Dissipation of 17β-estradiol in composted poultry litter.
The excreted estrogen rate of all livestock in the United States is estimated at 134 kg d. The influence of manure treatment on the fate of estrogens is critical in deciding the recycling of over 300 million dry tons of livestock produced annually. The effects of two common manure management practices, heated composting and ambient temperature decomposition, on the fate of 17β-estradiol in poultry litter were determined. A mixture of poultry litter, wood chips, and straw was amended with [C]17β-estradiol and allowed to undergo decomposition with a laboratory-scale heated composter (HC) or room temperature incubation (RTI) for 24 d. Radiolabel in the finished products was fractionated into water-extractable, acetone-extractable, nonextractable, and mineralized fractions. Total 17β-estradiol radioactive residues in the HC and RTI ( = 2) treatments were not different ( > 0.05), except that statistically less 17β-estradiol was mineralized to CO during HC than RTI (1.1 vs. 10.0% for HC and RTI, respectively). Estrone was the major degradation product in extracts of HC and RTI treatments as determined by liquid chromatography/mass spectrometry analyses. The nonextractable residues indicated no quantitative differences among the humins between the treatments. An estimated 3% of the fortified estrogenicity remained after HC treatment, and 15% of the fortified estrogenicity remained after RTI treatment. If reduction of water-removable, biologically active 17β-estradiol is the treatment goal, then HC treatment would be slightly preferred over ambient temperature degradation. However, unmanaged, ambient temperature litter piles are less costly and time consuming for food animal producers and result in greater mineralization and similar immobilization of estradiol.


[A localized reaction to sublingual immunotherapy].
An otherwise healthy 31-year-old woman with allergic rhinoconjunctivitis developed considerable swelling of the floor of her mouth after sublingual allergen-specific immunotherapy with the hyposensitization product 'Slit One grass pollen'. After discontinuation, complaints disappeared and she was successfully put on a regimen of subcutaneous immunotherapy. Despite a lack of reports of serious adverse reactions in clinical trials, the Inspectorate of Health Care and The Netherlands Pharmacovigilance Centre Lareb received several reports of sometimes serious localized reactions to oral and sublingual allergen-specific immunotherapy. Under-reporting is likely since local reactions are more or less expected. Caution should be exercised with allergen treatment, even in the case of non-invasive administration.


Epidemiology of the inherited ataxias.
Current epidemiologic studies of the inherited ataxias are limited by complex and confusing systems of nomenclature and by the lack of minimal diagnostic criteria. Despite the difficulties of comparing one study to another, most descriptive investigations provide a prevalence estimate of less than 6 cases/100,000. In isolated, inbred populations, a prevalence as high as 23 cases/100,000 has been reported. Neuroepidemiologic techniques and current knowledge concerning the epidemiology of the inherited ataxias can be applied to future studies in three broad areas--definition, classification, and etiology. Future etiologic investigations based on a goal-oriented, collaborative effort following a case-control format offer the greatest likelihood of success.


The interaction between stereoscopic and luminance motion.
An interaction in apparent motion between perceived three-dimensional forms defined by stereopsis and local luminous elements is reported. Vertical stripes of cyclopean square gratings were simulated by random-dot stereograms. Alternation of two-frame stereograms whose phases differed by 90 deg caused two kinds of percepts, planes' motion in depth (first-order stereoscopic motion, first-order SM) or lateral motion of gratings (higher-order stereoscopic motion, higher-order SM). Experiment 1 explored the conditions under which higher-order SM frequently arose, as opposed to local luminance-based in-depth motion (first-order SM). The results show that, when the spatial arrangements of two-frame random dots were correlated, higher-order SM dominated for long ISI conditions (ISI > 73 msec). When they were uncorrelated, higher-order SM dominated even under zero ISI conditions. Subjects reported that, when higher-order SM was seen, dots were attached to the surfaces of the moving cyclopean figure (motion capture). Experiment 2 tested which factor caused the domination of higher-order SM under uncorrelated conditions in Experiment 1, the larger distance of dot jump or the varied directions of the dots' motion. The results show that, when the distance of dot jump is large or when the directions of dots' motion are incoherent, higher-order SM arises more frequently. When local first-order motion signals are weakened by appropriate temporal and spatial conditions or by incoherent motion directions, higher-order SM dominates and it captures the motion of dots.


The structure of rat 28S ribosomal ribonucleic acid inferred from the sequence of nucleotides in a gene.
The nucleotide sequence of a rat 28S rRNA gene was determined. The 28S rRNA encoded in the gene contains 4718 nucleotides and the molecular weight estimated from the sequence is 1.53 x 10(6). The guanine and cytosine content is 67%. The sequence of rat 28S rRNA diverges appreciably from that of Saccharomyces carlsbergensis 26S rRNA (about 50% identity), but more closely approximates that of Xenopus laevis 28S rRNA (about 75% identity). Rat 28S rRNA is larger than the analogous nucleic acids from yeast (3393 nucleotides) and X, laevis (4110 nucleotides) ribosomes. The additional bases are inserted in specific regions and tend to be rich in guanine and cytosine. 5.8S rRNA can interact with 28S rRNA by extensive hydrogen bonding at two sites near the 5' end of the latter.


Malignant phyllode tumor metastatic to the duodenum.
Phyllode tumor (PT) is extremely rare tumor of the breast. Distant metastasis occurs in 10%-20% of patients with malignant phyllode tumor. The most common sites of metastases are the lungs and bones. Although theoretically any organ may have metastasis, an isolated duodenum metastasis has not been documented as yet in the English-language literature. We report herein a case with a isolated duodenal metastasis from PT of breast in a 31 year-old-woman who underwent right mastectomy 4 years before because of the recurrent malignant PT. She presented to our hospital with massive upper gastrointestinal bleeding. Clinical evaluation revealed a huge mass originated from duodenum. Urgent laparotomy and pancreaticoduodenectomy were carried out in order to remove the bleeding duodenal mass. The pathologic examination of the resected specimen showed a malignant spindle cell tumor consistent with metastatic malignant PT. Our case of gastrointestinal bleeding due to an isolated duodenal metastasis as a result of hematogenous spread from malignant phyllode tumor of breast is unique in the English literature and pancreaticoduodenectomy is a curative treatment for patients with isolated duodenal involvement.


Association between functional social support and cognitive function in middle-aged and older adults: a protocol for a systematic review.
Maintenance of cognitive function into old age is important for ageing populations. Researchers seek to identify modifiable risk and protective factors for cognitive function. One such modifiable factor is functional social support, that is, one's perception of whether their social network can provide resources such as material help, companionship, information and emotional contact, if needed. While the literature generally reports positive associations between functional social support and cognitive function, results vary according to study methods such as the tool used to measure functional social support or the specific cognitive domain under investigation. Our review will summarise the association between functional social support and cognitive function in middle-aged and older-aged adults who reside in any setting (eg, community dwelling, long-term care facilities). We will also identify sources of discrepant findings between studies. This protocol was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. PubMed, PsycINFO, Sociological Abstracts, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Scopus will be searched from inception to the present using a search strategy developed with a medical librarian's help. We will supplement the database searches with a grey literature search. English-language or French-language studies with a comparison group will be subject to inclusion, regardless of the measures used to assess functional social support or cognitive function. We will assess risk of bias with the Cochrane Risk of Bias Tool-Version 2 or the Newcastle-Ottawa Scale, narratively synthesise the extracted data and conduct a meta-analysis of studies with similar characteristics (eg, sample age and sex, cognitive function outcomes). Two independent raters will screen articles and assess risk of bias. This review is timely given the push toward early diagnosis and treatment of dementia/major neurocognitive disorder and other types of cognitive impairment. This protocol does not require a formal ethics review. We will publish our findings in a peer-reviewed journal.


Benson group additivity values of phosphines and phosphine oxides: Fast and accurate computational thermochemistry of organophosphorus species.
Composite quantum chemical methods W1X-1 and CBS-QB3 are used to calculate the gas phase standard enthalpy of formation, entropy, and heat capacity of 38 phosphines and phosphine oxides for which reliable experimental thermochemical information is limited or simply nonexistent. For alkyl phosphines and phosphine oxides, the W1X-1, and CBS-QB3 results are mutually consistent and in excellent agreement with available G3X values and empirical data. In the case of aryl-substituted species, different computational methods show more variation, with G3X enthalpies being furthest from experimental values. The calculated thermochemical data are subsequently used to determine Benson group additivity contributions for 24 Benson groups and group pairs involving phosphorus, thereby allowing fast and accurate estimations of thermochemical data of many organophosphorus compounds of any complexity. Such data are indispensable, for example, in chemical process design or estimating potential hazards of new chemical compounds. © 2018 Wiley Periodicals, Inc.


Placental transfer of vigabatrin (gamma-vinyl GABA) and its effect on concentration of amino acids in the embryo of TO mice.
The mechanism of the teratogenicity of vigabatrin (VGB) is unknown. The objectives of this study were to determine the placental transfer of VGB and to evaluate the effect of VGB on maternal, placental, and fetal concentrations of amino acids. A single dose of 400 mg/kg VGB in physiological saline was administered intraperitoneally to a group of Theiler outbred (TO) mice on gestational day (GD) 10. The controls received a proportionate volume of saline. Maternal blood samples, embryos, and placentas were collected at 3.5, 6.0, and 9.0 hr after treatment and their total amino acid concentrations determined in an ion-exchange amino acid analyzer. At 3.5 hr, there was a decrease in concentrations of some amino acids in the blood, placenta, and embryos of VGB-treated mice, but the decrease in methionine was most marked. gamma-aminobutyric acid (GABA) was significantly higher in the VGB group in both the embryos and the placentas at 3.5 hr but at 6.0 and 9.0 hr the differences were not significant. Vigabatrin levels were higher in the placenta than in the embryo at 3.5 hr, but at 6.0 hr there was an overlap of the VGB peak with that of tryptophan with very much lower levels than at 3.5 hr. At 9.0 hr, there was no vigabatrin peak in either the placenta or the embryo. Maternal exposure to VGB results in peak levels of the drug after 3.5 hr in the placenta and embryo. Methionine concentration is most severely affected in VGB-treated mothers, placentas, and fetuses. We speculate that this deficiency could be a possible mechanism for the teratogenic effects of vigabatrin.


Normobaric hypoxia training: the effects of breathing-gas flow rate on symptoms.
The U.S. Navy has replaced segments of refresher low-pressure chamber instruction with normobaric hypoxia training using a reduced oxygen breathing device (ROBD). A previous training evaluation revealed that this alternative instructional paradigm is a preferred means of training experienced jet aviators to recognize and recover from hypoxia. However, findings from this earlier work also indicated that air hunger was the most commonly reported symptom during ROBD training. This finding raised concern that air hunger could have resulted from a training artifact caused by the lower breathing-gas flow rate produced by the ROBD when compared to more familiar jet aircraft breathing systems. In an effort to address this issue, a software change was made that increased ROBD mask flow from 30 to 50 L x min(-1) (LPM). The purpose of this retrospective study was to determine if there are differences in the hypoxia symptoms reported by aviators trained on the ROBD upgrade (ROBD-50) compared to those trained on the original device (ROBD-30). Hypoxia training was provided to 156 aviators using the ROBD-50, and survey results were compared to those obtained from 121 aviators trained on the ROBD-30. There was a significant decrease in the number of aviators who reported experiencing air hunger while training on the ROBD-50 (44.2%) as compared to the ROBD-30 (59.4%) [Pearson chi2 (1) = 5.45, P < 0.051. These findings suggest that the ROBD breathing-gas flow rate is an important contributor to the symptom of air hunger and, therefore, may impact training fidelity.


A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (AD). Our laboratory reported increased levels of amyloid-beta (Aβ) and phosphorylated Tau (P-Tau) and reported that abnormal interactions between Aβ and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in AD. These abnormal interactions result in the proliferation of dysfunctional mitochondria in AD neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in AD. To determine the impact of reduced Drp1 in AD, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed the cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology and mitochondrial function and dendritic spines in Tau mice relative to double mutant mice. When compared with Tau mice, double mutant mice did better on the Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA- and protein-level autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared with Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number was reduced and length was increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.


Hemodynamic, hormonal, and renal effects of (pro)renin receptor blockade in experimental heart failure.
The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.


[Meniscal harvesting, processing and preservation for allogeneic transplantation].
The allogeneic meniscal transplantation (AMT) has received much attention lately for the treatment of young, active patients with painful knees previously subjected to meniscectomy. Show the current concepts on AMT as well as the methods for meniscal harvesting, processing and preservation that the Tissue Bank must implement. Based on the results of the short- and medium-term studies, the AMT has proven to relieve pain and improve function in patients with symptomatic knees and a history of meniscectomy. To respond to the requests from surgeons, the Tissue Bank should supply grafts that assure the appropriate processing and quality of the meniscus.


Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer.
Gallbladder cancer (GBC) is a particularly deadly type of cancer with a 5-year survival rate of only 10%. New effective therapeutic strategies are greatly needed. Recently, we have shown that Hedgehog (Hh) signaling is reactivated in various types of cancer and is a potential therapeutic target. However, little is known about the biological significance of Hh signaling in human GBC. In this study, we determined whether Hh signaling could be a therapeutic target in GBC. The Hh transcription factor Gli1 was detected in the nucleus of GBC cells but not in the nucleus of normal gallbladder cells. The expression levels of Sonic Hh (Shh) and Smoothened (Smo) in human GBC specimens (n = 37) were higher than those in normal gallbladder tissue. The addition of exogenous Shh ligand augmented the anchor-dependent and anchor-independent proliferation and invasiveness of GBC cells in vitro. In contrast, inhibiting the effector Smo decreased the anchor-dependent and anchor-independent proliferation. Furthermore, the suppression of Smo decreased GBC cell invasiveness through the inhibition of MMP-2 and MMP-9 expression and inhibited the epithelial-mesenchymal transition. In a xenograft model, tumor volume in Smo siRNA-transfected GBC cells was significantly lower than in control tumors. These results suggest that Hh signaling is elevated in GBC and may be involved in the acquisition of malignant phenotypes, and that Hh signaling may be a potential therapeutic target for GBC.


PER2 regulates odontoblastic differentiation of dental papilla cells in vitro via intracellular ATP content and reactive oxygen species levels.
Dental papilla cells (DPCs) are one of the key stem cells for tooth development, eventually forming dentin and pulp. Previous studies have reported that PER2 is expressed in a 24-hour oscillatory pattern in DPCs in vitro. In vivo, PER2 is highly expressed in odontoblasts (which are differentiated from DPCs). However, whether PER2 modulates the odontogenic differentiation of DPCs is uncertain. This research was to identify the function of PER2 in the odontogenic differentiation of DPCs and preliminarily explore its mechanisms. We monitored the expression of PER2 in DPCs differentiated in vivo. We used PER2 overexpression and knockdown studies to assess the role of PER2 in DPC differentiation and performed intracellular ATP content and reactive oxygen species (ROS) assays to further investigate the mechanism. PER2 expression was considerably elevated throughout the odontoblastic differentiation of DPCs in vivo. Overexpressing Per2 boosted levels of odontogenic differentiation markers, such as dentin sialophosphoprotein (Dspp), dentin matrix protein 1 (Dmp1), and alkaline phosphatase (Alp), and enhanced mineralized nodule formation in DPCs. Conversely, the downregulation of Per2 inhibited the differentiation of DPCs. Additionally, downregulating Per2 further affected intracellular ATP content and ROS levels during DPC differentiation. Overall, we demonstrated that PER2 positively regulates the odontogenic differentiation of DPCs, and the mechanism may be related to mitochondrial function as shown by intracellular ATP content and ROS levels.


Control of the cAMP pathway by the cell cycle start function, CDC25, in Saccharomyces cerevisiae.
We investigated the relationship in Saccharomyces cerevisiae between the cell cycle start function, CDC25, and two mutants defining components of the cAMP pathway. The thermolabile adenylate cyclase mutant cyr1-2(ts) is phenotypically similar to the temperature-sensitive mutant cdc25(ts) in that both mutants, when shifted to the restrictive temperature, arrest in G1 of the cell cycle and permit the initiation of meiosis and sporulation. The mutant bcy1 [a lesion resulting in a low level of regulatory (R) subunit and a high level of active, catalytic (C) subunit of the cAMP-dependent protein kinase] suppresses the temperature-sensitive phenotype of cyr1-2(ts) and confers an asporogenous phenotype. We found that cdc25(ts) complemented cyr1-2(ts), and, unlike cyr1-2(ts), was not suppressible by bcy1, demonstrating that CYR1 and CDC25 must encode different functions. Also our results indicate that CDC25 does not encode the R subunit of the cAMP-dependent protein kinase. In addition, although the cdc25(ts)bcy1 double mutant was temperature sensitive like cdc25(ts), we found that the cdc25(ts)bcy1 homozygous diploid was asporogenous like bcy1/bcy1. The inability of the cdc25(ts)bcy1 double mutant to sporulate demonstrated that CDC25 does not encode the C subunit of the cAMP kinase, and indicated that the CDC25 function modulates the cAMP pathway to control meiosis and sporulation. Further, the temperature-sensitive phenotype of the double mutant, and hence the inability of bcy1 to suppress cdc25(ts), suggested that a second CDC25 cell cycle function exists which is independent of the cAMP pathway.(ABSTRACT TRUNCATED AT 250 WORDS)


Flavoenzyme-catalyzed formation of disulfide bonds in natural products.
Nature provides a rich source of compounds with diverse chemical structures and biological activities, among them, sulfur-containing metabolites from bacteria and fungi. Some of these compounds bear a disulfide moiety that is indispensable for their bioactivity. Specialized oxidoreductases such as GliT, HlmI, and DepH catalyze the formation of this disulfide bridge in the virulence factor gliotoxin, the antibiotic holomycin, and the anticancer drug romidepsin, respectively. We have examined all three enzymes by X-ray crystallography and activity assays. Despite their differently sized substrate binding clefts and hence, their diverse substrate preferences, a unifying reaction mechanism is proposed based on the obtained crystal structures and further supported by mutagenesis experiments.


Poly(oligo(ethylene glycol) methyl ether methacrylate) Brushes on High-κ Metal Oxide Dielectric Surfaces for Bioelectrical Environments.
Advances in electronics and life sciences have generated interest in "lab-on-a-chip" systems utilizing complementary metal oxide semiconductor (CMOS) circuitry for low-power, portable, and cost-effective biosensing platforms. Here, we present a simple and reliable approach for coating "high-κ" metal oxide dielectric materials with "non-fouling" (protein- and cell-resistant) poly(oligo(ethylene glycol) methyl ether methacrylate (POEGMA) polymer brushes as biointerfacial coatings to improve their relevance for biosensing applications utilizing advanced electronic components. By using a surface-initiated "grafting from" strategy, POEGMA films were reliably grown on each material, as confirmed by ellipsometric measurements and X-ray photoelectron spectroscopy (XPS) analysis. The electrical behavior of these POEGMA films was also studied to determine the potential impact on surrounding electronic devices, yielding information on relative permittivity and breakdown field for POEGMA in both dry and hydrated states. We show that the incorporation of POEGMA coatings significantly reduced levels of nonspecific protein adsorption compared to uncoated high-κ dielectric oxide surfaces as shown by protein resistance assays. These attributes, combined with the robust dielectric properties of POEGMA brushes on high-κ surfaces open the way to incorporate this protein and cell resistant polymer interface into CMOS devices for biomolecular detection in a complex liquid milieu.


Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor.
Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal proliferation of transformed myofibroblasts, with a prominent inflammatory cell component, that can mimic other spindle cell processes such as nodular fasciitis, desmoid tumor, and gastrointestinal stromal tumor. Genetic analyses have recently demonstrated rearrangements of anaplastic lymphoma kinase (ALK), located at 2p23, in a subset of IMTs. Molecular characterizations have identified ALK fusions involving tropomyosin-3 and -4 (TPM-3 and -4), the clathrin heavy chain (CLTC), and the cysteinyl-tRNA synthetase (CARS) genes as fusion partners. Here we describe two IMTs with a novel ALK fusion that involves the Ran-binding protein 2 (RANBP2) gene at 2q13, which normally encodes a large (358-kDa) nucleopore protein localized at the cytoplasmic side of the nuclear pore complex. The N-terminal 867 residues of RANBP2 are fused to the cytoplasmic segment of ALK in the 1,430-amino acid RANBP2-ALK chimeric protein. Myofibroblasts that express RANBP2-ALK exhibit nuclear membrane-associated ALK staining that is unique compared to the subcellular localization observed with other ALK fusions in IMT, presumably attributable to heteroassociation of the fusion with normal RANBP2 at the nuclear pore. These findings expand the spectrum of ALK abnormalities observed in IMT and further confirm the clonal, neoplastic nature of these lesions.


Scar Formation and Debris Elimination during Hair Cell Degeneration in the Adult DTR Mouse.
The auditory sensory epithelium of the mammalian inner ear is a highly organized structure that contains sensory hair cells (HCs) and non-sensory supporting cells (SCs). Following the partial loss of HCs after cochlear insults such as overstimulation or ototoxic drugs, SCs seal the luminal epithelial surface (reticular lamina) and reorganize its cellular pattern. Here we investigated the changes in the sensory epithelium following a rapid and severe cochlear insult in the diphtheria toxin receptor (DTR) mouse, where diphtheria toxin (DT) injection leads to a HC-specific lesion resulting in a complete HC loss. We found that DT-induced selective HC ablation could lead to a pattern of scar formation and apical cell-cell adherens and tight junction reorganization similar to that occurring after other types of cochlear insult. Prestin, an outer HC-specific protein, was present in amorphous clumps at the sites where SCs had expanded to fill the spaces vacated by the dead HCs for up to 2 months after the DT induced lesion. Many of the prestin clumps appeared to occupy spaces within SCs, suggesting that SCs participate in the removal process of HC corpses in the DTR deafness model. Prestin clumps could be seen in different areas all along the length of the SCs, and appeared to be inside the SCs as well as in the inter-cellular spaces between SCs. The findings suggest that HC elimination in the DTR deafness model follows a mechanism similar to that in overstimulation or ototoxicity models, making the DTR mouse useful for understanding the process underlying HC elimination and the role of SCs in this process.


Crystal structure of human cystatin C stabilized against amyloid formation.
Human cystatin C (HCC) is a family 2 cystatin inhibitor of papain-like (C1) and legumain-related (C13) cysteine proteases. In pathophysiological processes, the nature of which is not understood, HCC is codeposited in the amyloid plaques of Alzheimer's disease or Down's syndrome. The amyloidogenic properties of HCC are greatly increased in a naturally occurring L68Q variant, resulting in fatal cerebral amyloid angiopathy in early adult life. In all crystal structures of cystatin C studied to date, the protein has been found to form 3D domain-swapped dimers, created through a conformational change of a beta-hairpin loop, L1, from the papain-binding epitope. We have created monomer-stabilized human cystatin C, with an engineered disulfide bond (L47C)-(G69C) between the structural elements that become separated upon domain swapping. The mutant has drastically reduced dimerization and fibril formation properties, but its inhibition of papain is unaltered. The structure confirms the success of the protein engineering experiment to abolish 3D domain swapping and, in consequence, amyloid fibril formation. It illustrates for the first time the fold of monomeric cystatin C and allows verification of earlier predictions based on the domain-swapped forms and on the structure of chicken cystatin. Importantly, the structure defines the so-far unknown conformation of loop L1, which is essential for the inhibition of papain-like cysteine proteases.


Configuration Control in the Synthesis of Homo- and Heteroleptic Bis(oxazolinylphenolato/thiazolinylphenolato) Chelate Ligand Complexes of Oxorhenium(V): Isomer Effect on Ancillary Ligand Exchange Dynamics and Implications for Perchlorate Reduction Catalysis.
This study develops synthetic strategies for N,N-trans and N,N-cis Re(O)(LO-N)2Cl complexes and investigates the effects of the coordination spheres and ligand structures on ancillary ligand exchange dynamics and catalytic perchlorate reduction activities of the corresponding [Re(O)(LO-N)2](+) cations. The 2-(2'-hydroxyphenyl)-2-oxazoline (Hhoz) and 2-(2'-hydroxyphenyl)-2-thiazoline (Hhtz) ligands are used to prepare homoleptic N,N-trans and N,N-cis isomers of both Re(O)(hoz)2Cl and Re(O)(htz)2Cl and one heteroleptic N,N-trans Re(O)(hoz)(htz)Cl. Selection of hoz/htz ligands determines the preferred isomeric coordination sphere, and the use of substituted pyridine bases with varying degrees of steric hindrance during complex synthesis controls the rate of isomer interconversion. The five corresponding [Re(O)(LO-N)2](+) cations exhibit a wide range of solvent exchange rates (1.4 to 24,000 s(-1) at 25 °C) and different LO-N movement patterns, as influenced by the coordination sphere of Re (trans/cis), the noncoordinating heteroatom on LO-N ligands (O/S), and the combination of the two LO-N ligands (homoleptic/heteroleptic). Ligand exchange dynamics also correlate with the activity of catalytic reduction of aqueous ClO4(-) by H2 when the Re(O)(LO-N)2Cl complexes are immobilized onto Pd/C. Findings from this study provide novel synthetic strategies and mechanistic insights for innovations in catalytic, environmental, and biomedical research.


Overall management of emergency general surgery patients during the surge of the COVID-19 pandemic: an analysis of procedures and outcomes from a teaching hospital at the worst hit area in Spain.
To assess how the COVID-19 outbreak has affected emergency general surgery (EGS) care during the pandemic, indications for surgery, types of procedures, perioperative course, and final outcomes. This is a retrospective study of EGS patients during the pandemic period. The main outcome was 30-day morbidity and mortality according to severity and COVID-19 infection status. Secondary outcomes were changes in overall management. A logistic regression analysis was done to assess factors predictive of mortality. One hundred and fifty-three patients were included. Half of the patients with an abdominal ultrasound and/or CT scan had signs of severity at diagnosis, four times higher than the previous year. Non-COVID patients underwent surgery more often than the COVID group. Over 1/3 of 100 operated patients had postoperative morbidity, versus only 15% the previous year. The most common complications were septic shock, pneumonia, and ARDS. ICU care was required in 17% of patients, and was most often required in the SARS-CoV-2-infected group, which also had a higher morbidity and mortality. The 30-day mortality in the surgical series was of 7%, with no differences with the previous year. The strongest independent predictors of overall mortality were age > 70 years, ASA III-IV, ESS > 9, and SARS-CoV-2 infection. Non-operative management (NOM) was undertaken in a third of patients, and only 14% of operated patients had a perioperative confirmation of -CoV-2 infection. The severity and morbidity of COVID-19-infected patients was much higher. Late presentations for medical care may have added to the high morbidity of the series.


"MOONSTROKE": Lunar patterns of stroke occurrence combined with circadian and seasonal rhythmicity--A hospital based study.
Both time of the day and season have been shown to have a significant effect on stroke incidence. In contrast, the role played by the moon has been little studied. We aimed to investigate the potential association of the lunar phase with the incidence of stroke subtypes [intracerebral hemorrhage (ICH), transient ischemic attack (TIA) and ischemic stroke (IS)], adjusted by circadian and seasonal variations. Consecutive stroke admissions to the Royal Melbourne Hospital (RMH) were analyzed from 2004-2011. Of 6252 patients, 4085 (65.3%) had confirmed dates and hour of the day. Of these, 632 (15.5%) had ICH, 658 (16.1%) presented with TIA and 2202 (53.9%) had IS. There were also 593 (14.5%) stroke mimics. We measured the association of stroke incidence with a particular lunar phase using an incidence rate ratio (IRR) with 95% confidence intervals (CI) using Poisson regression model (new moon set as reference). Compared with new moon phase, ICHs occurred significantly more during the first quarter (IRR, 1.55; 95%CI, 1.04 to 2.30; p = 0.03). More TIAs were observed during the first quarter and full moon than in new moon (IRR, 1.69; 95%CI, 1.16 to 2.46; p = 0.01; IRR, 1.52; 95%CI, 0.00 to 2.31; p = 0.05; respectively). Both ICH and TIA occurrence slightly decreased as lunar illumination increased (IRR, 0.99; 95%CI, 0.99 to 1.00; p = 0.01; IRR, 0.99; 95%CI, 0.99 to 1.00; p = 0.04; respectively). No association was found between lunar phase or illumination and IS. All stroke subtypes were less likely to happen between 12AM and 6AM than the remaining 18 h of the day. IS occurrence was significantly higher during the spring than summer (IRR, 1.14; 95%CI, 1.02 to 1.28; p = 0.03). For the patients older than 65 years, incidence of both ICH and IS was higher in spring than in summer (IRR, 1.33; 95%CI, 1.01 to 1.74; p = 0.04; IRR, 1.22; 95%CI, 1.06 to 1.39; p = 0.005; respectively). The lunar phase and illumination are associated with both ICH and TIA incidence. These findings should be tested on other stroke databases.


Treatment of Mooren's ulcer with cyclosporin A: report of three cases.
Three patients with severe, bilateral, progressive Mooren's ulcers, unresponsive to medical and surgical therapy, were treated with cyclosporin A. All three responded rapidly to the drug and there has been no recurrence of the Mooren's ulcers since (average follow-up 14 months). Peripheral blood T lymphocyte subsets were estimated prior to and during treatment. No significant abnormalities were found initially. Suppressor cells increased on treatment, and a corresponding drop of the helper/suppressor cell ratio occurred in two patients.


Direct observation of dynamical bifurcation between two driven oscillation states of a Josephson junction.
We performed a novel phase-sensitive microwave reflection experiment which directly probes the dynamics of the Josephson plasma resonance in both the linear and the nonlinear regime. When the junction was driven below the plasma frequency into the nonlinear regime, we observed for the first time the transition between two different dynamical states predicted for nonlinear systems. In our experiment, this transition appears as an abrupt change in the reflected signal phase at a critical excitation power. This controlled dynamical switching can form the basis of a sensitive amplifier, in particular, for the readout of superconducting qubits.


Infection burden and its association with neurite orientation dispersion and density imaging markers in the UK Biobank.
Infection burden (IB), although linked to neurodegeneration, including Alzheimer's Disease (AD), has not been examined against neurite orientation, dispersion, and density imaging (NODDI) measures. Among 38,803 UK Biobank adults (Age:40-70 years), we tested associations of total IB (IBtotal, 47.5 %) and hospital-treated IB (IBhosp, 9.7 %) with NODDI measures (5-15 years later), including volume fraction of Gaussian isotropic diffusion (ISOVF), intra-cellular volume fraction (ICVF) and orientation dispersion (OD) indices, using multiple linear regression models. Total and hospital-treated infection burdens (IBtotal and IBhosp) were associated with increased ISOVF, indicating increased free-water component. IBtotal was positively associated with OD, indicating that at higher IBtotal there was greater fanning of neurites. This was more evident in the lower cardiovascular health group. IBhosp was associated with higher OD, and lower ICVF at higher AD polygenic risk. Together, these findings indicate that both total and hospital-treated infections have effects on NODDI outcomes in the direction of poor brain health. These effects were largely homogeneous across cardiovascular health and AD polygenic risk groups, with some effects shown to be stronger at poor cardiovascular health and/or higher AD risk. Total and hospital-treated infections were associated with poorer white matter microstructure (higher ISOVF or OD or lower ICVF), with some heterogeneity across cardiovascular health and AD risk. Longitudinal studies with multiple repeats on neuroimaging markers in comparable samples are needed.


Self-Monitoring Kidney Function Post Transplantation: Reliability of Patient-Reported Data.
The high frequency of outpatient visits after kidney transplantation is burdensome to both the recovering patient and health care capacity. Self-monitoring kidney function offers a promising strategy to reduce the number of these outpatient visits. The objective of this study was to investigate whether it is safe to rely on patients' self-measurements of creatinine and blood pressure, using data from a self-management randomized controlled trial. For self-monitoring creatinine, each participant received a StatSensor Xpress-i Creatinine Meter and related test material. For self-monitoring blood pressure, each participant received a Microlife WatchBP Home, an oscillometric device for blood pressure self-measurement on the upper arm. Both devices had a memory function and the option to download stored values to a computer. During the first year post transplantation, 54 patients registered their self-measured creatinine values in a Web-based Self-Management Support System (SMSS) which provided automatic feedback on the registered values (eg, seek contact with hospital). Values registered in the SMSS were compared with those logged automatically in the creatinine device to study reliability of registered data. Adherence to measurement frequency was determined by comparing the number of requested with the number of performed measurements. To study adherence to provided feedback, SMSS-logged feedback and information from the electronic hospital files were analyzed. Level of adherence was highest during months 2-4 post transplantation with over 90% (42/47) of patients performing at least 75% of the requested measurements. Overall, 87.00% (3448/3963) of all registered creatinine values were entered correctly, although values were often registered several days later. If (the number of) measured and registered values deviated, the mean of registered creatinine values was significantly lower than what was measured, suggesting active selection of lower creatinine values. Adherence to SMSS feedback ranged from 53% (14/24) to 85% (33/39), depending on the specific feedback. Patients' tendency to postpone registration and to select lower creatinine values for registration and the suboptimal adherence to the feedback provided by the SMSS might challenge safety. This should be well considered when designing self-monitoring care systems, for example by ensuring that self-measured data are transferred automatically to an SMSS.


Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women.
Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.


Exploring the psychological factors involved in the Ladbroke Grove rail accident.
Ten years after the event and the question as to exactly why a driver passed a signal at danger to cause the Ladbroke Grove rail disaster is still an open one. This paper uses the literature on human error and cognition, combined with critical path analysis, to provide further insight. Five aspects of train operation are drawn out of the known facts surrounding the incident: custom and practice in the use of the Driver's Reminder Appliance, operation and use of the Automatic Warning System, the sequence of signalling information, methods of supplying route information, and speed restrictions. Associated with each are several important human factors issues which, combined, give rise to five potential explanations. Critical path analysis is used to map these explanations onto the known facts of the situation. It is suggested that the proximal cause of the Ladbroke Grove rail crash was a combination of an association-activation error and a mode error (leading the driver to mistakenly assume he had activated the Reminder Appliance) together with a loss-of-activation error (the driver failing to remember that a previous signal was showing caution) and a data-driven-activation error (by associating an in-cab warning to the wrong external source). The findings support the original inquiry recommendations, but also go further into predictive methods of detecting problems at the human/transport system interface.


Clinician discomfort with life support plans for mechanically ventilated patients.
To examine the incidence and predictors of clinician discomfort with life support plans for ICU patients. Prospective cohort in 13 medical-surgical ICUs in four countries. 657 mechanically ventilated adults expected to stay in ICU at least 72 h. Daily we documented the life support plan for mechanical ventilation, inotropes and dialysis, and clinician comfort with these plans. If uncomfortable, clinicians stated whether the plan was too technologically intense (the provision of too many life support modalities or the provision of any modality for too long) or not intense enough, and why. At least one clinician was uncomfortable at least once for 283 (43.1%) patients, primarily because plans were too technologically intense rather than not intense enough (93.9% vs. 6.1%). Predictors of discomfort because plans were too intense were: patient age, medical admission, APACHE II score, poor prior functional status, organ dysfunction, dialysis in ICU, plan to withhold dialysis, plan to withhold mechanical ventilation, first week in the ICU, clinician, and city. Clinician discomfort with life support perceived as too technologically intense is common, experienced mostly by nurses, variable across centers, and is more likely for older, severely ill medical patients, those with acute renal failure, and patients lacking plans to forgo reintubation and ventilation. Acknowledging the sources of discomfort could improve communication and decision making.


Tc-99m sulfur colloid scintigraphy for detecting perigraft flow following endovascular aortic aneurysm repair: A feasibility study.
To determine if scintigraphy with Tc-99m sulfur colloid can be used to detect perigraft flow after stent-graft repair of abdominal aortic aneurysm (AAA). Twenty-three men and two women aged 56-84 years (mean 71 years) underwent endoluminal AAA repair as part of the EVT Phase II trial [EVT = Endovascular Technologies (Menlo Park, CA, USA)]. Aneurysm size averaged 5.4 cm (range 3-8 cm). Sixteen bifurcated, seven tube, and two aorto-uniiliac grafts were placed. Two days after stent-graft placement, patients underwent both contrast-enhanced computed tomography (CT), including delayed views, and Tc-99m sulfur colloid scintigraphy. Perigraft flow was found in only one patient at completion of angiography. Four additional patients had perigraft flow, discovered during their postoperative follow-up CT. Four patients had leaks at an attachment site and one had retrograde branch flow. Tc-99m sulfur colloid scintigraphy failed to diagnose any of the five leaks prospectively. In two of these patients, however, some abnormal paraaortic activity was noted in retrospect. Tc-99m sulfur colloid scintigraphy was unable to demonstrate endoleak with either rapid flow (attachment site leak) or slow filling (branch flow).


Patterns of Pupillary Activity During Binocular Disparity Resolution.
This study examined the dynamic coordination between disconjugate, vergence eye movements, and pupil size in 52 normal subjects during binocular disparity stimulation in a virtual reality display. Eye movements and pupil area were sampled with a video-oculographic system at 100 Hz during performance of two tasks, (1) fusion of a binocular disparity step (±1.5° of visual angle in the horizontal plane) and (2) pursuit of a sinusoidally varying binocular disparity stimulus (0.1 Hz, ±2.6° of visual angle in the horizontal plane). Pupil size data were normalized on the basis of responses to homogeneous illumination increments ranging from 0.42 to 65.4 cd/m2. The subjects produced robust vergence eye movements in response to disparity step shifts and high fidelity sinusoidal vergence responses (R 2 relative to stimulus profile: 0.933 ± 0.088), accompanied by changes in pupil area. Trajectory plots of pupil area as a function of vergence angle showed that the pupil area at zero vergence is altered between epochs of linear vergence angle-pupil area relations. Analysis with a modified Gath-Geva clustering algorithm revealed that the dynamic relationship between the ocular vergence angle and pupil size includes two different transient, synkinetic response patterns. The near response pattern, pupil constriction during convergence and pupil dilation during divergence, occurred ~80% of the time across subjects. An opposite, previously undescribed synkinetic pattern was pupil constriction during divergence and pupil dilatation during convergence; it occurred ~15% of the time across subjects. The remainder of the data were epochs of uncorrelated activity. The pupil size intercepts of the synkinetic segments, representing pupil size at initial tropia, had different relationships to vergence angle for the two main coordinated movement types. Hippus-like movements of the pupil could also be accompanied by vergence movements. No pupil coordination was observed during a conjugate pursuit task. In terms of the current dual interaction control model (1), findings suggest that the synkinetic eye and pupillary movements are produced by a dynamic switch of the influence of vergence related information to pupil control, accompanied by a resetting of the pupil aperture size at zero-vergence.


QuantWorm: a comprehensive software package for Caenorhabditis elegans phenotypic assays.
Phenotypic assays are crucial in genetics; however, traditional methods that rely on human observation are unsuitable for quantitative, large-scale experiments. Furthermore, there is an increasing need for comprehensive analyses of multiple phenotypes to provide multidimensional information. Here we developed an automated, high-throughput computer imaging system for quantifying multiple Caenorhabditis elegans phenotypes. Our imaging system is composed of a microscope equipped with a digital camera and a motorized stage connected to a computer running the QuantWorm software package. Currently, the software package contains one data acquisition module and four image analysis programs: WormLifespan, WormLocomotion, WormLength, and WormEgg. The data acquisition module collects images and videos. The WormLifespan software counts the number of moving worms by using two time-lapse images; the WormLocomotion software computes the velocity of moving worms; the WormLength software measures worm body size; and the WormEgg software counts the number of eggs. To evaluate the performance of our software, we compared the results of our software with manual measurements. We then demonstrated the application of the QuantWorm software in a drug assay and a genetic assay. Overall, the QuantWorm software provided accurate measurements at a high speed. Software source code, executable programs, and sample images are available at www.quantworm.org. Our software package has several advantages over current imaging systems for C. elegans. It is an all-in-one package for quantifying multiple phenotypes. The QuantWorm software is written in Java and its source code is freely available, so it does not require use of commercial software or libraries. It can be run on multiple platforms and easily customized to cope with new methods and requirements.


Functions and regulation of MUC13 mucin in colon cancer cells.
MUC13 is overexpressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. Stable cell lines with either overexpressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. Overexpression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase, sonic hedgehog, B cell lymphoma murine like site 1, and GATA like transcription factor 1. Additionally, MUC13-overexpressing cells showed increased HER2 and P-ERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of the JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6-induced MUC13 expression. IHC analysis showed increased expression of both P-STAT5 and MUC13 in colon cancer as compared to adjacent normal tissue. The results of this study, for the first time, suggest functional roles of MUC13 in colon cancer progression and provide information regarding the regulation of MUC13 expression via JAK2/STAT5 which may reveal promising therapeutic approaches for colon cancer treatment.


Motor inhibition affects the speed but not accuracy of aimed limb movements in an insect.
When reaching toward a target, human subjects use slower movements to achieve higher accuracy, and this can be accompanied by increased limb impedance (stiffness, viscosity) that stabilizes movements against motor noise and external perturbation. In arthropods, the activity of common inhibitory motor neurons influences limb impedance, so we hypothesized that this might provide a mechanism for speed and accuracy control of aimed movements in insects. We recorded simultaneously from excitatory leg motor neurons and from an identified common inhibitory motor neuron (CI1) in locusts that performed natural aimed scratching movements. We related limb movement kinematics to recorded motor activity and demonstrate that imposed alterations in the activity of CI1 influenced these kinematics. We manipulated the activity of CI1 by injecting depolarizing or hyperpolarizing current or killing the cell using laser photoablation. Naturally higher levels of inhibitory activity accompanied faster movements. Experimentally biasing the firing rate downward, or stopping firing completely, led to slower movements mediated by changes at several joints of the limb. Despite this, we found no effect on overall movement accuracy. We conclude that inhibitory modulation of joint stiffness has effects across most of the working range of the insect limb, with a pronounced effect on the overall velocity of natural movements independent of their accuracy. Passive joint forces that are greatest at extreme joint angles may enhance accuracy and are not affected by motor inhibition.


Acetyl-CoA and the regulation of metabolism: mechanisms and consequences.
Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a 'growth' or 'fed' state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under 'survival' or 'fasted' states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitate the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes.


Helping patients receive medical benefits. Collaboration between hospitals and legal services assists providers and low-income Kansans.
In Kansas, legal services lawyers have teamed up with Catholic healthcare administrators to help uninsured and underinsured hospital patients receive healthcare benefits from programs for which they may be eligible. The project--Hospital Patient Assistance Program--provides comprehensive assistance in establishing a patient's eligibility for medical benefits. Hospital participation in the program is simple. When business office or admissions staff discover that a self-pay patient has been registered with the program, they refer the patient to Kansas Legal Services; Inc. (KLS). KLS staff members try to determine if the patient is eligible for benefits from any of a number of programs, including Medicaid, Medicare, and Crime Victims Assistance. If KLS finds no programs for which the patient is eligible, it does not accept the case and notifies the hospital. Hospitals participating in the program have found that many accounts they previously wrote off as not collectible can be paid. Since the program began in 1990, participating hospitals have realized almost $8 million in payments from various benefit sources.


Prepubertal PTU treatment in rat increases Sertoli cell number and sperm production.
The number of Sertoli cells (SCs) ultimately determines the upper limit of sperm production in the testis. Previous studies have shown that thyroid hormones (TH) receptors are abundantly expressed in developing SCs; therefore, it was highly significant to discover that transient neonatal hypothyroidism induced by the goitrogen 6-n-propyl-2-thiouracil (PTU) can extend SCs proliferation beyond the first 2 weeks postnatal and increase testis weight and sperm production. Further studies concluded that treatment must begin before day 8 post birth in rats. Recent studies, however, showed that SCs present in the transition region at the rete testis exhibit a more immature phenotype and have prolonged mitotic activity, which led to the hypothesis that SCs in this region will retain the capacity to respond to PTU treatment over a longer period of time. In the present study, male Wistar rats were treated with PTU from days 21 to 40 and were evaluated at 40 and 160 days of age. Similar to neonatal rat SCs, it was demonstrated that prepubertal SCs in the transition region have a high mitotic activity and are highly sensitive to TH levels. This delayed, transient hypothyroidism resulted in significantly increased testis weight, SCs number and daily sperm production. The results demonstrate for the first time that Sertoli cells showing plasticity in the transition region can be stimulated to increase proliferation and contribute to a late stage surge in testis weight and sperm output.


Deep sequencing for de novo construction of a marine fish (Sparus aurata) transcriptome database with a large coverage of protein-coding transcripts.
The gilthead sea bream (Sparus aurata) is the main fish species cultured in the Mediterranean area and constitutes an interesting model of research. Nevertheless, transcriptomic and genomic data are still scarce for this highly valuable species. A transcriptome database was constructed by de novo assembly of gilthead sea bream sequences derived from public repositories of mRNA and collections of expressed sequence tags together with new high-quality reads from five cDNA 454 normalized libraries of skeletal muscle (1), intestine (1), head kidney (2) and blood (1). Sequencing of the new 454 normalized libraries produced 2,945,914 high-quality reads and the de novo global assembly yielded 125,263 unique sequences with an average length of 727 nt. Blast analysis directed to protein and nucleotide databases annotated 63,880 sequences encoding for 21,384 gene descriptions, that were curated for redundancies and frameshifting at the homopolymer regions of open reading frames, and hosted at http://www.nutrigroup-iats.org/seabreamdb. Among the annotated gene descriptions, 16,177 were mapped in the Ingenuity Pathway Analysis (IPA) database, and 10,899 were eligible for functional analysis with a representation in 341 out of 372 IPA canonical pathways. The high representation of randomly selected stickleback transcripts by Blast search in the nucleotide gilthead sea bream database evidenced its high coverage of protein-coding transcripts. The newly assembled gilthead sea bream transcriptome represents a progress in genomic resources for this species, as it probably contains more than 75% of actively transcribed genes, constituting a valuable tool to assist studies on functional genomics and future genome projects.


Deregulated expression of the per2 gene in human colorectal carcinoma.
The circadian system is involved in the control of cell proliferation and apoptosis. The aim of this study was to analyze expression of the human per2 gene in patients who underwent surgery for colorectal carcinoma. The study included 25 patients of both genders. Patients were exposed to light from 6:00 a.m. until 9:00 p.m. according to standard hospital practice. Tissue samples were taken from the tumor as well as from the proximal and distal areas of the resected colon at the time of surgery. Surgery was performed during the morning hours. Expression of per2 mRNA was measured by real-time PCR. There was a significant negative correlation between per2 gene expression and tumor staging. Expression of per2 mRNA did not correlate with whether the tumor was localized in the colon or rectum. In comparison with ectomized tissue without malignancy from patients with colorectal carcinoma, our data demonstrate per2 mRNA deregulation in tumor tissue, and suggest a way in which the circadian system can influence tumorigenesis.


Periodontal Outcomes in Liver Transplantation Individuals: A Systematic Review and Meta-analysis.
To systematically review the literature for observational studies evaluating periodontal outcomes in pre- and post-liver transplant (LT) individuals compared to a control group. Specific strategies were designed to search five databases and the grey literature. Hand-searches were also performed. The following periodontal outcomes were analyzed in pre-LT, post-LT and control groups: plaque index (PI), gingival index (GI), gingival growth (GO), alveolar bone loss (ABL) probing depth (PD) and clinical attachment level (CAL). Meta-analyses and subgroup analyses were conducted. Among the 257 studies retrieved, 11 studies were included. Four studies were incorporated into the meta-analysis and showed that PI (mean difference=0.15, 95%CI: 0.12-0.18) and GI (mean difference=0.31, 95%CI: 0.06-0.56) were significantly higher in post-LT individuals compared to the control group. There was no significant mean difference of PD (mean difference=0.49, 95%CI: -0.26-1.25) but CAL (mean differ- ence=1.47, 95%CI: 0.19-2.75) were significantly higher in pre-LT individuals compared to the control group. The higher means of PI and GI in post-LT and CAL in pre-LT compared to healthy individuals suggest a relationship between the periodontal condition and the transplantation status.


On some properties of a new steroid curare-like compound pipecurium bromide.
In experiments on cats it has been shown that 2 beta, 16 beta-bis (4'-dimethyl-1'-piperazino)-3 alpha, 17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), is a non-depolarizing muscular blocker. The order of myorelaxation evoked by this agent is characteristic: first the chewing and limb muscles, then abdominal muscles and diaphragm and at the end intercostal muscles are relaxed. Pipercurium bromide has no cardiotropic, atropine-like, or ganglion-blocking activity. It fails to influence the coronary blood-supply or myocardial oxygen consumption. No acetylcholinesterase inhibiting action of the compound was seen. It does not affect the central nervous system.


Measures of sympathetic and parasympathetic autonomic outflow from heartbeat dynamics.
Reliable and effective noninvasive measures of sympathetic and parasympathetic peripheral outflow are of crucial importance in cardiovascular physiology. Although many techniques have been proposed to take up this long-lasting challenge, none has proposed a satisfying discrimination of the dynamics of the two separate branches. Spectral analysis of heart rate variability is the most currently used technique for such assessment. Despite its widespread use, it has been demonstrated that the subdivision in the low-frequency (LF) and high-frequency (HF) bands does not fully reflect separate influences of the sympathetic and parasympathetic branches, respectively, mainly due to their simultaneous action in the LF. Two novel heartbeat-derived autonomic measures, the sympathetic activity index (SAI) and parasympathetic activity index (PAI), are proposed to separately assess the time-varying autonomic nervous system synergic functions. Their efficacy is validated in landmark autonomic maneuvers generally employed in clinical settings. The novel measures move beyond the classical frequency domain paradigm through identification of a set of coefficients associated with a proper combination of Laguerre base functions. The resulting measures were compared with the traditional LF and HF power. A total of 236 ECG recordings were analyzed for validation, including autonomic outflow changes elicited by procedures of different nature and temporal variation, such as postural changes, lower body negative pressure, and handgrip tests. The proposed SAI-PAI measures consistently outperform traditional frequency-domain indexes in tracking expected instantaneous autonomic variations, both vagal and sympathetic, and may aid clinical decision making, showing reduced intersubject variability and physiologically plausible dynamics. NEW & NOTEWORTHY While it is possible to obtain reliable estimates of parasympathetic activity from the ECG, a satisfying method to disentangle the sympathetic component from HRV has not been proposed yet. To overcome this long-lasting limitation, we propose two novel HRV-based indexes, the sympathetic and parasympathetic activity indexes.


Characterization of eukaryotic transcriptional control signals by assay of herpes simplex virus type 1 thymidine kinase.
We describe the characteristics of a general assay for eukaryote transcription-control sequences using the herpes simplex virus (HSV) thymidine kinase (tk) gene. After transfection of cultured cells with tk-containing recombinant plasmids, two assays were used to measure gene expression: short term or transient levels of tk mRNA and TK enzyme activity, and the rate of biochemical transformation from a TK- to a TK+ phenotype in selective growth medium (HAT). Deletion of the endogenous tk promoter results in 500-fold inactivation of gene expression. Replacement with exogenous transcription-control sequences from the human epsilon globin, mouse beta major globin, simian virus 40 and Moloney murine sarcoma virus (MoMuSV) genomes results in reactivation of gene expression. The presence of enhancers or activators of gene expression can also be conveniently measured. The transient expression assay ranged over two orders of magnitude while the transformation assay was almost two orders of magnitude more sensitive using the same recombinants. Analysis of the transcription-control domains in the MoMuSV LTR sequences shows the presence of both an enhancer and a promoter whose activity equalled that of the tk endogenous promoter. Insertion of the LTR promoter between the LTR enhancer and the tk promoter had little effect on modulating gene expression, suggesting no absolute preference for proximal promoters by this element. The different levels of gene expression obtained appears to be mediated by transcriptional control of full-length tk mRNA. There was an apparent correlation between the results obtained with the transient expression and transformation assays. However, cultured transformed cells all contained roughly the same levels of tk DNA, tk mRNA and tk enzyme activity. We propose that initial expression levels have a major effect in determining the transformation efficiency but that additional genetic controls are superimposed in cells grown in selective HAT medium.


Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 1: Location of YF3 in the LnF3 Series According to Its Chemical and Structural Characteristics.
A lanthanide contraction(LC) of 14 lanthanides (Ln) from 58Ce to 71Lu consists of the interaction of Ln nucleus with 4f-electrons. Rare earth elements (REEs-R) include Sc, Y, La, and 14 Ln. They are located in 4-6th periods of the subgroup of group III. The electronic structure divides R into short (d- Sc, Y, La) and long (14 f-elements Ce-Lu) homologous series. The most important chemical consequence of LC is the creation of a new conglomerate of 16 RF3 by mixing fluorides of d- (Y, La) and f-elements. This determines the location of YF3 among LnF3. The location of YF3 depends on the structural (formula volumes-Vform) and thermochemical (temperatures and heats of phase transformations, phase diagrams) properties. The location of YF3 between HoF3 and ErF3 was determined by Vform at a standard pressure (Pst) and temperature (Tst). The location of YF3 according to heats of phase transformations ΔHfus and ΔHtrans is in a dimorphic structural subgroup (SSGr) D (Ln = Er-Lu), but without the exact "pseudo ZY". According to the temperatures of phase transformations (Ttrans) in LnF3 (Ln = Dy-Lu), YF3 is located in the SSGr D between ErF3 and TmF3. The ErF3-YF3 and YF3-TmF3 phase diagrams show it to be between ErF3 and TmF3. The crystals of five β-LnF3 (Ln = Ho-Lu) and β-YF3 were obtained in identical conditions and their crystal structures were studied. Vform (at Pst and Tst) with "pseudo" atomic numberZY = 67.42 was calculated from the unit cell parameters, which were defined with ±5 × 10-4 Å accuracy. It determines the location of YF3 between HoF3 and ErF3.


Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.
In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer dissociation, which leads to partially unfolded monomers that aggregate and polymerize into amyloid fibrils. This process can be counteracted by stabilization of the tetramer. Several small compounds, such as diclofenac, diflunisal and flufenamic acid, have been reported to bind to TTR in vitro, in the T4 (thyroxine) binding channel that runs through the TTR tetramer, and consequently are considered to stabilize TTR. However, if these agents bind plasma proteins other than TTR, decreased drug availability will occur, compromising their use as therapeutic agents for TTR amyloidosis. In the present work, we compared the action of these compounds and of new derivatives designed to increase both selectivity of binding to TTR and inhibitory potency in relation to TTR amyloid fibril formation. We found two diflunisal derivatives that, in contrast with diclofenac, flufenamic acid and diflunisal, displaced T4 from TTR in plasma preferentially over binding to albumin and thyroxine binding globulin. The same diflunisal derivatives also had a stabilizing effect on TTR tetramers in plasma, as studied by isoelectric focusing of whole plasma under semi-denaturing conditions. In addition, by transmission electron microscopy, we demonstrated that, in contrast with other proposed TTR stabilizers (namely diclofenac, flufenamic acid and diflunisal), one of the diflunisal derivatives tested efficiently inhibited TTR aggregation. Taken together, our ex vivo and in vitro studies present evidence for the selectivity and efficiency of novel diflunisal derivates as TTR stabilizers and as inhibitors of fibril formation.


Improvement in Offaxis Neuromuscular Control Under Slippery Conditions Following Six-Week Pivoting Leg Neuromuscular Training.
Knee injuries are usually associated with offaxis loadings in the transverse and frontal planes. Thus, improvement of lower limb offaxis neuromuscular control is important in knee injury prevention and post-injury rehabilitation. The goal of this paper was to investigate the effects of six-week pivoting offaxis intensity adjustable neuromuscular control training (POINT) using a custom-made offaxis elliptical trainer on lower limb offaxis neuromuscular control performance in trained and untrained functional tasks under slippery conditions. Twenty-six subjects participated in 18 sessions of POINT (three sessions per week for six weeks) and 25 subjects served as controls who did a regular workout. Offaxis neuromuscular control performance measures in terms of pivoting instability, sliding instability, and time-to-peak offaxis EMG entropy were evaluated on both groups under slippery conditions including a trained free pivoting task and untrained free sliding task and free pivoting and sliding task. Compared with the control group, the training group significantly decreased pivoting instability and the time-to-peak offaxis EMG entropy in lower limb muscles, indicating improvement in offaxis neuromuscular control performance. Furthermore, the training group showed reduced pivoting instability and sliding instability during the untrained free pivoting and sliding task. This paper may help us develop more focused and effective offaxis training programs to reduce knee injuries associated with offaxis loadings.


Anthrax in Western and Central African great apes.
During the period of December 2004 to January 2005, Bacillus anthracis killed three wild chimpanzees (Pan troglodytes troglodytes) and one gorilla (Gorilla gorilla gorilla) in a tropical forest in Cameroon. While this is the second anthrax outbreak in wild chimpanzees, this is the first case of anthrax in gorillas ever reported. The number of great apes in Central Africa is dramatically declining and the populations are seriously threatened by diseases, mainly Ebola. Nevertheless, a considerable number of deaths cannot be attributed to Ebola virus and remained unexplained. Our results show that diseases other than Ebola may also threaten wild great apes, and indicate that the role of anthrax in great ape mortality may have been underestimated. These results suggest that risk identification, assessment, and management for the survival of the last great apes should be performed with an open mind, since various pathogens with distinct characteristics in epidemiology and pathogenicity may impact the populations. An animal mortality monitoring network covering the entire African tropical forest, with the dual aims of preventing both great ape extinction and human disease outbreaks, will create necessary baseline data for such risk assessments and management plans.


Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.
Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.


Children's difficulty in learning homonyms.
Mazzocco (1997) claimed that children have persistent difficulty in learning pseudo-homonyms--words like rope used to refer to a novel object (e.g. spade). Because the novel objects were familiar, the pseudohomonyms in her study were also synonyms (i.e. rope and spade both now mean spade). The results could therefore be due to children's well-known difficulties in learning synonyms. In Experiment 1, 55 six- to ten-year-olds used story context to select referents for pseudo-homonyms from picture sets containing the intended referents, with primary referents amongst the distractors. Children were equally poor when the intended referents were familiar (e.g. spade) as when they were unfamiliar (e.g. tapir)-35 and 38% correct, respectively. This indicates that familiarity of referent does not account for children's difficulties. In Experiment 2, 64 five- to ten-year-olds received instruction about homonymy, then a story set without pictures of the primary referents, in order to make the experimenter's intentions clear. Children were then shown one of the story sets from Experiment 1. Performance was just as poor (38% correct), indicating that misunderstanding of task demands did not account for failure. The conclusion is that Mazzocco's findings represent a psychologically interesting developmental difficulty.


Salmonella enteritidis surveillance by egg immunology: impact of the sampling scheme on the release of contaminated table eggs.
Design of surveillance programs to detect infections could benefit from more insight into sampling schemes. We address the effect of sampling schemes for Salmonella Enteritidis surveillance in laying hens. Based on experimental estimates for the transmission rate in flocks, and the characteristics of an egg immunological test, we have simulated outbreaks with various sampling schemes, and with the current boot swab program with a 15-week sampling interval. Declaring a flock infected based on a single positive egg was not possible because test specificity was too low. Thus, a threshold number of positive eggs was defined to declare a flock infected, and, for small sample sizes, eggs from previous samplings had to be included in a cumulative sample to guarantee a minimum flock level specificity. Effectiveness of surveillance was measured by the proportion of outbreaks detected, and by the number of contaminated table eggs brought on the market. The boot swab program detected 90% of the outbreaks, with 75% fewer contaminated eggs compared to no surveillance, whereas the baseline egg program (30 eggs each 15 weeks) detected 86%, with 73% fewer contaminated eggs. We conclude that a larger sample size results in more detected outbreaks, whereas a smaller sampling interval decreases the number of contaminated eggs. Decreasing sample size and interval simultaneously reduces the number of contaminated eggs, but not indefinitely: the advantage of more frequent sampling is counterbalanced by the cumulative sample including less recently laid eggs. Apparently, optimizing surveillance has its limits when test specificity is taken into account.


Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway.
Gap junction intercellular communication (GJIC) between cardiomyocytes is essential for synchronous heart contraction and relies on connexin-containing channels. Connexin 43 (Cx43) is a major component involved in GJIC in heart tissue, and its abnormal expression is closely associated with various cardiac diseases. Silica nanoparticles (SNPs) are known to induce cardiovascular toxicity. However, the mechanisms through which GJIC plays a role in cardiomyocytes apoptosis induced by SNPs remain unknown. The aim of the present study is to determine whether SNPs-decreased GJIC promotes apoptosis in rat cardiomyocytes cell line (H9c2 cells) via the mitochondrial pathway using CCK-8 Kit, scrape-loading dye transfer technique, Annexin V/PI double-staining assays, and Western blot analysis. The results showed that SNPs elicited cytotoxicity in H9c2 cells in a time- and concentration-dependent manner. SNPs also reduced GJIC in H9c2 cells in a concentration-dependent manner through downregulation of Cx43 and upregulation of P-Cx43. Inhibition of gap junctions by gap junction blocker carbenoxolone disodium resulted in decreased survival and increased apoptosis, whereas enhancement of the gap junctions by retinoic acid led to enhanced survival but decreased apoptosis. Furthermore, SNPs-induced apoptosis through the disrupted functional gap junction was correlated with abnormal expressions of the proteins involved in the mitochondrial pathway-related apoptosis such as Bcl-2/Bax, cytochrome C, Caspase-9, and Caspase-3. Taken together, our results provide the first evidence that SNPs-decreased GJIC promotes apoptosis in cardiomyocytes via the mitochondrial pathway. In addition, downregulation of GJIC by SNPs in cardiomyocytes is mediated through downregulation of Cx43 and upregulation of P-Cx43. These results suggest that in rat cardiomyocytes cell line, GJIC plays a protective role in SNPs-induced apoptosis and that GJIC may be one of the targets for SNPs-induced biological effects.


Increased blood-brain barrier permeability on perfusion computed tomography predicts hemorrhagic transformation in acute ischemic stroke.
Perfusion computed tomography (CT) is capable of measuring the permeability surface product (PS). PS reflects the permeability of the blood-brain barrier, involved in the pathophysiology of hemorrhagic transformation (HT) of ischemic stroke. The aim of our study was to determine if an increased PS can predict HT. A total of 86 patients with ischemic stroke were included. They underwent multimodality CT, including the measurement of PS. We compared the clinical and radiological characteristics of patients who developed HT to those who did not, using univariate analysis. Multivariate regression analyses were then used to determine HT predictors. HT was observed in 27 patients (31%). Infarct PS was significantly associated with HT (p = 0.047), as were atrial fibrillation (p = 0.03), admission National Institute of Health Stroke Scale score (p = 0.02), infarct volume (p = 0.0004), presence of large-vessel occlusion (p = 0.0005) and a poorer collateral status (p = 0.003). Using logistic regression modeling, an infarct PS >0.84 ml/100 g/min was an independent predictor of HT (OR 28, 95% CI 1.75-452.98; p = 0.02). Other independent predictors of HT were infarct volume and a history of atrial fibrillation. Our findings suggest that infarct PS can be a predictor of HT and may help clinicians to improve patient care around thrombolysis decisions in the acute phase of ischemic stroke.


Amplicon deep sequencing of five highly polymorphic markers of Plasmodium falciparum reveals high parasite genetic diversity and moderate population structure in Ethiopia.
Plasmodium falciparum genetic diversity can add information on transmission intensity and can be used to track control and elimination interventions. Dried blood spots (DBS) were collected from patients who were recruited for a P. falciparum malaria therapeutic efficacy trial in three malaria endemic sites in Ethiopia from October to December 2015, and November to December 2019. qPCR-confirmed infections were subject to amplicon sequencing of polymorphic markers ama1-D3, csp, cpp, cpmp, msp7. Genetic diversity, the proportion of multiclonal infections, multiplicity of infection, and population structure were analysed. Among 198 samples selected for sequencing, data was obtained for 181 samples. Mean MOI was 1.38 (95% CI 1.24-1.53) and 17% (31/181) of infections were polyclonal. Mean He across all markers was 0.730. Population structure was moderate; populations from Metema and Metehara 2015 were very similar to each other, but distinct from Wondogent 2015 and Metehara 2019. The high level of parasite genetic diversity and moderate population structure in this study suggests frequent gene flow of parasites among sites. The results obtained can be used as a baseline for additional parasite genetic diversity and structure studies, aiding in the formulation of appropriate control strategies in Ethiopia.


Visualization of macrophage recruitment in head and neck carcinoma model using fluorine-19 magnetic resonance imaging.
To evaluate the role of infiltrating macrophages in murine models of single and double mutation head and neck tumors using a novel fluorine-19 (19 F) MRI technology. Tumor cell lines single-hit/SCC4 or double-hit/Cal27, with mutations of TP53 and TP53 & FHIT, respectively, were injected bilaterally into the flanks of (n = 10) female mice. With tumors established, perfluorocarbon nanoemulsion was injected intravenously, which labels in situ predominantly monocytes and macrophages. Longitudinal spin density-weighted 19 F MRI data enabled quantification of the macrophage burden in tumor and surrounding tissue. The average number of 19 F atoms within the tumors was twice as high in the Cal27 group compared with SCC4 (3.9 × 1019 and 2.0 × 101919 F/tumor, respectively; P = 0.0034) two days after contrast injection, signifying increased tumor-associated macrophages in double-hit tumors. The difference was still significant 10 days after injection. Histology stains correlated with in vivo results, exhibiting numerous perfluorocarbon-labeled macrophages in double-hit tumors and to a lesser extent in single-hit tumors. This study helps to establish 19 F MRI as a method for quantifying immune cells in the tumor microenvironment, allowing distinction between double and single-hit head and neck tumors. This technique would be extremely valuable in the clinic for pretreatment planning, prognostics, and post-treatment surveillance. Magn Reson Med 79:1972-1980, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Neuropsychological function in schizophrenia. Selective impairment in memory and learning.
Unmedicated schizophrenic patients (according to DSM-III-R criteria) (n = 36) and age-matched normal controls (n = 36), balanced for parental socioeconomic status, were administered a battery of standardized neuropsychological tests. Patients showed generalized impairment relative to controls and a selective deficit in memory and learning compared with other functions. Selective impairment was not found on tests related to frontal system function (abstraction, verbal fluency, and motor). The observed pattern is consistent with greater involvement of the temporal-hippocampal system, against the background of diffuse dysfunction. Although impairment in memory and learning has been reported, the selectivity and relative severity compared with other behavioral functions have not been recognized. The specificity of this profile merits further examination. These findings lend support to the hypothesized importance of the temporal-hippocampal region in understanding the pathophysiology of schizophrenia.


Critical consciousness in children and adolescents: A systematic review, critical assessment, and recommendations for future research.
Critical consciousness refers to an individual's awareness of oppressive systemic forces in society, a sense of efficacy to work against oppression, and engagement in individual or collective action against oppression. In the past few decades, interest in critical consciousness as a resource that may promote thriving in marginalized people has grown tremendously. This article critically examines the results of a systematic review of 67 studies of critical consciousness in children and adolescents, published between 1998 and 2019. Across these studies, major themes included the role of socialization experiences, relationships, and context in the development of critical consciousness. In addition, critical consciousness was associated with a number of adaptive developmental outcomes, including career-related, civic, social-emotional, and academic outcomes-especially for marginalized youth. However, our analysis highlights several critical gaps in the literature. We highlight the need for further delineation of the impacts of parent and peer socialization on critical consciousness in specific developmental periods and for studying critical consciousness at multiple levels of the ecological system. We further note the dearth of rigorous experimental or quasi-experimental studies in the area of interventions to promote critical consciousness. In addition, we note that developmental questions-questions about the nature and function of critical consciousness over time-are largely unanswered in the literature, including questions about how critical consciousness manifests and develops during childhood. Leveraging the findings of our systematic review, we outline key next steps for this rapidly growing area of research. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Explicating narrow and broad conceptualizations of environmental influences on personality.
A surge of studies aims to identify environmental factors that explain individual differences, personality stability, and personality development. This special issue builds on this large interest and solicited articles on broad and narrow environmental factors of personality. We provide an overview of the motivations behind the special issue, review each of the articles, and present data on researchers' perceptions of environmental factors contributing to personality expression and development. We review 16 special issue articles, thematically grouped into seven topics-culture and race, genes and environment, geography and habitat, major/minor life events, social relationships, socioeconomic status and economic inequality, and work. We also present data on researchers' (N = 223) responses and ratings of environmental influences on personality expression and development. In the open-ended responses, the most important environmental influences were family, culture, peers, relationships, and trauma. Among the least important were weather, birth order, geography, climate, and shared environment. Nearly all the environmental influences featured in this special issue were considered at least somewhat important; however, there was considerable heterogeneity in how important researchers found each topic. There is no perfect consensus among researchers as to which environmental factors contribute most to personality expression and development. We hope that there is a larger surge of studies on personality constructs beyond traits, that contextualize concepts within a cultural and historical framework and develop more stringent theories to hypothesize about the environmental influences on personality.


Systematic Review and Meta-analysis: Outcomes of Routine Specialist Mental Health Care for Young People With Depression and/or Anxiety.
Depression and anxiety are the most prevalent mental health problems in youth, yet almost nothing is known about what outcomes are to be expected at the individual level following routine treatment. This paper sets out to address this gap by undertaking a systematic review of outcomes following treatment as usual (TAU) with a particular focus on individual-level outcomes. MEDLINE, Embase and PsycInfo were searched for articles published between 1980 and January 2019 that assessed TAU outcomes for youth depression and anxiety accessing specialist mental health care. Meta-analysis considered change at both group-level pre-post effect size (ES) and individual-level recovery, reliable change, and reliable recovery. Temporal analysis considered stability of primary and secondary outcomes over time. Subgroup analysis considered the moderating effect of informant; presenting problem; study design; study year; mean age of youth; use of medication; intervention dosage and type of treatment offered on outcomes. A protocol was preregistered on PROSPERO (CRD42017063914). Initial screening of 6,350 publications resulted in 38 that met the inclusion criteria, and that were subsequently included in meta-analyses. This resulted in a final full pooled sample of 11,739 young people (61% of whom were female, mean age 13.8 years). The pre-post ES (Hedges' g) at first/final outcome (13/26 weeks) was -0.74/-0.87. The individual-level change on measures of self-report was 38% reliable improvement, 44% no reliable change, and 6% reliable deterioration. Outcomes varied according to moderators, informant, problem type and dosage. Poor data quantity and quality are limitations, but this is the first study that indicates likely rates of reliable improvement for those accessing TAU. We propose the need for improved reporting of both individual-level metrics and details of TAU to enable greater understanding of likely current outcomes from routine care for youths with depression and anxiety in order to allow the potential for further improvement of impact.


Accessing the different redox states of alpha-iminopyridines within cobalt complexes.
Cobalt coordination complexes featuring the redox-active alpha-iminopyridine ligand are described. The quite reducing bis(ligand)cobalt monoanion (1(red)) was isolated and characterized by X-ray crystallography. The complex forms a three-membered electron-transfer series along with its neutral and monocationic counterparts, which were previously reported. The electronic structures in this series are all consistent with divalent cobalt and the redox events being ligand-centered. The reactivity profile of 1(red) was briefly explored, and two new compounds were isolated, bis(ligand)methylcobalt (2) and bis(ligand)iodocobalt (3). Though 2 and 3 are isostructural, they are characterized by different electronic structures. The methylcobalt complex is best described by a Co(III) center with two ligand radicals, whereas the iodocobalt species is more aptly assigned as a Co(II) center with only one ligand radical. Further evidence of their different electronic structures is that a low-lying excited state is populated at room temperature in the case of the iodocobalt compound, whereas the methylcobalt complex is an energetically well-isolated spin singlet. Magnetic susceptibility data, structural data, variable temperature NMR spectroscopy, and density functional theory calculations lend support to this proposal.


Mycoplasma pneumoniaeassociated transverse myelitis presenting as asymmetric flaccid paralysis.
Acute transverse myelitis is a rare spinal cord inflammatory disorder that manifests as sudden onset of motor, sensory, and autonomic dysfunctions. Here, we report a case of acute transverse myelitis in a 13- year-old boy secondary to Mycoplasma pneumoniae infection. He presented with left facial palsy and contralateral upper extremity weakness without sensory or autonomic changes. The patient was diagnosed with transverse myelitis based on his magnetic resonance imaging findings, although his presentation was mainly motor dysfunction, which is more consistent with acute flaccid paralysis.