = 0.0019). Making family plans was cited by 83% of women as difficult if they choose to become a CT surgeon. Women thought that attaining their career interests and life goals (76%) or access to female CT surgery mentors (63%) would make the field more appealing. Over 70% of preclinical women were interested in shadowing a CT surgeon. Of these women, 12% attempted to shadow. Although baseline interest in CT surgery is low among women, there are many targets for increasing interest especially during preclinical years. Residency programs have the opportunity to entice women to the field by addressing their priorities of lifestyle, family planning, and addressing health disparities.


Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice.
Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. We studied mice with disruptions in Nr0b2 (called small heterodimer partner [SHP]-null mice), betaine-homocysteine S-methyltransferase (Bhmt), or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (National Institute on Alcohol Abuse and Alcoholism binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%) or high-fat diets (60%). Serum and livers were collected during a 24-hour light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative polymerase chain reaction, immunoblot, and chromatin immunoprecipitation assays. SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1. Expression of Bhmt and cystathionine γ-lyase was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control, but not SHP-null, mice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice. Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1.


[Experimental endolymphatic hydrops. Biochemical data in the guinea pig].
The electrochemical and osmotic composition of the inner ear fluids has been studied during experimental endolymphatic hydrops in guinea pig. The data showed that the modifications of the electrochemical composition of endolymph has been detected only after more than 2 weeks after the hydrops induction. The endocochlear potential, the K and Cl concentrations, and the osmolality progressively decreased between 6 and 9 weeks of hydrops. The longitudinal gradients disappeared. After 24 weeks of hydrops, the endocochlear potential was 50% of the initial value whereas the K and Cl concentrations and the osmolality were higher than that measured at 9 weeks but remained lower than contralateral, normal values. These results suggest that the alterations of the electrochemical and osmotic composition of endolymph that were observed during the evolution of experimental endolymphatic hydrops in guinea pig are related to an alteration of the permeabilities of the Reissner's membrane induced by an increase of hydrostatic pressure.