Adenotonsillectomy for sleep-disordered breathing in a predominantly obese pediatric population.
To determine the efficacy of adenotonsillectomy (T&A) in the treatment of pediatric sleep-disordered breathing, and to determine the natural history in untreated children. The charts of children aged 1-12 who underwent polysomnography (PSG) between 1/2006 and 6/2009 were reviewed to identify children with positive studies. Children not treated by T&A were recruited and matched by age, time since initial PSG, and apnea-hypopnea index (AHI) to children who underwent T&A. All participants were evaluated by a clinical assessment score (CAS-15), follow-up PSG, and the Child Behavior Checklist (CBCL). Sixteen matched pairs completed the study. Ten (63%) T&A patients were overweight or obese compared with 14 (88%) untreated patients. There was a greater median improvement in AHI in the surgical group compared to the nonsurgical group (10.3 vs. 6.5, p=0.044). Although the T&A children were more likely to have a follow-up AHI<5 (81% vs. 69%) and <1 (44% vs. 25%), these results were not significant. The T&A group had significantly lower mean (SD) scores on the CAS-15 [8.9(6.1) vs. 29.4(16.2), p<0.001] and the CBCL total problem score [43.9(8.7) vs. 58.9(13.0), p<0.001]. Younger age at presentation (rho=-0.76, p<0.001), initial AHI (0.87, p<0.001), and initial AI (0.63, p=0.05) were correlated with change in AHI among T&A subjects. T&A was more effective in reducing AHI than no surgery. Median AHI improved in the nonsurgical group, and 4/16 (25%) untreated patients were cured (AHI<1).


Anti-adhesion molecule therapy as an interventional strategy for autoimmune inflammation.
Functional inactivation of leukocyte adhesion molecules has been used to intervene in the development of tissue injury in experimental models of postperfusion infarction as well as autoimmune inflammation. We investigated the use of humanized monoclonal antibodies (mAb) against CD18 in the treatment of five patients with vasculitic tissue injury sufficient to threaten infarction or gangrene. The treatment was monitored in three ways: (i) whole-body gamma camera scintiscanning of autologous indium-labeled PMN, (ii) an index of the therapeutic inhibition of adhesion derived from comparison pre, during, and post mAb treatment of the ability of patients' PMN to be aggregated after activation by fMLP, and (iii) flow cytometric analysis of PMN CD18 expression. Four of five patients given anti-CD18 at 20 mg/day for up to 3 weeks showed prompt clinical improvement, with healing of the ulceration and restoration of limb function within 4 weeks, which was sustained. The fifth patient, who was not doing well clinically, decided to withdraw from all active treatment: at autopsy there was no evidence of the underlying vasculitis evident pretreatment. Our findings suggest that anti-adhesion molecule treatment might be an effective immediate treatment in severe vasculitis especially when tissue viability is threatened by progressive infarction and/or development of gangrene.


A cosmid for selecting genes by complementation in Aspergillus nidulans: Selection of the developmentally regulated yA locus.
We constructed a 9.9-kilobase cloning vector, designated pKBY2, for isolating genes by complementation of mutations in Aspergillus nidulans. pKBY2 contains the bacteriophage lambda cos site, to permit in vitro assembly of phage particles; a bacterial origin of replication and genes for resistance to ampicillin and chloramphenicol, to permit propagation in Escherichia coli; the A. nidulans trpC(+) gene, to permit selection in Aspergillus; and a unique BamHI restriction site, to permit insertion of DNA fragments produced by digestion with restriction endonucleases BamHI, BglII, Mbo I, or Sau3A. We used this cosmid to form a quasirandom recombinant DNA library containing 35- to 40-kilobase DNA fragments from a wild-type strain of A. nidulans. DNA from this library transformed a yellow-spored (yA(-)) pabaA(-)trpC(-)Aspergillus strain (FGSC237) to trpC(+) at frequencies of approximately 10 transformants per mug of DNA. Three of approximately 1000 trpC(+)pabaA(-) colonies obtained were putative yA(+) transformants, because they produced wild-type (green) spores. DNA from each of the green-spored transformants contained pKBY2 sequences and DNA from two transformants transduced E. coli to ampicillin resistance following treatment in vitro with a lambda packaging extract. The cosmids recovered in E. coli had similar restriction patterns and both yielded trpC(+) transformants of A. nidulans FGSC237, 85% of which produced green spores. Several lines of evidence indicate that the recovered cosmids contain a wild-type copy of the yA gene.


High minimum inhibitory concentration of imipenem as a predictor of fatal outcome in patients with carbapenem non-susceptible Klebsiella pneumoniae.
Carbapenem resistance in Klebsiella pneumoniae is important because of its increasing prevalence and limited therapeutic options. To investigate the clinical and microbiological characteristics of patients infected or colonized with carbapenem non-susceptible K. pneumoniae (CnsKP) in Taiwan, we conducted a retrospective study at Taipei Veterans General Hospital from January 2012 to November 2013. Carbapenem non-susceptibility was defined as a minimum inhibitory concentration (MIC) of ≥2 mg/L for imipenem or meropenem. A total of 105 cases with CnsKP were identified: 49 patients with infection and 56 patients with colonization. Thirty-one isolates had genes that encoded carbapenemases (29.5%), including K. pneumoniae carbapenemase (KPC)-2 (n = 27), KPC-3 (n = 1), VIM-1 (n = 1) and IMP-8 (n = 2). The in-hospital mortality among patients with CnsKP was 43.8%. A MIC for imipenem ≥16 μg/mL, nasogastric intubation and Acute Physiology and Chronic Health Evaluation II score were independent risk factors for in-hospital mortality for all patients with CnsKP. A MIC for imipenem ≥16 μg/mL was also an independent risk factor for 14-day mortality in patients with CnsKP. In conclusion, a positive culture for CnsKP was associated with high in-hospital mortality. A high imipenem MIC of CnsKP can predispose a patient to a poor prognosis.


Computational prediction and experimental validation of microRNAs in the brown alga Ectocarpus siliculosus.
We used an in silico approach to predict microRNAs (miRNAs) genome-wide in the brown alga Ectocarpus siliculosus. As brown algae are phylogenetically distant from both animals and land plants, our approach relied on features shared by all known organisms, excluding sequence conservation, genome localization and pattern of base-pairing with the target. We predicted between 500 and 1500 miRNAs candidates, depending on the values of the energetic parameters used to filter the potential precursors. Using quantitative polymerase chain reaction assays, we confirmed the existence of 22 miRNAs among 72 candidates tested, and of 8 predicted precursors. In addition, we compared the expression of miRNAs and their precursors in two life cycle states (sporophyte, gametophyte) and under salt stress. Several miRNA precursors, Argonaute and DICER messenger RNAs were differentially expressed in these conditions. Finally, we analyzed the gene organization and the target functions of the predicted candidates. This showed that E. siliculosus miRNA genes are, like plant miRNA genes, rarely clustered and, like animal miRNA genes, often located in introns. Among the predicted targets, several widely conserved functional domains are significantly overrepresented, like kinesin, nucleotide-binding/APAF-1, R proteins and CED-4 (NB-ARC) and tetratricopeptide repeats. The combination of computational and experimental approaches thus emphasizes the originality of molecular and cellular processes in brown algae.


Cryptic antigenic determinants on the extracellular pyruvate dehydrogenase complex/mimeotope found in primary biliary cirrhosis. A probe by affinity mass spectrometry.
Affinity mass spectrometry (AMS) was used to evaluate the structural diversity of the E2 component of pyruvate dehydrogenase complex (PDC) in normal and diseased liver cells, including those from patients with the autoimmune disease primary biliary cirrhosis (PBC). Two different antibodies to PDC-E2, the immunodominant mitochondrial autoantigen in patients with PBC, were used. AMS was performed directly on frozen liver sections and purified bile duct epithelial cells. Mass spectrometric signals associated with the molecular recognition of PBC-specific antigenic determinants were enhanced by an in situ enzyme-linked signal amplification process. Samples from patients with PBC gave strong positive signals for the antigen(s) recognized by the monoclonal antibody C355.1. Conversely, tissues from normal and disease controls showed only a minimal signal. AMS was used to identify specific antigenic determinants within the E2 component of PDC for comparison with unknown antigenic determinants observed by affinity capture with C355.1 monoclonal antibody from PBC samples. PDC components bound to C355.1 were mapped and identified by mass before dissociation from the E2 component. A similar approach was used to identify unknown antigenic determinants associated with PBC. We believe AMS may be an important new approach with wide application to the identification of molecules associated with a number of disease states.


Myocardial bridges: morphological and functional aspects.
To assess the arrangement of myocardial bridges. A necropsy study of 90 consecutive hearts (56 male, 34 female). Myocardial bridges, either single or multiple, were seen in 50 (55.6%) of the 90 hearts. The left anterior descending artery was the most commonly affected artery. Thirty five of the 50 hearts which contained in total 41 muscle bridges were dissected further with a magnifying glass. Two different types of muscle bridges could be identified. Thirty one of these 41 myocardial bridges were superficial, crossing the artery transversely towards the apex of the heart at an acute angle or perpendicularly. The remaining 10 myocardial bridges crossed the left anterior descending coronary artery and surrounded it by a muscle bundle that arose from the right ventricular apical trabeculae and crossed the artery transversely, obliquely, or helically before terminating in the interventricular septum. The superficial type of myocardial bridge does not seem to constrict the artery during systole but the deep muscle bridges, by virtue of their relation with the left anterior descending coronary artery, could twist the vessel and thus compromise its diastolic flow. This may result in ischaemia.


Microstructure and Ion Exchange in Stearic Acid Langmuir-Blodgett Films Studied by Fourier Transform Infrared-Attenuated Total Reflection Spectroscopy.
Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectra have been recorded of 11-layer Langmuir-Blodgett (LB) films of stearic acid deposited at various surface pressures (0.1, 15, and 35 mN/m), and the molecular orientation angles were evaluated quantitatively, which supplied insight into the molecular order with the alkyl chains tightly packed like crystal in the LB films deposited at the zero and higher surface pressures. These experimental results indicate that, in the Langmuir film as the precursor of LB films, stearic acid molecules self-aggregate to form two-dimensional crystalline domains already even at the zero surface pressure, which results in the inhomogeneity of monolayer. The analysis of dependence of nu(C=O) intensity on the surface pressure, surface density, and subphase temperature leads to the conclusion that the defects in LB films originate from the Langmuir film and be conserved upon deposition. Annealing below 50 degrees C and cooling could improve the monolayer homogeneity, and thus a defect-free or low-defect LB films can be deposited. Furthermore, ion exchange conducted in the LB films, on the other hand, confirms the existence of structure defects in LB films of stearic acid. The polar plane microstructure, lateral transport along the polar planes and the coordination types of stearic acid/cation system may be the rate-limiting process. The results have implication on the possible uses of stearic acid LB films as ion-exchange materials or sensors. Copyright 2001 Academic Press.


Mixed mode oscillations in mouse spinal motoneurons arise from a low excitability state.
We explain the mechanism that elicits the mixed mode oscillations (MMOs) and the subprimary firing range that we recently discovered in mouse spinal motoneurons. In this firing regime, high-frequency subthreshold oscillations appear a few millivolts below the spike voltage threshold and precede the firing of a full blown spike. By combining intracellular recordings in vivo (including dynamic clamp experiments) in mouse spinal motoneurons and modeling, we show that the subthreshold oscillations are due to the spike currents and that MMOs appear each time the membrane is in a low excitability state. Slow kinetic processes largely contribute to this low excitability. The clockwise hysteresis in the I-F relationship, frequently observed in mouse motoneurons, is mainly due to a substantial slow inactivation of the sodium current. As a consequence, less sodium current is available for spiking. This explains why a large subprimary range with numerous oscillations is present in motoneurons displaying a clockwise hysteresis. In motoneurons whose I-F curve exhibits a counterclockwise hysteresis, it is likely that the slow inactivation operates on a shorter time scale and is substantially reduced by the de-inactivating effect of the afterhyperpolarization (AHP) current, thus resulting in a more excitable state. This accounts for the short subprimary firing range with only a few MMOs seen in these motoneurons. Our study reveals a new role for the AHP current that sets the membrane excitability level by counteracting the slow inactivation of the sodium current and allows or precludes the appearance of MMOs.


Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma.
BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that is involved in the regulation of cell growth. Recently, many somatic and germline mutations of BAP1 have been reported in a broad spectrum of tumors. In this study, we identified a novel somatic non-synonymous BAP1 mutation, a phenylalanine-to-isoleucine substitution at codon 170 (F170I), in 1 of 49 patients with esophageal squamous cell carcinoma (ESCC). Multiplex ligation-dependent probe amplification (MLPA) of BAP1 gene in this ESCC tumor disclosed monoallelic deletion (LOH), suggesting BAP1 alterations on both alleles in this tumor. The deubiquitinase activity and the auto-deubiquitinase activity of F170I-mutant BAP1 were markedly suppressed compared with wild-type BAP1. In addition, wild-type BAP1 mostly localizes to the nucleus, whereas the F170I mutant preferentially localized in the cytoplasm. Microarray analysis revealed that expression of the F170I mutant drastically altered gene expression profiles compared with expressed wild-type BAP1. Gene-ontology analyses indicated that the F170I mutation altered the expression of genes involved in oncogenic pathways. We found that one candidate, TCEAL7, previously reported as a putative tumor suppressor gene, was significantly induced by wild-type BAP1 as compared to F170I mutant BAP1. Furthermore, we found that the level of BAP1 expression in the nucleus was reduced in 44% of ESCC examined by immunohistochemistry (IHC). Because the nuclear localization of BAP1 is important for its tumor suppressor function, BAP1 may be functionally inactivated in a substantial portion of ESCC. Taken together, BAP1 is likely to function as a tumor suppressor in at least a part of ESCC.


Arteritic and idiopathic ischemic optic neuropathy.
Ischemic optic neuropathy is a frequent cause of sudden visual loss in the older patient. There are two major causes of ischemic optic neuropathy; one, arteritic, due to an inflammatory process, and the other, idiopathic, possibly linked to hypertension. This paper presents four illustrative cases of ischemic optic neuropathy, one with an associated serous retinal detachment. The clinical appearance of the disorder, differential diagnosis of the two major types of ischemic optic neuropathy, and the pathogenesis and prognosis for vision are discussed. Currently accepted modes of treatment are also included.


Fatty acid composition of the major phospholipids of Pneumocystic carinii: comparison with those in the lungs of normal and methylprednisolone-immunosuppressed rats.
Large numbers of viable organisms can be isolated from the corticosteroid-immunosuppressed rat model of Pneumocystis carinii pneumonia. With the development of purification protocols that provide organism preparations of high purity, meaningful lipid biochemical analyses of this important opportunistic pathogen can now be conducted. The phospholipid class composition of the pathogen was reported earlier, together with observations of changes that occur in the rat lungs in response to methylprednisolone immunosuppression treatment. In this report, analyses of the effects of corticosteroids on the fatty acid compositions of the major lung phospholipids, individually isolated and purified by thin-layer chromatography, were elucidated and quantified by gas-liquid chromatography. In response to methylprednisolone, there was a relative increase in palmitate and there were decreases in several unsaturated fatty acids of the rat whole-lung total polar lipids leading to a doubling of the saturation index. Reciprocal changes in the relative concentrations of palmitate and stearate in phosphatidylethanolamine, phosphatidylinositol, lysophosphatidylcholine, and cardiolipin were observed, suggesting that there is tight control of acylation of these phospholipids in the lung. Detailed phospholipid fatty acid analyses were also performed with mixed life cycle stages of P. carinii organisms. The most abundant phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, had much higher concentrations of oleic acid and lower concentrations of palmitate in P. carinii than in lung tissue. Sphingomyelin in lung tissue and P. carinii differed from the glycerophospholipids by the presence of high levels of saturated C(22) and C(24) fatty acids. This study represents the most comprehensive fatty acid analysis of rat lung phospholipids and the changes that occur in response to corticosteroid treatment. It is the first report about the fatty acids of individual phospholipids of the opportunistic protist P. carinii carinii.


Evaluation of anorectal function in patients with tethered cord syndrome: saline enema test and fecoflowmetry.
Disturbance in anorectal function is a major factor restricting the activities of daily living in patients with spinal cord disorders. To detect changes in anorectal motilities due to a tethered spinal cord, anorectal functions were evaluated using a saline enema test and fecoflowmetry before and after patients underwent untethering surgery. The bowel functions in five patients with a tethered cord syndrome (TCS) were evaluated by performing a saline enema test and fecoflowmetry. The contractile activity of the rectum, the volume of infused saline tolerated in the rectum, anal canal pressure, and the ability to evacuate rectal content were examined. The characteristic findings in anorectal motility studies conducted in patients with TCS were a hyperactive rectum, diminished rectal saline-retention ability, and diminished maximal flow in saline evacuation. A hyperactive rectum was considered to be a major contributing factor to fecal incontinence. In one asymptomatic patient diminished anal squeezing pressure was exhibited and was incontinent to liquid preoperatively, but recovered after surgery. Two patients who underwent surgery for myeloschisis as infants complained of progressive fecal incontinence when they became adolescents. In one patient fecal incontinence improved but in another patient no improvement was observed after untethering surgery. Fecodynamic studies allow the detection of neurogenic disturbances of the anorectum in symptomatic and also in asymptomatic patients with TCS. More attention should be paid to the anorectal functions of patients with TCS.


Classification of mental disorder as a collection of hypothetical constructs.
In this article, I explore the implications of viewing psychiatric classification as a collection of hypothetical constructs. In this view, a taxonomic construct includes meaning surplus to the descriptive features provided by operational definitions, such as those provided in the American Psychiatric Association's 4th edition of the Diagnostic and Statistical Manual of Mental Disorders. This surplus meaning includes ties to etiology and treatment that for many disorders are as yet unknown. Despite these unknowns, it is proposed that a taxonomic construct must be embedded in a theory that provides some meaningful context for the construct and that falsification of such theories constitutes the primary enterprise of taxonomic research.


Prospective of 68Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation.
During the last decade, the utilization of 68Ga for the development of imaging agents has increased considerably with the leading position in the oncology. The imaging of infection and inflammation is lagging despite strong unmet medical needs. This review presents the potential routes for the development of 68Ga-based agents for the imaging and quantification of infection and inflammation in various diseases and connection of the diagnosis to the treatment for the individualized patient management.


[Intracellular calcium homeostasis in sensory neurons during hypoxia].
Hypoxia is the main reason leading to neuronal death during different forms of brain diseases. The main phenomenon observed at hypoxia is excessive growth of intraneuronal Ca2+ concentration leading to irreversible cell damage. Despite extensive studies of this process, the intracellular mechanisms responsible for disturbance in Ca2+ are still unclear. The aim of present investigations was to explore these mechanisms. Ca2+ was measured by spatial screening of isolated dorsal root ganglion (sensory) neurons loaded with fluorescent dye Fura-2AM after exposing them hypoxic solution. Hypoxia resulted in a reversible elevation of Ca2+, which could be partly prevented by several pharmacological agents. We concluded that in sensory neurons hypoxia-induced elevation of cytosolic Ca2+ is induced by primary changes in ionic channels and secondary in function of mitochondria.


Carrier proteins boost expression of PR-39-derived peptide in Pichia pastoris.
Multidrug resistance presents difficulties in preventing and treating bacterial infections. Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial growth by affecting the intracellular targets rather than by permeabilizing the membrane. The aim of this study was to develop a yeast-based fusion carrier system using calmodulin (CaM) and xylanase (XynCDBFV) as two carriers to express the model PrAMP PR-39-derived peptide (PR-39-DP) in Pichia pastoris. Fusion protein secreted into the culture supernatant was purified in a one-step on-column digestion using human rhinovirus 3C protease, obtaining the target peptide PR-39-DP. The growth curves of Escherichia coli were monitored by recording the OD600 values of the bacteria. The antibacterial activity of PR-39-DP was evaluated in killing assays performed on E. coli. The yield of PR-39-DP was 1.0-1.2 mg l-1 in the CaM fusion carrier system, approximately three times that of the XynCDBFV fusion carrier system. The minimal inhibitory concentration (MIC) of PR-39-DP was about 10.5 μg ml-1. CaM and XynCDBFV provide increased stability and promote the expression and secretion of active PR-39-DP.


Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy.
Background The objective of this study was to assess the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and anti-tumor efficacy of CKD-581, a novel pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma (MM) refractory to standard therapy. Methods In this phase I study, CKD-581 was intravenously administered on days 1, 8, and 15 of a 28-day cycle. A standard 3 + 3 cohort design was used to determine the MTD. Acetylated histones H3 and H4 in peripheral blood mononuclear cells were measured for pharmacodynamic assessment in a subpopulation of patients. Results Thirty-nine patients were treated with CKD-581 at 9 dose levels from 10 mg/m2 to 210 mg/m2. The DLTs were grade 3 neutropenia that delayed the treatment for >2 weeks (one patient at a dose of 50 mg/m2) and grade 4 thrombocytopenia (two patients at a dose of 210 mg/m2). The MTD of CKD-581 was 160 mg/m2. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (n = 5, 12.8%) and neutropenia (n = 2, 5.1%). The peak concentration and area under the curve values for CKD-581 increased in proportion to the dose, indicating linear pharmacokinetics. A partial response was observed in 2 patients (5.6%), and stable disease was observed in 16 (44.4%) patients. In the pharmacodynamic evaluation, acetylation of H3 and H4 was observed at all doses of ≥50 mg/m2. Conclusion CKD-581 was well tolerated by the patients with lymphoma or MM refractory to standard therapy. It exhibited dose-proportional pharmacokinetics and modest anti-tumor efficacy.


Important role of the tetraloop region of 4.5S RNA in SRP binding to its receptor FtsY.
Binding of Escherichia coli signal recognition particle (SRP) to its receptor, FtsY, requires the presence of 4.5S RNA, although FtsY alone does not interact with 4.5S RNA. In this study, we report that the exchange of the GGAA tetraloop sequence in domain IV of 4.5S RNA for UUCG abolishes SRP-FtsY interaction, as determined by gel retardation and membrane targeting experiments, whereas replacements with other GNRA-type tetraloops have no effect. A number of other base exchanges in the tetraloop sequence have minor or intermediate inhibitory effects. Base pair disruptions in the stem adjacent to the tetraloop or replacement of the closing C-G base pair with G-C partially restored function of the otherwise inactive UUCG mutant. Chemical probing by hydroxyl radical cleavage of 4.5S RNA variants show that replacing GGAA with UUCG in the tetraloop sequence leads to structural changes both within the tetraloop and in the adjacent stem; the latter change is reversed upon reverting the C-G closing base pair to G-C. These results show that the SRP-FtsY interaction is strongly influenced by the structure of the tetraloop region of SRP RNA, in particular the tetraloop stem, and suggest that both SRP RNA and Ffh undergo mutual structural adaptation to form SRP that is functional in the interaction with the receptor, FtsY.


The role of analogies in learning to read.
A number of factors contribute to proficient word recognition, including phonological awareness and the ability to make orthographic analogies. The present study considered the relative contribution analogy abilities make toward early reading ability. Two analogy tasks and measures of phonological awareness, orthographic knowledge, visual memory, general language ability, and non-verbal intelligence were administered to 20 second grade good readers and 20 third and fourth grade poor readers. The analogy tasks did make a significant contribution to early reading ability; however, the analogy tasks were not very different from the measures of reading they predicted. In other words, it seems difficult to isolate the use of analogies from basic phonological decoding abilities.


Hearing brighter: changing in-depth visual perception through looming sounds.
Rapidly approaching (looming) sounds are ecologically salient stimuli that are perceived as nearer than they are due to overestimation of their loudness change and underestimation of their distance (Neuhoff, 1998; Seifritz et al., 2002). Despite evidence for crossmodal influence by looming sounds onto visual areas (Romei, Murray, Cappe, & Thut, 2009, 2013; Tyll et al., 2013), it is unknown whether such sounds bias visual percepts in similar ways. Nearer objects appear to be larger and brighter than distant objects. If looming sounds impact visual processing, then visual stimuli paired with looming sounds should be perceived as brighter and larger, even when the visual stimuli do not provide motion cues, i.e. are static. In Experiment 1 we found that static visual objects paired with looming tones (but not static or receding tones) were perceived as larger and brighter than their actual physical properties, as if they appear closer to the observer. In a second experiment, we replicate and extend the findings of Experiment 1. Crucially, we did not find evidence of such bias by looming sounds when visual processing was disrupted via masking or when catch trials were presented, ruling out simple response bias. Finally, in a third experiment we found that looming tones do not bias visual stimulus characteristics that do not carry visual depth information such as shape, providing further evidence that they specifically impact in-depth visual processing. We conclude that looming sounds impact visual perception through a mechanism transferring in-depth sound motion information onto the relevant in-depth visual dimensions (such as size and luminance but not shape) in a crossmodal remapping of information for a genuine, evolutionary advantage in stimulus detection.


Genetic control of immunity to Trichinella spiralis in mice: capacity of cells from slow responder mice to transfer immunity in syngeneic and F1 hybrid recipients.
Mice of the C57BL/10 (B10) strain are slow responders to infection with T. spiralis in terms of ability to expel worms from the intestine. Compared with rapid-responder NIH mice, infection stimulates a slower and reduced blast cell response in the draining mesenteric lymph node (MLN). Transfer of immune cells from the MLN (MLNC) does not accelerate worm expulsion from naive B10 recipient mice, even though MLNC from this strain effectively transfer immunity to (B10 X NIH) F1 recipients. In common with other B10 background mice C57BL/10 show an infection-dose related suppression of immunity to T. spiralis. Such suppression does not appear to determine the response to MLNC, as adoptive transfer into B10 recipients was not enhanced by reducing the level of challenge infection given, and transfer into F1 recipients was unaffected by simultaneous transfer of lymphocyte populations from donors infected at a level which would induce suppression. A hypothesis is proposed which relates slow response status to (i) the inherent capacity of the intestinal inflammatory component of worm expulsion, and (ii) the outcome of infection-dose related stimulatory and suppressive influences acting on the two interacting lymphocyte components of expulsion. The relevance of H-2-linked and non-H-2 genes to the control of the response is discussed.


[Investigation of beta-lactamase genes and clonal relationship among the extended-spectrum beta-lactamase producing nosocomial Escherichia coli isolates].
Extended-spectrum beta-lactamase (ESBL) producing microorganisms currently cause a major problem. Among theseCTX-M beta-lactamase producing Escherichia coli has also disseminated worldwide as an important cause of both nosocomial and community-acquired infections. The aims of this study were to determine the prevalence of the beta-lactamase genes, antibiotic susceptibilities and clonal relationships of ESBL-producing nosocomial E.coli isolates. A total of 76 ESBL-producing E.coli strains isolated from urine (n= 26), blood (n= 25) and wound (n= 25) specimens of hospitalized patients identified as nosocomial infection agents according to the CDC criteria between June 2010-June 2011 were included in the study. Antibiotic susceptibilities of the isolates were detected by Kirby-Bauer disc diffusion method according to CLSI recommendations. ESBL production was tested by double disc diffusion method, and cefotaxime/cefotaxime-clavulanic acid E-test strips (AB Biodisk, Sweden) were used for indeterminate results. Presence of TEM, SHV, CTX-M, OXA-2 group, 0XA-10 group, PER, VEB and GES beta-lactamase genes were investigated by polymerase chain reaction (PCR) using specific primers. Pulsed-field gel electrophoresis (PFGE) method was used for the detection of clonal relationships among the strains. Most of the ESBL-producing E.coli strains were isolated from samples of inpatients in intensive care (35%), internal medicine (16%) and general surgery (13%) units. All of the 76 strains were found susceptible to imipenem, meropenem and amikacin; however all were resistant to cefotaxime and ceftriaxone. The susceptibility rates of the isolates to cefoxitin, ertapenem, cefoperazone/sulbactam, piperacillin-tazobactam, gentamicin, ciprofloxacin, cefepime, amoxicillin-clavulanic acid, aztreonam and ceftazidime were 96%, 83%, 63%, 61%, 50%, 41%, 25%, 21%, 20% and 18%, respectively. Among E.coli isolates, the frequency of CTX-M, TEM, OXA-2 group, PER, SHV and OXA-10 group beta-lactamase genes were found as 89.5%, 59.2%, 15.8%, 14.5%, 11.8% and 3.9%, respectively, while none of the isolates were positive for VEB and GES beta-lactamase genes. In 1 (1.3%) strain none of the investigated genes were detected. PCR analyses of the isolates revealed that 25 harbored CTX-M and TEM genes together, while 20 harbored only CTX-M and two harbored only TEM genes. Single SHV gene was not detected in any of the isolates. PFGE demonstrated no major clonal relationship between ESBL-producing isolates. This study indicated that CTX-M type enzymes were highly endemic among ESBL-producing nosocomial E.coli strains in our hospital, with the polyclonal spread of ESBL-producing bacteria without any dominant epidemic clone. In conclusion, it was considered that further studies are needed to explain the relationship between epidemic clones and plasmids with the use of plasmid analysis and multilocus sequence typing methods.


Anatomically and Biomechanically Relevant Monolithic Total Disc Replacement Made of 3D-Printed Thermoplastic Polyurethane.
Various implant treatments, including total disc replacements, have been tried to treat lumbar intervertebral disc (IVD) degeneration, which is claimed to be the main contributor of lower back pain. The treatments, however, come with peripheral issues. This study proposes a novel approach that complies with the anatomical features of IVD, the so-called monolithic total disc replacement (MTDR). As the name suggests, the MTDR is a one-part device that consists of lattice and rigid structures to mimic the nucleus pulposus and annulus fibrosus, respectively. The MTDR can be made of two types of thermoplastic polyurethane (TPU 87A and TPU 95A) and fabricated using a 3D printing approach: fused filament fabrication. The MTDR design involves two configurations-the full lattice (FLC) and anatomy-based (ABC) configurations. The MTDR is evaluated in terms of its physical, mechanical, and cytotoxicity properties. The physical characterization includes the geometrical evaluations, wettability measurements, degradability tests, and swelling tests. The mechanical characterization comprises compressive tests of the materials, an analytical approach using the Voigt model of composite, and a finite element analysis. The cytotoxicity assays include the direct assay using hemocytometry and the indirect assay using a tetrazolium-based colorimetric (MTS) assay. The geometrical evaluation shows that the fabrication results are tolerable, and the two materials have good wettability and low degradation rates. The mechanical characterization shows that the ABC-MTDR has more similar mechanical properties to an IVD than the FLC-MTDR. The cytotoxicity assays prove that the materials are non-cytotoxic, allowing cells to grow on the surfaces of the materials.


Risk Factors for Radiotherapy Failure in the Treatment of Spinal Metastases.
Retrospective cohort study. To build a predictive model for risk factors for failure of radiation therapy, hypothesizing a higher SINS would correlate with failure. Patients with spinal metastasis being treated with radiation at a tertiary care academic center between September 2014 and October 2018 were identified. The primary outcome measure was radiation therapy failure as defined by persistent pain, need for re-irradiation, or surgical intervention. Risk factors were primary tumor type, Karnofsky and ECOG scores, time to treatment, biologically effective dose (BED) calculations using α/β ratio = 10, and radiation modality. A logistic regression was used to construct a prediction model for radiation therapy failure. One hundred and seventy patients were included. Median follow up was 91.5 days. Forty-three patients failed radiation therapy. Of those patients, 10 required repeat radiation and 7 underwent surgery. Thirty-six patients reported no pain relief, including some that required re-irradiation and surgery. Total SINS score for those who failed reduction therapy was <7 for 27 patients (62.8%), between 7-12 for 14 patients (32.6%), and >12 for 2 patients (4.6%). In the final prediction model, BED (OR .451 for BED > 43 compared to BED ≤ 43; P = .174), Karnofksy score (OR .736 for every 10 unit increase in Karnofksy score; P = .008), and gender (OR 2.147 for male compared to female; P = .053) are associated with risk of radiation failure (AUC .695). A statistically significant association between SINS score and radiation therapy failure was not found. In the multivariable model, BED ≤ 43, lower Karnofksy score, and male gender are predictive for radiotherapy failure. SINS score was among the candidate risk factors included in multivariable model building procedure, but it was not selected in the final model. Prognostic level III.


How laboratory dogs accommodate meals of different size but similar composition.
Healthy laboratory dogs appear to absorb a mixed meal from the gut at a constant rate. This rate is apparently not affected by meal size. If this is the case, then duration of absorption should depend on total or integrated meal size, whereas metabolite and hormonal levels would be independent of the number of feedings. To explore these hypotheses further, we compared the metabolite and hormonal responses with a single mixed meal and one divided in two halves, provided in two feedings 4 h apart. We detected no effect of the second meal in the metabolic response levels of glucose, lactate, pyruvate, alanine, free fatty acids, or 3-hydroxybutyrate or the hormonal responses of insulin, pancretic glucagon, gastrin, or secretin. Only minor differences were detectable in the hormonal response levels of pancreatic polypeptide, gastric inhibitory peptide, and enteroglucagon, consistent with a response to a second meal. We conclude that the observed change in circulating metabolite or hormone concentration is independent of the size of meal eaten, but the duration of the excursion depends on meal size. Thus, during the bulk phase of nutrient uptake, the absorption mechanism of the laboratory dog appears to be saturated.


Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth.
The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial. The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors. In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 - 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months. VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future. http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.


Induction of antitumor immunity after cure of pulmonary metastases, using staphylococcal enterotoxin B and bispecific antibody.
The combination of staphylococcal enterotoxin B (SEB) and anti-p97 x anti-CD3 bispecific antibody (bsAb) cures 60%-80% of mice with established pulmonary metastases of the syngeneic p97+ murine melanoma, CL62. We investigated the ability of cured mice to generate protective antitumor immunity. In tumor rechallenge experiments, CL62-cured mice developed protective immunity against rechallenge with CL62. The majority of mice also rejected the p97-negative parental cell line, K1735, indicating an immune response to tumor antigens common to both cell lines that were not bsAb-targeted. A significant humoral response developed against p97 antigen, but not against other antigens common to both CL62 and K1735. That the majority of cured mice nevertheless rejected K1735 suggests that tumor immunity is not antibody-dependent. Evidence of cellular immunity was obtained from the results of delayed-type hypersensitivity, proliferation and cytotoxicity assays, which revealed the presence of tumor-specific memory in bsAb-treated, CL62-cured mice. CD8+ T cells from cured, but not control mice were able to lyse tumor; however, memory CD4 cells had no cytolytic function. In vivo, however, both CD4 and CD8 T cells were required for effective protective immunity. These studies demonstrate that treatment with SEB and bsAb not only confers passive immune effects of tumor eradication, but also actively promotes the generation of a host antitumor immune response.


Current status of imaging diagnosis in the transplanted kidney. A review of the literature with a special focus on contrast-enhanced ultrasonography.
Ultrasonographic scanning is currently the most widespread imaging diagnostic procedure. The method provides real-time morphological, vascular and elastographic information in a non-invasive manner. In recent years, harmonic vascular examination has become accessible using intravenous contrast agents. In urological pathology, this procedure is used in the detection and evaluation of vascular and ischemic complications, in the classification of complex cysts according to the Bosniak system, also in the renal lesions with uncertain etiology and in acute pyelonephritis for the detection of abscesses. The contrast agent (SonoVue) is angiospecific and can be used in patients transplanted immediately after surgery without adverse effects or impaired renal function. Thus, it is desirable to be used in the nephrological pathology of the renal graft and to develop diagnostic models based on the evaluation of renal microvascularization, as well as the quantitative data resulting from the graphical representation of the specific parameters. The purpose of this review is to evaluate the current state of the literature regarding the place and role of contrast substance ultrasound in the early diagnosis of acute renal graft dysfunction and to make a differential diagnosis of this pathological entity. This review quantifies the role of contrast ultrasound in the diagnosis of acute complications of the renal graft. The research was conducted based on the databases PubMed, MedScape, Cochrane, according to the search criteria such as contrast-enhanced ultrasound + kidney transplant, "time intensity curves" + "kidney transplant", filtered for the period 2004-2018. In the nephrological pathology of the renal graft, contrast-enhanced ultrasound is a valuable tool, superior to Doppler ultrasound in predicting the evolution of the renal graft, identifying very small early defects in renal microvascularization. A number of studies succeeded in identifying acute graft dysfunction, some of which establish its etiology - humoral rejection versus acute tubular necrosis. On the other hand, the contrast-enhanced ultrasound parameters do not have the ability to distinguish between cellular and humoral rejection. If, at present, the histopathological examination is the only one that can differentiate with certainty the cause of acute renal graft dysfunction, we consider that contrast-enhanced ultrasound, as a non-invasive imaging technique, opens a favorable perspective for increasing the survival of the renal graft and decreasing the complications in the renal transplant. The combination of other ultrasound techniques, together with contrast-enhanced ultrasound, could lead to the development of new diagnostic models.


Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.


Low rate of bacteremia with a subcutaneously implanted central venous access device.
Patients at long-term acute care hospitals (LTACs) are medically complex with multiple comorbidities and high rates of antibiotic and device use. The objective of the study was to analyze the incidence and rate of central line-associated bloodstream infections (CLABSI) and the critical factors for patient care, management, placement and maintenance of the implanted central venous access device at this LTAC. A 13-year retrospective chart review was performed comprising 191 medically complex patients with multiple comorbidities who had an implanted central line port. Information analyzed included (1) number of catheters; (2) number of patients; (3) number of catheter line days; (4) patient demographics; (5) port location; (6) admission diagnoses; (7) type, incidence and rate of catheter-related complications. The total number of catheter days was over 183,183 with a mean of 959 catheter days per patient. The mean rate of CLABSI was 0.087 per 1,000 days; incidence was less than 8% of patients with catheters. The study found a markedly lower rate of CLABSI than reported for other LTACs as well as intensive care units, over 14- to 100-fold lower than other LTACs. The authors propose that standardized catheter placement with implementation of rigorous, prospective catheter care plans and a team approach to management were responsible for extremely low complication rates. These results can be extrapolated to different settings across the healthcare continuum.


Effectiveness of High-Dose Clonazepam Versus Low-Dose Clonazepam With Cognitive Behavioral Therapy in Older Adults With Moderately Severe Insomnia: A Prospective Cohort Study.
To evaluate the effectiveness of high-dose clonazepam (1 mg) versus low-dose clonazepam (0.5 mg) with cognitive behavioral therapy for insomnia (CBT-i) in older adults with moderately severe insomnia. A prospective cohort study was conducted in patients who did not respond to low-dose clonazepam for insomnia secondary to chronic medical conditions. After starting with 0.25 mg of clonazepam, their dose was increased to 0.5 mg, then to 1 mg (Group A), or to the same dose with additional CBT-i (Group B). They were followed for 24 weeks, and scores of the insomnia severity index (ISI) and subjective units of distress scale (SUDS) were recorded. Patient adverse drug reactions (ADRs) were documented and assessed for their causality. ISI and SUDS scores were considered primary outcome measures. Between-group analysis revealed a significant decline in the mean score of ISI at week 16 (P < 0.05) and for SUDS at week 20 (P < 0.05) in group B compared to group A. Similarly, within-group analysis also revealed a statistically significant reduction of the mean score in ISI and SUDS scores at week 4 and 8 (P < 0.05) in both groups. ADRs occurred more frequently in group A (14%) than in group B (5%). Assessments of causality showed that the majority of cases were possible. For individuals who were resistant to 0.5 mg of clonazepam, adding CBT-i with low-dose clonazepam is a viable alternative to increasing the dose to 1 mg.


Study progression of anti-angiogenetic therapy and its combination with other agents for the treatment of advanced hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a common malignancy worldwide and is especially prevalent in the Chinese population. Treatment of advanced HCC has posed a considerable challenge to clinicians and highly effective therapies remain elusive. Angiogenesis contributes greatly to the pathogenesis, invasion and metastasis of HCC. Therefore, anti-angiogenesis therapy could be instrumental to the treatment of HCC. In recent years, several anti-angiogenesis drugs have generated significant outcomes in a few key clinical studies, and in this light, anti-angiogenesis therapy has become a critical aspect of comprehensive treatment of HCC. In this article, to provide a reference for clinicians, we review these advances and discuss the future direction of development.


[Effect of age and gender on genotoxic and biochemical indexes in animal blood after low doses of radiation-mercury exposures].
The study was executed with the young (4-5 months) and elderly (15-18 months) rats of both gender at the experiment start. The mercury salt was administered into animals with drinking water in 1 mcg/l concentration during 3 months before and 1 month after single X-irradiation with 25 cGy dose. The genotoxic effects in leukocytes were evaluated on the base of the content and structure DNA alterations in 24 hrs and in 1 month after irradiation. The alaninaminotransferase activity and the urea content in serum were determined to evaluate functional status of liver and kidney, respectively. The irradiation of rats receiving mercury with drinking water resulted in increase of the leukocyte DNA content in young male and decrease of the leukocyte quantity in young female at the early terms. At the same time the decrease of monocyte content and the alterations of the blood leukocyte DNA structure were observed in the elderly female. One month after combined exposures the whole leukocyte amount in young females was increased to the intact control level and the leukocytosis was observed in elderly females accompanied by significant condensation of the leukocyte DNA structure. At the same time granulocyte quantity was observed in young males in compare with the intact rats, and the tendency of the increased genotoxicity was lasted out. After combined exposures the functional liver alterations were observed in the highest degree among young male rats (+62%), in approximately identical degree among young and elderly females (+38% and +27%), and practically were absent among elderly males. The absence of the urea concentration increase in the serum of the all experimental group animals in comparison with the intact control rats evidenced, that lesion of kidneys did not take place. So, in despite of the fact that young females revealed sensitivity to the radiation-mercury environment exposure with the low doses in the early term, then they demonstrated the better restoration in compare with the young males and the elderly females. The elderly males were found the least sensitive to the radiation-mercury exposure with low doses among the studied animal groups.


An adaptable peptide-based porous material.
Porous materials find widespread application in storage, separation, and catalytic technologies. We report a crystalline porous solid with adaptable porosity, in which a simple dipeptide linker is arranged in a regular array by coordination to metal centers. Experiments reinforced by molecular dynamics simulations showed that low-energy torsions and displacements of the peptides enabled the available pore volume to evolve smoothly from zero as the guest loading increased. The observed cooperative feedback in sorption isotherms resembled the response of proteins undergoing conformational selection, suggesting an energy landscape similar to that required for protein folding. The flexible peptide linker was shown to play the pivotal role in changing the pore conformation.


A prototype for unsupervised analysis of tissue microarrays for cancer research and diagnostics.
The tissue microarray (TMA) technique enables researchers to extract small cylinders of tissue from histological sections and arrange them in a matrix configuration on a recipient paraffin block such that hundreds can be analyzed simultaneously. TMA offers several advantages over traditional specimen preparation by maximizing limited tissue resources and providing a highly efficient means for visualizing molecular targets. By enabling researchers to reliably determine the protein expression profile for specific types of cancer, it may be possible to elucidate the mechanism by which healthy tissues are transformed into malignancies. Currently, the primary methods used to evaluate arrays involve the interactive review of TMA samples while they are viewed under a microscope, subjectively evaluated, and scored by a technician. This process is extremely slow, tedious, and prone to error. In order to facilitate large-scale, multi-institutional studies, a more automated and reliable means for analyzing TMAs is needed. We report here a web-based prototype which features automated imaging, registration, and distributed archiving of TMAs in multiuser network environments. The system utilizes a principal color decomposition approach to identify and characterize the predominant staining signatures of specimens in color space. This strategy was shown to be reliable for detecting and quantifying the immunohistochemical expression levels for TMAs.


Three-month cumulative incidence of thromboembolism and bleeding after periprocedural anticoagulation management of arterial vascular bypass patients.
The objective of this study was to determine 3-month cumulative incidence of peri-procedural thromboembolism (TE) including graft occlusion, and peri-procedural bleeding for chronically anticoagulated vascular bypass graft (BG) patients requiring temporary warfarin interruption for an invasive procedure. Appropriate peri-procedural management of patients receiving chronic warfarin therapy to preserve lower extremity arterial BG patency is unknown. In a protocol driven, cohort study design, all BG patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation (1997-2007) were followed forward in time to estimate the 3-month cumulative incidence of TE and bleeding. Decisions to provide "bridging" low molecular weight heparin (LMWH) were individualized based on estimated risk of TE and bleeding. There were 78 BG patients (69 ± 10 years; 38% women), of whom 73% had a distal autogenous and 53% had prosthetic BG; 45% received antiplatelet therapy. Peri-procedural LMWH was prescribed for 77% of patients and did not vary by BG distal anastomosis location or type. The 3-month cumulative incidence of TE was 5.1% (95% CI 1.4-12.6), including two BG occlusions, one DVT, and one myocardial infarction. Major bleeding occurred in 1 patient (1.28%, 95% CI 0.0-6.94). One patient died due to heart failure. TE and bleeding did not differ by bridging status. The 3-month cumulative incidence of TE among BG patients in whom warfarin is temporarily interrupted for an invasive procedure may be higher than in other "bridging" populations (atrial fibrillation, prosthetic heart valve, venous thromboembolism). This finding underscores the often tenuous nature of distal bypass grafts necessitating an aggressive approach to peri-procedural anticoagulation management.


[Neuropeptides and behavior. Methodologic and critical reflections].
Relations between a peptide, hormone or neurotransmitter and behavior involve a molecule and a frequently complex process. The psychobiologist suggest the need for caution against extensive, operative and pharmacologic use of the notion of behavior. Multifactorial organization of adaptive behavior lends itself poorly to a reductionism leading to the equation molecule-behavior; however, neuropeptides do modulate behavior, sometimes potently. These subjects are discussed from a methodologic and critical point of view. Neurobiologists and endocrinologists have too often neglected the organizational and controlling roles of behavior on global neurobiologic and neuroendocrine reactions. Several examples are given to illustrate these various propositions.


The effect of ions at the surface of calcium oxalate monohydrate crystals on cell-crystal interactions.
Magnesium is an abundant ion in biologic systems, including renal tubular fluid; however, the precise role of magnesium during the interaction of calcium oxalate crystals with cells has not been previously defined. In addition, the respective roles of calcium and hydrogen ions during the cell-crystal bonding interaction remain poorly defined. Here we report an atomic level three-dimensional study of a single crystal of calcium oxalate monohydrate (COM; whewellite) which was bathed in a solution of magnesium hexahydrate for 1 year. Magnesium was not incorporated into the structure of whewellite to any significant degree. Instead, COM accepted magnesium primarily as an adsorbate in a binding configuration which, as a surface phenomenon, is controlled by localized charge effects. The effect of magnesium and calcium on the efficiency of calcium oxalate crystal binding to renal cells was also investigated. When present in supraphysiologic concentrations (greater than 0.1 M), magnesium progressively inhibited adhesion of pre-formed COM crystals to cultured renal cells. Therefore, even though magnesium does not incorporate into the crystal structure of calcium oxalate, magnesium can exert important surface effects and change the interaction of pre-formed COM with molecules anchored on the cell surface. Similarly, binding was nearly blocked when the exogenous calcium concentration was > or =0.1 M (supraphysiologic range), although in lower concentrations (within the physiologic range) exogenous calcium promoted crystal adhesion. Finally, the ambient hydrogen ion concentration also influenced calcium oxalate crystal interactions with renal cells, with maximal binding occurring at a pH of 4. Therefore, hypercalciuria and/or an acidic urine could each promote renal stone formation via increased crystal adhesion to renal cells, a previously under-appreciated potential mechanism.


Enthalpy of Formation of N2H4 (Hydrazine) Revisited.
In order to address the accuracy of the long-standing experimental enthalpy of formation of gas-phase hydrazine, fully confirmed in earlier versions of Active Thermochemical Tables (ATcT), the provenance of that value is re-examined in light of new high-end calculations of the Feller-Peterson-Dixon (FPD) variety. An overly optimistic determination of the vaporization enthalpy of hydrazine, which created an unrealistically strong connection between the gas phase thermochemistry and the calorimetric results defining the thermochemistry of liquid hydrazine, was identified as the probable culprit. The new enthalpy of formation of gas-phase hydrazine, based on balancing all available knowledge, was determined to be 111.57 ± 0.47 kJ/mol at 0 K (97.42 ± 0.47 kJ/mol at 298.15 K). Close agreement was found between the ATcT (even excluding the latest theoretical result) and the FPD enthalpy.


Bond Energy Density Analysis Combined with Informatics Technique.
Bond energy density analysis, a two-body energy decomposition scheme, was extended by revisiting the constraint conditions and using the informatics technique. The present scheme can evaluate the bond energies (BEs) for all interatomic pairs including both strong chemical bonds and weak through-space/bond interactions, and bond dissociation energies (BDEs) constructed from BEs. The newly derived formula, presented in the form of the system of linear equations, tends to result in the overfitting problem owing to the small components originating from the weak through-space/bond interactions. Hence, we adopt the least absolute shrinkage and selection operator technique. Numerical assessments of the present scheme were performed for C-C and C-H bonds in typical hydrocarbons as well as 44 chemical bonds, i.e., covalent and ionic bonds, in 33 small molecules involving second- and third-row atoms. The statistics for the BDE estimation confirms the accuracy of the present scheme.


Comparing kidney outcomes in type 2 diabetes treated with different sulphonylureas in real-life clinical practice.
Although several sulphonylureas are widely used in type 2 diabetes (T2D), their differential impacts on long-term major kidney outcomes remain unclear. This study aimed to investigate the effects of the two most commonly prescribed sulphonylureas, glimepiride and gliclazide, on kidney outcomes in patients with T2D. A total of 4486 patients treated with either glimepiride or gliclazide for more than 2 years were followed for up to 5.5 years (median: 4.7 years). A propensity score based on baseline characteristics was used to match 1427 patients treated with glimepiride with 1427 gliclazide-treated patients; incidences of end-stage renal disease (ESRD) and sustained doubling of creatinine to>132.6 μmol/L (1.5mg/dL) were also compared. In the matched cohort with 12,122 person-years of follow-up, there was no significant difference between groups in risk of ESRD [hazard ratio (HR): 0.57, 95% confidence interval (CI): 0.29-1.12] or doubling of creatinine (HR: 0.74, 95% CI: 0.44-1.26), although there was a trend towards higher risks in the glimepiride group. Subgroup analyses showed that, compared with glimepiride, gliclazide was associated with a lower risk of doubling of creatinine in patients with preserved renal function (glomerular filtration rate ≥ 60 mL/min/1.73 m(2), HR: 0.21, 95% CI: 0.04-0.99) and good glycaemic control (HbA1c < 7%, HR: 0.35, 95% CI: 0.14-0.86), and in older subjects (≥ 62 years, HR: 0.52, 95% CI: 0.27-0.99). In a real-life setting, there was no significant difference in clinical outcomes of kidney disease for patients treated with glimepiride vs gliclazide. However, gliclazide appeared to protect against renal complication progression in certain populations.


An Analysis of Plan Robustness for Esophageal Tumors: Comparing Volumetric Modulated Arc Therapy Plans and Spot Scanning Proton Planning.
Planning studies to compare x-ray and proton techniques and to select the most suitable technique for each patient have been hampered by the nonequivalence of several aspects of treatment planning and delivery. A fair comparison should compare similarly advanced delivery techniques from current clinical practice and also assess the robustness of each technique. The present study therefore compared volumetric modulated arc therapy (VMAT) and single-field optimization (SFO) spot scanning proton therapy plans created using a simultaneous integrated boost (SIB) for dose escalation in midesophageal cancer and analyzed the effect of setup and range uncertainties on these plans. For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors. Dose-volume metrics were compared for the optimal and uncertainty plans, with P<.05 (Wilcoxon) considered significant. SFO reduced the mean lung dose by 51.4% (range 35.1%-76.1%) and the mean heart dose by 40.9% (range 15.0%-57.4%) compared with VMAT. Proton plan robustness to a 3.5% range error was acceptable. For all patients, the clinical target volume D98 was 95.0% to 100.4% of the prescribed dose and gross tumor volume (GTV) D98 was 98.8% to 101%. Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT. The clinical target volume D98 was lower by 0.6% to 7.8% of the prescribed dose, and the GTV D98 was lower by 0.3% to 2.2% of the prescribed GTV dose. The SFO plans achieved significant sparing of normal tissue compared with the VMAT plans for midesophageal cancer. The target dose coverage in the SIB proton plans was less robust to random setup errors and might be unacceptable for certain patients. Robust optimization to ensure adequate target coverage of SIB proton plans might be beneficial.


[Sexual differences in the interhemispheric asymmetry of the transcallosal responses of the associative areas in the cat neocortex].
Sex differences of hemisphere asymmetry of homo- and heterotopic transcallosal responses in association cortex of 48 cats (24 male and 24 female) immobilized by tubocurarine have been studied by means of topographic EPs recordings in both hemispheres. In males left hemisphere dominates by the amplitude of homotopic and positive wave of heterotopic EPs and right hemisphere dominates by the amplitude of negative wave of heterotopic sensorimotor cortex EPs. The individual asymmetry of EPs has been observed in sensomotor cortex of females and in parietal cortex of animals of both sex. The interhemispheric asymmetry is expressed distinctly in females than in males. It is concluded that sex dimorphism is present in functional organization of associative system of (callosal and intracortical) connections in cat's neocortex projection and association areas which means its more expressed hemisphere lateralization in males with more expressed interhemispheric asymmetry of functional transcallosal connections in females.


Wise management of investments: the CFO's role.
Asset pools of investable funds are major sources of revenue for healthcare organizations. A prudent investment program can assure that these funds will be controlled adequately and managed efficiently. This type of program clearly defines the goals of investment, the characteristics of appropriate investment instruments, the means of monitoring and reporting fund activities, and the responsibilities and qualifications of the institutional investor.


Differential anti-Golgi complex autoantibody production following murine lactate dehydrogenase-elevating virus infection.
Lactate dehydrogenase-elevating virus (LDV) causes asymptomatic infection and persistent viremia in mice with unique infectious specificity directed to a certain subpopulation of macrophages leading to chronic infection and an immunological disorder that includes hyperimmunoglobulinemia and production of autoantibodies. Infection with a species of LDV originally isolated from mice carrying an LDV-contaminated transplantable tumor (LDV-W) was reported to induce anti-Golgi complex antibody (AGA) production. In contrast, infection with the most common LDV species (LDV-P) was not associated with AGA production. Here we performed the first independent side by side comparison of the effects of the two LDV strains on their hosts as an initial approach to investigating the production of AGA. After viral inoculation, both LDV-W and LDV-P infected mice exhibited similar changes in lactate dehydrogenase in plasma suggesting similar viral activity. However, AGA production was observed in only the LDV-W infected mice and these mice exhibited plasma IgG elevation and immune complex formation. These data validated the differential potential of LDV-W and LDV-P in the production of AGA. Future comparative characterizations in the immune processing of Golgi complex autoantigens using these viral strains may be useful in obtaining specific insights in the specific anti-Golgi complex autoimmune responses.


Mean platelet volume levels in patients with cardiac myxoma.
Thromboembolic events such as cerebrovascular stroke are common and serious complications in patients with cardiac myxomas (CMs). Previous studies have reported that a high mean platelet volume (MPV) level reflects an activated platelet function and has been proven to be an independent risk factor for thromboembolic events. The aim of this study was to evaluate the relation between MPV level and CM. We compared the MPV levels between patients with CM and control subjects, and also evaluated the differences in the MPV levels in patients with CM before and after a successful surgical treatment. Furthermore, we compared the MPV levels in patients with and without cerebrovascular embolic symptoms. Fifty-one consecutive patients (13 men, 38 women, mean age 51.1 ± 16.9 years) who underwent excision of CM in our hospital in the last 13 years and 50 normal subjects as the control group were included in this study. The patients with CM were divided into two groups according to the presence or absence of cerebrovascular embolic symptoms. The preoperative and postoperative MPV levels of each CM patient was evaluated. MPV levels were found to be significantly higher in patients with CM than in control subjects (9.86 ± 1.30 fL vs. 7.63 ± 0.78 fL, p < 0.001). Moreover, the MPV levels significantly decreased after the surgical removal of CM (9.86 ± 1.30 fL vs. 8.68 ± 1.20 fL, p < 0.001). We also found that the MPV values were significantly higher in patients with neurological embolic events (10.55 ± 1.29 fL vs. 9.59 ± 0.78 fL, p = 0.016). We conclude that increased MPV levels might be considered as a marker of increased thromboembolic risk in patients with CM.


[The single administration of ethanol and the amplitude of the action potentials of the neocortical neurons in rats: extracellular studies].
On outbred rats the influence was studied of acute administration of moderate dozes of ethanol (150 mg--1.2 g/kg, intraperitoneally) on the motor cortex neurones. It was shown that ethanol in the range of these dozes led to a change of the amplitude of extracellularly recorded action potentials, which could be directed to an increase or decrease. In the used range minimum as well as maximum dozes in various animals might elicit contrary effects, i.e. no dependence was observed of the direction of reaction of the studied neurones on the administrated doze. Possible mechanisms are discussed which may be the basis of the change of the amplitude of extracellular action potentials. Conclusion is made that use of moderate dozes of ethanol is a useful condition for studies directed to a search of mechanisms of initial reaction to alcohol action.


Machine Learning Based Linking of Patient Reported Outcome Measures to WHO International Classification of Functioning, Disability, and Health Activity/Participation Categories.
In the primary and secondary medical health sector, patient reported outcome measures (PROMs) are widely used to assess a patient's disease-related functional health state. However, the World Health Organization (WHO), in its recently adopted resolution on "strengthening rehabilitation in all health systems", encourages that all health sectors, not only the rehabilitation sector, classify a patient's functioning and health state according to the International Classification of Functioning, Disability and Health (ICF). This research sought to optimize machine learning (ML) methods that fully and automatically link information collected from PROMs in persons with unspecific chronic low back pain (cLBP) to limitations in activities and restrictions in participation that are listed in the WHO core set categories for LBP. The study also aimed to identify the minimal set of PROMs necessary for linking without compromising performance. A total of 806 patients with cLBP completed a comprehensive set of validated PROMs and were interviewed by clinical psychologists who assessed patients' performance in activity limitations and restrictions in participation according to the ICF brief core set for low back pain (LBP). The information collected was then utilized to further develop random forest (RF) methods that classified the presence or absence of a problem within each of the activity participation ICF categories of the ICF core set for LBP. Further analyses identified those PROM items relevant to the linking process and validated the respective linking performance that utilized a minimal subset of items. Compared to a recently developed ML linking method, receiver operating characteristic curve (ROC-AUC) values for the novel RF methods showed overall improved performance, with AUC values ranging from 0.73 for the ICF category d850 to 0.81 for the ICF category d540. Variable importance measurements revealed that minimal subsets of either 24 or 15 important PROM variables (out of 80 items included in full set of PROMs) would show similar linking performance. Findings suggest that our optimized ML based methods more accurately predict the presence or absence of limitations and restrictions listed in ICF core categories for cLBP. In addition, this accurate performance would not suffer if the list of PROM items was reduced to a minimum of 15 out of 80 items assessed.


Direct and indirect genetic effects of sex-specific mitonuclear epistasis on reproductive ageing.
Mitochondria are involved in ageing and their function requires coordinated action of both mitochondrial and nuclear genes. Epistasis between the two genomes can influence lifespan but whether this also holds for reproductive senescence is unclear. Maternal inheritance of mitochondria predicts sex differences in the efficacy of selection on mitonuclear genotypes that should result in differences between females and males in mitochondrial genetic effects. Mitonuclear genotype of a focal individual may also indirectly affect trait expression in the mating partner. We tested these predictions in the seed beetle Callosobruchus maculatus, using introgression lines harbouring distinct mitonuclear genotypes. Our results reveal both direct and indirect sex-specific effects of mitonuclear epistasis on reproductive ageing. Females harbouring coadapted mitonuclear genotypes showed higher lifetime fecundity due to slower senescence relative to novel mitonuclear combinations. We found no evidence for mitonuclear coadaptation in males. Mitonuclear epistasis not only affected age-specific ejaculate weight, but also influenced male age-dependent indirect effects on traits expressed by their female partners (fecundity, egg size, longevity). These results demonstrate important consequences of sex-specific mitonuclear epistasis for both mating partners, consistent with a role for mitonuclear genetic constraints upon sex-specific adaptive evolution.


Spatial Learning and Memory in Barnes Maze Test and Synaptic Potentiation in Schaffer Collateral-CA1 Synapses of Dorsal Hippocampus in Freely Moving Rats.
Synaptic plasticity has been suggested as the primary physiological mechanism underlying memory formation. Many experimental approaches have been used to investigate whether the mechanisms underlying Long-Term Potentiation (LTP) are activated during learning. Nevertheless, little evidence states that hippocampal-dependent learning triggers synaptic plasticity. In this study, we investigated if learning and memory in the Barnes maze test are accompanied by the occurrence of LTP in Schaffer collateral to CA1 synapses in freely moving rats. The rats were implanted with a recording electrode in stratum radiatum and stimulating electrodes in Schaffer collaterals of the CA1 region in the dorsal hippocampus of the right hemisphere. Following the recovery period of at least 10 days, field potentials were recorded in freely moving animals before and after training them in Barnes maze as a hippocampal-dependent spatial learning and memory test. The slope of extracellular field Excitatory Postsynaptic Potentials (fEPSPs) was measured before and after the Barnes maze test. The results showed that the fEPSP slope did not change after learning and memory in the Barnes maze test, and this spatial learning did not result in a change in synaptic potentiation in the CA1 region of the hippocampus. Spatial learning and memory in the Barnes maze test are not accompanied by LTP induction in Schaffer collateral-CA1 synapses.


Assessing health-related quality of life among cancer survivors during systemic and radiation therapy in Bangladesh: a cancer-specific exploration.
Evaluating the effects of cancer diagnosis and treatment on a patient's overall well-being is crucial and health-related quality of life (HRQoL) is a reliable metric for assessing this impact. Little is known about HRQoL among cancer survivors across various stages and treatments. The study examined individual and clinical factors influencing HRQoL among cancer survivors. A cross-sectional study was conducted in two specialised cancer care hospitals in Dhaka, Bangladesh. Cancer-diagnosed adults receiving treatment at selected hospitals from January to May 2022 were enrolled. The 5-level EuroQol-5 Dimensions version (EQ-5D-5L) instrument was used to collect HRQoL data. HRQoL scores were derived using UK value sets. The investigation used a multivariable Tobit regression model to determine the association between independent variables and HRQoL scores. A total of 607 adult patients were enrolled, with 55% being females and 66% aged 36 to 64 years. Reported health problems in five EQ-5D domains include mobility (11%), self-care (11%), usual daily activities (19%), pain/discomfort (21%), and anxiety/depression (46%). Patients with throat, brain, lung, blood, and liver cancer had lower utility scores. Advanced-stage cancer survivors had lower utility scores (β = -49 units, 95% codfidence interval [CI]: -0.75 to -0.22) compared to early-stage survivors. Physically inactive survivors had lower utility scores by 0.41 units (95% CI: -0.51 to -0.30) compared to their counterparts. Private hospital patients had higher utility scores, whereas patients belonged to poor socioeconomic groups scored worse than wealthier ones. This study highlights the impact of clinical and individual characteristics on HRQoL among cancer survivors. These findings advocate for an enhanced Bangladeshi cancer patient care model through timely interventions or programs, early detection or diagnosis, tailored treatments, and the promotion of physical activity to bolster HRQoL outcomes.


Skill memory escaping from distraction by sleep--evidence from dual-task performance.
Sleep facilitates off-line consolidation of memories, as shown for learning of motor skills in the absence of concomitant distractors. We often perform complex tasks focusing our attention mostly on one single part of them. However, we are equally able to skillfully perform other concurrent tasks. One may even improve performance on disregarded parts of complex tasks, which were learned implicitly. In the present study we investigated the role of sleep in the off-line consolidation of procedural skills when attention is diverted from the procedural task because of interference from a concurrent task. We used a dual-task paradigm containing (i) procedural serial reaction time task (SRTT), which was labeled as subordinate and unimportant and (ii) declarative word-pair association task (WPAT), performed concomitantly. The WPAT served as a masked distractor to SRTT and was strongly reinforced by the instructions. One experimental and three control groups were tested. The experimental group was re-tested after two nights of sleep (sleep group, SG). The first control group had sleep deprivation on the first post-learning night (nighttime-awake group, NA), the second control group was tested in the morning and then re-tested after 12-hours (daytime-awake group, DA); the third one had the same assignments as DA but with a subsequent, instead of a concomitant, WPAT (daytime-awake-subsequent-WPAT group, DAs). We found SRTT performance gains in SG but not in NA and DA groups. Furthermore, SG reached similar learning gains in SRTT as the DAs group, which gained in SRTT performance because of post-training interference from the declarative task. The results demonstrate that sleep allows off-line consolidation, which is resistant to deteriorating effects of a reinforced distractor on the implicit procedural learning and allowing for gains which are consistent with those produced when inhibited declarative memories of SRTT do not compete with procedural ones.


The potential of autofluorescence for the detection of single living cells for label-free cell sorting in microfluidic systems.
A novel method for studying unlabeled living mammalian cells based on their autofluorescence (AF) signal in a prototype microfluidic device is presented. When combined, cellular AF detection and microfluidic devices have the potential to facilitate high-throughput analysis of different cell populations. To demonstrate this, unlabeled cultured cells in microfluidic devices were excited with a 488 nm excitation light and the AF emission (> 505 nm) was detected using a confocal fluorescence microscope (CFM). For example, a simple microfluidic three-port glass microstructure was used together with conventional electroosmotic flow (EOF) to switch the direction of the fluid flow. As a means to test the potential of AF-based cell sorting in this microfluidic device, granulocytes were successfully differentiated from human red blood cells (RBCs) based on differences in AF. This study demonstrated the use of a simple microfabricated device to perform high-throughput live cell detection and differentiation without the need for cell-specific fluorescent labeling dyes and thereby reducing the sample preparation time. Hence, the combined use of microfluidic devices and cell AF may have many applications in single-cell analysis.


Disaster medicine: current assessment and blueprint for the future. SAEM Disaster Medicine White Paper Subcommittee.
Emergency services for disaster-affected populations require the application of out-of-hospital planning, curative acute medical skills, and public health principles. SAEM can play an important role in promoting the research and educational agendas for disaster medicine through its network of EM educators at academic health centers. Testing of disaster medicine principles as part of the EM certification process will emphasize the importance of disaster medicine in the overall training of EPs. Postgraduate fellowships in disaster medicine also should be promoted and closely linked to disaster response organizations. Overall professional training must encompass the many facets described in this paper to prepare physicians to meet the challenges of disaster medicine.


[Malignant tumors of long bones in children: differential diagnosis and the role of imaging methods].
The aim of the study was to analyze primary malignant tumors and tumor-like lesions of long bones, in relation to their localization, characteristics and distribution in age groups, in children and young adults, and to assess the role of radiography and magnetic resonance imaging (MRI) in their diagnosis. Sixty-four patients, aged between 3 and 20 years, who were referred to us with the diagnosis of a suspected malignant long-bone tumor of osseous or cartilage origin in the period from 2000 to 2004 were included in the study. Plain radiography and MRI were carried out on the same day. For MRI, the Magnetom Open Viva system (magnetic field strength of 0.2 T) was used and examination comprised a conventional STIR (corresponding to fat saturation) and a T-weighed sequence. Most patients also underwent post-contrast examination with paramagnetic contrast medium infusion. In 26 children (40.6 %) a primary malignant tumor of osseous or cartilage origin was diagnosed; one child (1.5 %) had a giant-cell tumor. The definitive diagnoses in 37 children (57.9 %) included osteomyelitis in 12, fatigue fracture in 11, posttraumatic myositis ossificans in three children, and miscellaneous diagnoses in the remaining 11 children (one, cartilaginous exostosis; three, unicameral bone cyst; two, non-ossifying fibroma; one, fibrous dysplasia; one, subperiosteal abscess; one, histiocytosis; one, foreign body; one, negative MRI findings). To confirm the diagnosis of a malignant long-bone tumor, high quality X-ray and MRI are essential; CT examination is recommended in specific indications. The results of imaging methods cannot be assessed without reference to each other. Primary malignant tumors of long bones usually involve a large soft-tissue mass, and an exclusively intraosseous localization is rare. Osteosarcoma often invades the epiphysis. In making the differential diagnosis of primary malignant bone tumors, special attention must be paid to differentiation from osteomyelitis or fatigue fractures. The majority of juvenile bone lesions of any origin are usually detected between 10 and 13 years of age. These pathologic lesions are most frequently localized in the distal or proximal transition zones between the diaphysis and metaphysis.


Tumor-targeting peptide functionalized PEG-PLA micelles for efficient drug delivery.
Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.


The Th1 cell regulatory circuitry is largely conserved between human and mouse.
Gene expression programs controlled by lineage-determining transcription factors are often conserved between species. However, infectious diseases have exerted profound evolutionary pressure, and therefore the genes regulated by immune-specific transcription factors might be expected to exhibit greater divergence. T-bet (Tbx21) is the immune-specific, lineage-specifying transcription factor for T helper type I (Th1) immunity, which is fundamental for the immune response to intracellular pathogens but also underlies inflammatory diseases. We compared T-bet genomic targets between mouse and human CD4+ T cells and correlated T-bet binding patterns with species-specific gene expression. Remarkably, we found that the majority of T-bet target genes are conserved between mouse and human, either via preservation of binding sites or via alternative binding sites associated with transposon-linked insertion. Species-specific T-bet binding was associated with differences in transcription factor-binding motifs and species-specific expression of associated genes. These results provide a genome-wide cross-species comparison of Th1 gene regulation that will enable more accurate translation of genetic targets and therapeutics from pre-clinical models of inflammatory and infectious diseases and cancer into human clinical trials.


Running on a high: parkrun and personal well-being.
Sporting or physical recreation event participation can affect different domains of mental and social well-being if sufficiently frequent, yet previous research has focused mainly on the physical health benefits of single-location or infrequent mass-participation events. We examined overall and domain specific subjective well-being of adult participants of "parkrun", a weekly, community-based, highly accessible and widespread running event. Data were from a national online survey of 865 adult Australian parkrunners. Scores on nine individual measures and the global Personal Well-being Index (PWI) were compared to national, normative data. Regression models tested associations between personal well-being and perceived benefits of parkrun (mental health and connection to community). Of 100 scores, 28% of means for parkrunners fell outside overall and age and gender subgroups normative ranges. Satisfaction with health was higher for male, those aged over 45 and overall parkrunners; only parkrunners aged 18-24 fell below their age group norm. Satisfaction with life as a whole was positively associated with perceived mental health benefits of parkrun, but not perceived community connection for women, and neither measure for men. PWI was positively associated with perceived community connection for men and with mental health benefit for women. Australian parkrunners mostly reflect the general population on personal well-being, except report superior satisfaction with physical health. Women's personal well-being may benefit from parkrun through improved mental health and men's from community connectedness. parkrun may facilitate positive expression of identity and continuation of healthy habits among athletes, and non-demanding, health enhancing activity and social interaction for non-athletes.


The effect of growth conditions on in vitro adherence, invasion, and NAF expression by Proteus mirabilis 7570.
Proteus mirabilis is a common cause of upper urinary tract infections. Fimbriae-mediated adherence of this organism to urinary tract epithelium and invasion of host cells are factors thought to be important in its pathogenesis. We have assessed the effect of growth in serum, blood, and urine on the ability of P. mirabilis 7570 to adhere to and invade in vitro the cell line EJ/28, derived from a human urinary tract tumour, and to express nonagglutinating fimbriae (NAF). Proteus mirabilis was capable of adhering to EJ/28 cells to varying degrees depending upon the growth conditions used. It was invasive under all conditions, except when grown in urine, and was found to be particularly so when serum or blood was present in the media. Expression of NAF occurred under all growth conditions examined and was limited only by a decrease in temperature.


Secondary resistance of extra-gastrointestinal stromal tumors to imatinib mesylate: report of a case.
Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.


Conversion-associated recombination in yeast (hybrids-meiosis-tetrads-marker loci-models).
Gene conversion and conversion-associated reciprocal recombination have been studied in various Saccharomyces cerevisiae hybrids. In a sample of 11,023 unselected meiotic tetrads, 907 conversions were observed at the arg4, thr3, his1, and SUP6 loci. Of these conversions, 445 (or 49.1%) were associated with reciprocal recombination of bracketing markers no more than 20-centimorgans apart. For conversions of two other loci, his2 and thr1, for which the bracketing markers were more than 20-centimorgans apart, recombination frequencies were significantly greater than 50%. These findings are discussed in terms of current models of genetic recombination. It is suggested that all meiotic crossing-over is characterized by the recombination events that are associated with conversion.


The serendipity case of the pedunculopontine nucleus low-frequency brain stimulation: chasing a gait response, finding sleep, and cognition improvement.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapy for Parkinson's disease (PD) but its effects on non-motor facets may be detrimental. The low-frequency stimulation (LFS) of the pedunculopontine nucleus (PPN or the nucleus tegmenti pedunculopontini - PPTg-) opened new perspectives. In our hands, PPTg-LFS revealed a modest influence on gait but increased sleep quality and degree of attentiveness. At odds with potential adverse events following STN-DBS, executive functions, under PPTg-ON, ameliorated. A recent study comparing both targets found that only PPTg-LFS improved night-time sleep and daytime sleepiness. Chances are that different neurosurgical groups influence either the PPN sub-portion identified as pars dissipata (more interconnected with GPi/STN) or the caudal PPN region known as pars compacta, preferentially targeting intralaminar and associative nucleus of the thalamus. Yet, the wide electrical field delivered affects a plethora of en passant circuits, and a fine distinction on the specific pathways involved is elusive. This review explores our angle of vision, by which PPTg-LFS activates cholinergic and glutamatergic ascending fibers, influencing non-motor behaviors.


Replication of obesity and associated signaling pathways through transfer of microbiota from obese-prone rats.
Aberrations in gut microbiota are associated with metabolic disorders, including obesity. However, whether shifts in the microbiota profile during obesity are a characteristic of the phenotype or a consequence of obesogenic feeding remains elusive. Therefore, we aimed to determine differences in the gut microbiota of obese-prone (OP) and obese-resistant (OR) rats and examined the contribution of this microbiota to the behavioral and metabolic characteristics during obesity. We found that OP rats display a gut microbiota distinct from OR rats fed the same high-fat diet, with a higher Firmicutes-to-Bacteroidetes ratio and significant genera differences. Transfer of OP but not OR microbiota to germ-free (GF) mice replicated the characteristics of the OP phenotype, including reduced intestinal and hypothalamic satiation signaling, hyperphagia, increased weight gain and adiposity, and enhanced lipogenesis and adipogenesis. Furthermore, increased gut permeability through conventionalization resulted in inflammation by proinflammatory nuclear factor (NF)-κB/inhibitor of NF-κB kinase subunit signaling in adipose tissue, liver, and hypothalamus. OP donor and GF recipient animals harbored specific species from Oscillibacter and Clostridium clusters XIVa and IV that were completely absent from OR animals. In conclusion, susceptibility to obesity is characterized by an unfavorable microbiome predisposing the host to peripheral and central inflammation and promoting weight gain and adiposity during obesogenic feeding.