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Annals of Neurology: Volume 82, Number 2, August 2017

ON THE COVER: A section through the brain of a patient with type-2 diabetes showing vascular deposition of amylin (brown) and astroglial reaction (green stain for glial fibrillary acidic protein). See Ly et al, pages 208–222, in this issue for details.

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Functional insights into pathogen biology from 3D electron microscopy

Abstract

In recent years, novel imaging approaches revolutionised our understanding of the cellular and molecular biology of microorganisms. These include advances in fluorescent probes, dynamic live cell imaging, superresolution light and electron microscopy. Currently, a major transition in the experimental approach shifts electron microscopy studies from a complementary technique to a method of choice for structural and functional analysis. Here we review functional insights into the molecular architecture of viruses, bacteria and parasites as well as interactions with their respective host cells gained from studies using cryogenic electron tomography and related methodologies.

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Renal denervation decreases susceptibility of the heart to ventricular fibrillation in a canine model of chronic kidney disease

Abstract

Renal denervation (RDN) has been shown to have therapeutic values in patients with chronic kidney disease (CKD). This study aimed to investigate whether RDN could decrease susceptibility of the heart to ventricular fibrillation in a canine model of CKD. Twenty-one dogs were included in this study. CKD was produced by subtotal nephrectomy in sixteen dogs with RDN treatment (CKD + RDN group, N = 8) or sham RDN (CKD group, N = 8). Another 5 dogs underwent sham operation and sham RDN to serve as controls (CTR group). Parameters of renal function, blood pressure, echocardiography, electrocardiogram, norepinephrine and inflammation were measured at baseline and 6 weeks after the surgical procedure. The ventricular fibrillation threshold (VFT) was determined at the end of study. Subtotal nephrectomy successfully induced a canine CKD model. When compared to CTR group, subtotal nephrectomy in CKD group significantly elevated blood pressure; increased the left ventricular mass, the end-diastolic left ventricular internal dimension, the left ventricular end-diastolic posterior wall thickness, the end-diastolic interventricular septum thickness; prolonged the intervals of QT, corrected QT, Tpeak to Tend (Tp-e), corrected Tp-e, and increased the QT dispersion and the Tp-e/QT ratio; decreased the VFT; increased the serum levels of norepinephrine, C reactive protein, and interleukin 6. However, RDN significantly attenuated these changes induced by CKD. The present study demonstrated that RDN could decrease susceptibility of the heart to ventricular fibrillation in this CKD model. Improvement of left ventricular hypertrophy, sympathetic activation, and inflammation by RDN may be responsible for its beneficial effects.

This article is protected by copyright. All rights reserved

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How Cross-Linguistic Differences in the Grammaticalization of Future Time Reference Influence Intertemporal Choices

Abstract

According to Chen's (2013) Linguistic Savings Hypothesis (LSH), our native language affects our economic behavior. We present three studies investigating how cross-linguistic differences in the grammaticalization of future-time reference (FTR) affect intertemporal choices. In a series of decision scenarios about finance and health issues, we let speakers of altogether five languages that represent FTR with increasing strength, that is, Chinese, German, Danish, Spanish, and English, choose between hypothetical sooner-smaller and later-larger reward options. While the LSH predicts a present-bias that increases with FTR-strength, our decision makers preferred later-larger options and this future-bias increased with FTR-strength. In multiple regressions, the FTR-strength effect persisted when controlled for socioeconomic and cultural differences. We discuss why our findings deviate from the LSH and ask in how far the FTR-strength effect represents a habitual constitution of linguistic relativity or an instance of online decision framing.

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Identification of informative features for predicting proinflammatory potentials of engine exhausts

The immunotoxicity of engine exhausts is of high concern to human health due to the increasing prevalence of immune-related diseases. However, the evaluation of immunotoxicity of engine exhausts is currently b...

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A protocol for CABS-dock protein–peptide docking driven by side-chain contact information

The characterization of protein–peptide interactions is a challenge for computational molecular docking. Protein–peptide docking tools face at least two major difficulties: (1) efficient sampling of large-scal...

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Transcranial direct current stimulation as a motor neurorehabilitation tool: an empirical review

The present review collects the most relevant empirical evidence available in the literature until date regarding the effects of transcranial direct current stimulation (tDCS) on the human motor function. tDCS...

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Modeling EphB4-EphrinB2 protein–protein interaction using flexible docking of a short linear motif

Many protein–protein interactions are mediated by a short linear motif. Usually, amino acid sequences of those motifs are known or can be predicted. It is much harder to experimentally characterize or predict ...

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Evaluation of cervical posture improvement of children with cerebral palsy after physical therapy based on head movements and serious games

This paper presents the preliminary results of a novel rehabilitation therapy for cervical and trunk control of children with cerebral palsy (CP) based on serious videogames and physical exercise.

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Life-threatening intraoperative anaphylaxis as a result of chlorhexidine present in Instillagel

A 70-year-old man with left lower limb critical ischaemia was admitted to our vascular unit for a femoral-popliteal bypass. He had experienced a skin reaction to chlorhexidine 6 months previously during an angioplasty procedure. After intubation, once in the operating theatre, the patient had a urinary catheter inserted using Instillagel. Around 30 min later the patient had a full-blown anaphylactic reaction that required aggressive medical management and the abandoning of surgery. Postoperative allergy testing confirmed that the suspected primary trigger for the anaphylaxis was indeed chlorhexidine, which was present in Instillagel. The patient was also found to have allergies to atracurium and teicoplanin, which had been given on induction. This case report highlights the importance of recognising that Instillagel contains chlorhexidine, and that indeed intraurethral use during routine urinary catheterisation can be a cause of life-threatening anaphylaxis.

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A typical presentation of a hepatocellular carcinoma in a middle-aged patient

Description

A 54-year-old man was admitted to our hospital due to experiencing a sudden, severe pain in the right shoulder after mild exercise. He had been losing weight over the previous month and had noticed a lump near his right shoulder. A chest X-ray showed a lytic lesion in the lateral half of his right collarbone (figure 1A) with a cortical break and the presence of a soft-tissue component. A chest CT scan showed the destruction of the bone and a 10x8x7 cm mass associated with the pathological fracture of the collarbone (figure 1B). The diagnostic workup was completed with an abdominal CT scan, which showed a large hepatic tumour, an alpha-fetoprotein blood test level of 1468 ng/mL (normal range <10 ng/mL) and a fine-needle aspiration cytology, which yielded the final diagnosis of disseminated disease of a hepatocellular carcinoma. Cells showed both TTF-1 and hepatocyte antigen positivity, whereas CK7,...

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Effects of Autologous Cytokine-Induced Killer Cells Infusion in Colorectal Cancer Patients: A Prospective Study

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 221-226.


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In Vivo and In Vitro Effects of ATM/ATR Signaling Pathway on Proliferation, Apoptosis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 193-203.


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Clinical Effects of CpG-Based Treatment on the Efficacy of Hepatocellular Carcinoma by Skewing Polarization Toward M1 Macrophage from M2

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 215-219.


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Selected Literature Watch

Cancer Biotherapy & Radiopharmaceuticals Aug 2017, Vol. 32, No. 6: 227-228.


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Parental Gender Expectations by Socioeconomic Status and Nativity: Implications for Contraceptive Use

Abstract

Parental gender expectations, which may be egalitarian or not, could vary by nativity and socioeconomic status. Parental gender expectations provide a model for children's gender role attitudes and could also have effects on reproductive health over the life course, including women's contraceptive choices. Yet, parental gender expectations are not often studied quantitatively. Using the National Longitudinal Study of Adolescent to Adult Health, we examine how parental gender expectations in the United States vary by immigrant generation and socioeconomic status, whether parental gender expectations in adolescence are associated with young women's contraceptive use, and if nativity moderates that relationship. Results show that parental gender expectations vary significantly by immigrant generation and parental socioeconomic status. Both first and second generation women are significantly less likely to have lived in households with equal gender expectations compared to the third generation. Higher socioeconomic status is associated with equal gender expectations. Among participants from households with equal gender expectations, the second generation is more likely than the third generation is to use a male-controlled contraceptive method versus no method. Using a nationally representative sample, our study demonstrates that parental gender expectations vary by nativity and by the socioeconomic context of the family in which they are embedded as well as have a unique effect on the contraceptive behavior of second generation women.

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Immune mechanisms of respiratory viral infections in asthma

Hugo A Farne | Sebastian L Johnston

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The nonspecific face of adaptive immunity

Eric Muraille | Stanislas Goriely

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Protective immunity against tuberculosis: what does it look like and how do we find it?

Lu Huang | David G Russell

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Prevalence of Slow-growth Vancomycin Non-susceptibility In Methicillin-resistant Staphylococcus aureus [PublishAheadOfPrint]

We have previsously reported a novel phenotype of vancomycin-intermediate Staphylococcus aureus (VISA) strains, "slow-VISA," in which colonies appear only after 72 h of incubation. Slow-VISA strains can be difficult to detect because prolonged incubation is required and the phenotype is unstable. To develop a method for detection of slow-VISA isolates, we studied 23 slow-VISA isolates derived from heteroVISA clinical strain Mu3. We identified single nucleotide polymorphisms (SNP) in genes involved in various pathways such as purine/pyrimidine synthesis, cell metabolism, and cell-wall peptidoglycan synthesis, which have been implicated in the stringent response. We found that mupirocin, which also induces a stringent response, caused stable expression of vancomycin resistance. On the basis of these results, we developed a method for detection of slow-VISA using mupirocin 0.032 μg/ml (Patent Application No. PCT/JP2017/008975filed on March 7, 2017). Using this method, we detected 53 (15.6%) slow-VISA isolates among clinical methicillin-resistant S.aureus (MRSA) isolates. In contrast, the VISA phenotype was detected in fewer than 1% of isolates. Deep-sequencing analysis showed that slow-VISA clones are present in small numbers among hVISA isolates, and proliferate in the presence of vancomycin. This slow-VISA subpopulation could account in part for the recurrence and persistence of MRSA infection.

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Antibacterial Resistance in Ureaplasma species and Mycoplasma hominis Isolates from Urine Cultures in College-aged Females [PublishAheadOfPrint]

Urinary tract infections (UTIs) affect nearly 20% of women aged 15-29 and account for an estimated $3.5 billion in US costs. Antibiotic resistance prolongs UTI treatment and resistance profiles vary regionally. This regional variation is an important consideration in guiding empirical treatment selection. Regional studies in the US have identified tetracycline resistance in over a third of Ureaplasma spp. isolates, but no studies have evaluated antibiotic resistance levels in college-aged women with first-time UTI. We tested a panel of antibiotics and determined the MICs of Ureaplasma spp. (60 U. parvum; 13 U. urealyticum) and 10 Mycoplasma hominis isolates obtained from urine of college-aged women with first-time UTI. Low antibiotic resistance was found in this population of women with first-time UTI. Two U. parvum isolates were resistant: one to levofloxacin (MIC: 4 μg/ml) and one to tetracycline (MIC: 8 μg/ml). All M. hominis and U. urealyticum isolates were sensitive. For the Ureaplasma spp., MIC90s were highest against gentamicin (21 μg/ml) and lowest against doxycycline (0.25 μg/ml). When comparing MIC levels between Ureaplasma spp., U. urealyticum had significantly higher MICs against each antibiotic except doxycycline. For resistant isolates, the genetic mechanisms of resistance were determined. PCR amplification identified tetM present in the tetracycline resistant isolate, and a S83W mutation within the parC gene of the quinolone resistant isolate. To our knowledge, this study is the first to provide molecular and phenotypic evidence of the S83W parC mutation conferring levofloxacin resistance in U. parvum isolated from a patient in the United States.

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Comparison of Cytomegalovirus Terminase Gene Mutations Selected after Exposure to Three Distinct Inhibitor Compounds [PublishAheadOfPrint]

Letermovir, GW275175X (a benzimidazole) and tomeglovir (Bay38-4766) are chemically unrelated human cytomegalovirus (CMV) terminase complex inhibitors that have been tested in human subjects. UL56 gene mutations are the dominant pathway of letermovir resistance, while UL89 and UL56 mutations are known to confer benzimidazole resistance. This study compares the mutations elicited by the three inhibitors during in vitro CMV propagation. GW275175X consistently selected for UL89 D344E, and sometimes UL89 C347S, R351H, or UL56 Q204R. Tomeglovir consistently selected for UL89 V362M, and sometimes UL89 N329S, T350M, H389N, N405D, or UL56 L208M, E407D, H637Q or V639M. Adding to known and novel UL56 mutations, letermovir occasionally selected for UL89 N320H, D344E or M359I. Recombinant phenotyping confirmed that UL89 D344E conferred 9-fold resistance (increased EC50) for GW275175X, and increased the letermovir and tomeglovir EC50 by 1.7 to 2.1-fold for baseline virus and UL56 mutants Q204R, E237D, F261L and M329T. UL89 N320H and M359I conferred <2-fold letermovir resistance but 7-fold resistance for tomeglovir; mutant N320H was also 4-fold resistant to GW275175X. UL89 N329S conferred tomeglovir and letermovir cross-resistance. UL89 T350M conferred resistance to all three inhibitors. UL89 C347S conferred 27-fold GW275175X resistance. UL89 V362M and H389N conferred 98-fold and 29-fold tomeglovir resistance without cross-resistance. Thus, characteristic UL89 mutations confer substantial resistance to GW275175X and tomeglovir, and are an uncommon accessory pathway of letermovir resistance. Instances of moderate cross-resistance and proximity of the selected UL89 and UL56 mutations suggest targeting of a similar terminase functional locus involving UL56 and UL89 interaction.

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Antifungal Activity of SCY-078 and Standard Antifungal Agents Against 178 Clinical Isolates of Resistant and Susceptible Candida Species [PublishAheadOfPrint]

SCY-078 in vitro activity was determined for 178 isolates of resistant and susceptible C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. lusitaniae, and C. parapsilosis, including 44 Candida isolates having known genotypic (FKS1 or FKS2 mutations), phenotypic or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

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Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from United States Medical Centers (2013--2016) [PublishAheadOfPrint]

The in vitro activity of ceftazidime-avibactam and many comparator agents was determined against various resistant subsets of organisms selected among 36,380 Enterobacteriaceae and 7,868 Pseudomonas aeruginosa. Isolates were consecutively collected from 94 US hospitals, and all isolates were tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). Enterobacteriaceae isolates resistant to carbapenems (CRE) and/or ceftazidime-avibactam (MIC ≥16 μg/mL) were evaluated for the presence of genes encoding ESBLs, KPC, NDM, and transferable AmpC enzymes. Ceftazidime-avibactam inhibited >99.9% of all Enterobacteriaceae at the susceptible breakpoint of ≤8 μg/mL and was active against multidrug-resistant (MDR; n=2,953; MIC_50/90, 0.25/1 μg/mL; 99.2% susceptible), extensively drug-resistant (XDR; n=448; MIC_50/90, 0.5/2 μg/mL; 97.8% susceptible), and CRE (n=513; MIC_50/90, 0.5/2 μg/mL; 97.5% susceptible) isolates. Only 82.2% of MDR Enterobacteriaceae (n=2,953) and 64.2% of ceftriaxone-nonsusceptible Klebsiella pneumoniae (n=1,063) were meropenem-susceptible. Among Enterobacter cloacae (22.2% ceftazidime-nonsusceptible), 99.8% of isolates, including 99.3% of ceftazidime-nonsusceptible isolates, were ceftazidime-avibactam-susceptible. Only 23 of 36,380 Enterobacteriaceae (0.06%) isolates were ceftazidime-avibactam-nonsusceptible, including 9 metallo-β-lactamase producers and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all β-lactamases tested. Ceftazidime-avibactam showed potent activity against P. aeruginosa (MIC_50/90, 2/4 μg/mL; 97.1% susceptible), including MDR (MIC_50/90, 4/16 μg/mL; 86.5% susceptible) isolates and inhibited 71.8% of isolates nonsusceptible to meropenem, piperacillin-tazobactam, and ceftazidime (n=628). In summary, ceftazidime-avibactam demonstrated potent activity against a large collection (n=44,248) of contemporary gram-negative bacilli isolated from US patients, including organisms resistant to most currently available agents, such as CRE and meropenem-nonsusceptible P. aeruginosa.

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Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB [PublishAheadOfPrint]

Background. In a multiple dose ranging trial we have previously evaluated higher doses of rifampicin in patients for two weeks. The objectives of the current study were to administer higher doses of rifampicin for a longer period to compare pharmacokinetics, safety/tolerability and bacteriological activity of such regimens.

Methods. In a double-blinded, randomized, placebo-controlled, phase II clinical trial (ClinicalTrials.gov NCT00760149) 150 Tanzanian TB patients were randomized to receive either 600 (approximately 10 mg/kg), 900 or 1200 mg rifampicin combined with standard doses of isoniazid, pyrazinamide and ethambutol administered daily for two months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. Bacteriological response was assessed by culture conversion in liquid and solid media.

Results. Geometric mean total exposures (AUC_0-24h) were 24.6, 50.8 and 76.1 h*mg/L in the 600 mg, 900 mg and 1200 mg group respectively, reflecting a non-linear increase in exposure with the dose (p<0.001). Grade 3 events occurred in only 2 patients in the 600 mg arm, 4 patients in the 900 and 5 patients in the 1200 mg arm. No significant differences in bacteriological response were observed.

Conclusions: Higher daily doses of rifampicin (900 and 1200 mg) resulted in a more than proportional increase in rifampicin exposure in plasma, were safe and well tolerated when combined with other first-line TB drugs for two months, but did not result in improved bacteriological response in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampicin in follow-up trials.

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Effects of Echinocandins in combination with Nikkomycin Z against invasive Candida albicans bloodstream isolates and the fks mutants [PublishAheadOfPrint]

The in vitro and in vivo effects of nikkomycin Z combined with an echinocandin (anidulafungin or micafungin) against two Candida albicans isolates and their lab-derived echinocandin-resistant fks mutants with FKS1 S645Y and FKS1 S645P were evaluated. Synergistic effects were observed in all tested strains (FICI < 0.5). Enhanced survival were observed in an immunocompromised murine model (log-rank test, P < 0.02). Our study demonstrated the therapeutic potential of nikkomycin Z-echinocandin combinations in managing echinocandin resistance.

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MIXED FORMULATION OF CONVENTIONAL AND PEGYLATED MEGLUMINE ANTIMONIATE-CONTAINING LIPOSOMES REDUCES INFLAMMATORY PROCESS AND PARASITE BURDEN IN L. infantum INFECTED BALB/c MICE [PublishAheadOfPrint]

Pentavalent antimonial has been the first choice treatment for visceral leishmaniasis, however, it has several side effects that leads to low adherence to treatment. Liposome-encapsulated meglumine antimoniate (MA) arises as an important strategy for chemotherapy enhancement. Herein was evaluated the immunopathological changes using the mixture of conventional and pegylated liposomes with MA. The mice were infected with L. infantum and a single dose treatment regimen. Comparison was made with groups treated with saline, empty liposomes, free MA, and liposomal formulation of MA. Histopathological analyses demonstrated that animals treated with Lipo MA, showed a significant decrease in the inflammatory process and absence of granulomas. The in vitro stimulation of splenocytes showed a significant increase of IFN--produced by CD8⁺ T-cells and a decrease of IL-10-produced by CD4⁺ and CD8⁺ T-cells in the Lipo MA. Furthermore, Lipo MA group showed an increase in the IFN-/IL-10 ratio in both CD4⁺ and CD8⁺ T-cells subsets. According to the parasite load evaluation using qPCR, Lipo MA group showed no L. infantum DNA in spleen (0.0%) and 41.4% in liver. Additionally, we detected a low positive correlation between parasitism and histopathology findings (inflammatory process and granuloma formation). Thus, our results confirmed that the Lipo MA is a promising antileishmanial formulation able to reduce the inflammatory response and induce a type 1 immune response, accompanied by a significant reduction of the parasite burden into hepatic and splenic compartment in treated animals.

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PI-273, a substrate-competitive, specific small molecule inhibitor of PI4KII{alpha}, inhibits the growth of breast cancer cells

While phosphatidylinositol 4-kinase PI4KIIα has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIα are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIα. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC50 = 0.47 μM) and suppressed cell proliferation. Surface plasmon resonance (SPR) and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα. Additionally, PI-273 treatment retarded cell proliferation by blocking cells in G2/M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target.

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Monocarboxylate transporter MCT1 promotes tumor metastasis independently of its activity as a lactate transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion and metastasis. While host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activated transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. While pharmacological MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion and spontaneous metastasis. Our findings raise the possibility that pharmacological inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells.

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STRAP promotes stemness of human colorectal cancer via epigenetic regulation of the NOTCH pathway

NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer (CRC). Silencing STRAP sensitized CRC cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of CRC cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which form repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 CRC clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP-NOTCH1-HES1 molecular axis as a CSC regulator in CRC, with potential implications to improve treatment of this disease.

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Using the Kulldorff’s scan statistical analysis to detect spatio-temporal clusters of tuberculosis in Qinghai Province, China, 2009–2016

Although the incidence of tuberculosis (TB) in most parts of China are well under control now, in less developed areas such as Qinghai, TB still remains a major public health problem. This study aims to reveal...

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Large Subcapsular Splenic Hematoma with a Large Pancreatic Pseudocyst Was Successfully Treated with Splenic Arterial Embolization and Ultrasound-Guided Percutaneous Drainage of Pancreatic Pseudocyst

Subcapsular splenic hematoma is a rare complication of pancreatitis. The management for subcapsular splenic hematoma remains controversial. We herein report a case of a large subcapsular splenic hematoma with a large pancreatic pseudocyst, which was successfully treated with splenic arterial embolization and ultrasound- (US-) guided percutaneous drainage of pancreatic pseudocyst, for the first time. A 44-year-old male suffered from recurrent abdominal pain for more than two years. He had previous 3 episodes of pancreatitis. A subcapsular splenic hematoma (16.0 × 16.0 × 7.6 cm) with pancreatic pseudocyst (13.5 × 10.0 × 8.0 cm) was shown on abdominal computed tomography (CT). He underwent splenic arterial embolization to decrease the blood supply of the spleen and then ultrasound-guided percutaneous drainage of the large pancreatic pseudocyst. After 2 weeks, the repeated CT-Abdomen showed the disappearance of pancreatic pseudocyst and multiple areas of infarction on the spleen, while the splenic subcapsular hematoma had also significantly reduced. The patient was discharged after almost a month of his hospital admission with the drainage tube attached, and about 2 weeks later the drainage tube was removed upon CT scan confirmation of decrease in the volume of the subcapsular hematoma. Patient had no abdominal symptoms at the 1.5-year follow-up.

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Association of increased gait variability while dual tasking and cognitive decline: results from a prospective longitudinal cohort pilot study

Abstract

Dual task-related changes in gait are considered as a sensitive and a specific marker of adverse effects of cognitive impairment on the highest levels of gait control. No study has examined the longitudinal association between gait performance while dual tasking and the occurrence of cognitive decline. This study aims to examine the association of stride time parameters (i.e., mean value and coefficient of variation (CoV)) during single and dual tasking with the occurrence of cognitive decline in non-demented older community dwellers. A total of 56 non-demented community dwellers were recruited in a longitudinal prospective cohort study. Mini-Mental Status Examination (MMSE) scores at baseline assessment and at 5-year follow-up assessment, and mean value and CoV of stride time at self-selected usual pace, while usual walking and dual tasking (i.e., counting backward and verbal fluency task) at baseline assessment were recorded. Variation (i.e., delta) of MMSE score from baseline to follow-up assessment as well as of stride time parameters from single to dual task was used as outcomes. Worse stride time values were reported while dual tasking compared to single tasking (P < 0.03). An increase of mean value, CoV, and delta of CoV of stride time was associated with an increased delta MMSE while performing verbal fluency task (P < 0.05). Worsening stride time parameters while performing a verbal fluency task at baseline assessment was associated with decline in MMSE score during the 5-year follow-up period in this sample of older community dwellers.

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Duodenum-Preserving Resection of the Pancreatic Head versus Pancreaticoduodenectomy for Treatment of Chronic Pancreatitis with Enlargement of the Pancreatic Head: Systematic Review and Meta-Analysis

The results of this meta-analysis show that DPPHR should be established as first-line treatment because of lower level of severe early postoperative complications, maintenance of endocrine pancreatic functions, shortening of postoperative hospitalization time, and increase of quality of life compared to pancreaticoduodenectomy.

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10 things to know to improve pediatric out-of-hospital cardiac arrest survival in your community

Follow these 10 steps when treating pediatric cardiac arrest to save lives

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How Loud Is the Sun?

How loud would the sun be measured on Earth if its soundwaves could propagate through space? The answer might surprise you, as solar physicists estimate that the solar surface noise would be approximately 100dB by the time it reaches Earth! The enormity of the sun's surface paired with its capability of generating of tens of thousands of watts of sound energy per meter makes the sun astronomically loud.

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Medicare Telehealth Parity Act of 2017 Would Expand Role of Audiology

Much of the focus of the Over-the-Counter (OTC) Hearing Aid Act of 2017 (S.670 and H.R.1652) has been on improving accessibility and affordability to hearing aids by providing a "do-it-yourself" (DIY) distribution channel for patients who are comfortable with self-assessment and fitting of hearing aids.

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Let’s Take This Outside: Is There a Place for Outdoor Walking Meetings in Your Work Environment?

Do you wish your work meetings were more productive? Maybe it is time to leave the confines of the traditional conference room behind and take the meeting outdoors? 

Angel Chelick's article on the American Council of Exercise's website suggests that outdoor walking meetings improve creativity and facilitate conversation between co-workers. As an added bonus, we all know walking has cardiovascular health benefits (not to mention the added steps you will get on your fitness tracker).  

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Brain Health and Hearing

A recent commission from "The Lancet"  focused on dementia. In this review, the authors outline nine potentially modifiable health and lifestyle factors from different phases of life that, if eliminated, might prevent or at least delay dementia. The authors stress that dementia, much like hearing loss, is not an inevitable consequence of aging, rather it is multifaceted and potentially 1/3 of cases preventable.

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Recovery from TBI

A recent study suggests that recovery from TBI (traumatic brain injury) may be different between males and female subjects. Historically, TBI studies have used predominately male subjects, whether they be mice or men. However, investigating the effects of injury, disease, and pharmacological treatments in both male and female subjects has led to significant changes to clinical practice across numerous disciplines.

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EHDI and Vocabulary

Until recently, no studies have examined vocabulary outcomes of children with hearing loss that have met all three components of the EHDI guidelines:

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Why Do So Many Preemies Have Hearing Loss?

It is so very interesting how one can know two different facts very well but not connect them. For example, I have known from the very first days of studying audiology that the peripheral auditory structure is mature in the human by the third trimester of prenatal life. I have also known for a while that the incidence of hearing loss is higher in babies born prematurely, compared to those delivered after a full-term pregnancy. And when I say higher, I mean alarmingly higher.

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Can Bugs Talk?

Jason Moon of the New Hampshire Public Radio, reports that researchers at the University of New Hampshire are studying communication strategies of American Burying Beetles.

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NPR: Music to Ease Hearing Loss

NPR featured a piece on  "All Things Considered," considering how to improve speech understanding in noisy environments. The segment focused on an ongoing study by Frank Russo, the director of the Science of Music, Auditory Research, and Technology Lab (SMART Lab) at Ryerson University in Toronto.

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Falls Risk Reduction and Robotics

Understanding and reducing falls in the elderly is an important cornerstone in vestibular and balance rehabilitation, and there may be a new tool on the horizon that could change the way our patients achieve this, namely, exoskeleton technology. Previously, the use of exoskeletons assistance has been limited. Initial prototypes were cumbersome and designed for those with significant motor-control impairment, which left most of the control to the device itself. 

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Whispering Whales

Imagine traveling thousands of miles with your newborn in search of food. Now imagine doing this in almost complete darkness. This is exactly what humpback whales and their newborns do as a matter of routine. The journey to the food-rich Antarctic or Arctic waters from their tropical breeding grounds can be thousands of miles. The mother and calf swim in deep ocean waters where light is scarce and therefore vision is not very useful. The pair has to depend on sound to keep track of each other. But broadcasting their presence to killer whales can be fatal.  

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Sound Art

Got plans to visit Canada anytime soon?  The Museum London in London, Ontario, will be hosting the exhibit "Sounds Assembling: Communication and the Art of Noise."  The artwork includes glass panels etched with waveforms corresponding to spoken word (Artist: James Joynes) and a hand-cranked musical device that plays notes corresponding to the noise of insects (Artist: Kevin Curtis Norcross). 

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Is Cost the Primary Factor for Hearing Aid Adoption?

In 2015, the President's Council on Advisors on Science and Technology (PCAST) issued recommendations intended to improve hearing health- care delivery. Subsequently, the FDA and other federal agencies and consumer advocacy groups sponsored a study published by the National Academies of Sciences, Engineering, and Medicine in June 2016. Further considerations have been discussed in an FDA (April 2016) and FTC (April 2017) workshops. A common issue discussed in each of these reports and workshops is the high cost of hearing aids as a primary factor in adoption rates.

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ITIH4: Effective Serum Marker, Early Warning and Diagnosis, Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor evolved from cirrhosis. It is quite significant to seek accurate, easy markers for early warning and diagnosis of HCC. Through prospective cohort follow-up study and mass spectrometry, we discovered and verified a serum marker valuable for early warning and diagnosis. Follow-up observation was performed on cirrhosis patients. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was adopted to detect the serums of patients, and the serum polypeptides with a potential value in early HCC warning and diagnosis were screened. Electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-Q-TOF-MS/MS) was exploited to identify these screened polypeptides. Moreover, the serum marker concentration was determined by ELISA to validate the clinical value of the serum marker. Among 109 cirrhosis patients followed up for two years, 29 patients (26.6%) finally progressed into HCC. MALDI-TOF MS shows that the concentration of a 3155.66Da polypeptide was significantly different between the patients that progressed into HCC and those not. Through MS/MS identification, it is confirmed that the polypeptide is inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). The serum ITIH4 concentrations in two groups were measured with ELISA and compared with Alpha-fetoprotein (AFP). Results show that serum ITIH4 and AFP concentrations were negatively correlated (r=−0.263, p=0.0006), and the ITIH4 concentration had a significant intergroup difference (p=0.000). Receiver operating characteristic (ROC) curve indicates that its predictive value (area under the curve, AUC) is 0.667, superior to AFP. For the patients progressing into HCC, serum samples were separately collected when they were recruited and diagnosed as cirrhosis. Measurement on these samples reveals that ITIH4 was declining during the progression of HCC (p=0.006). By virtue of mass spectrometry, we discovered and identified a biomarker valuable for early HCC warning and diagnosis. This marker overperforms the commonly used AFP, demonstrating a bright prospect.

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Performance of ovarian cyst fluid fine-needle aspiration cytology

BACKGROUND

Although ovarian fine-needle aspiration (FNA) cytology is not commonly used as a primary modality of diagnosis for patients with ovarian lesions, many ovarian cysts are aspirated intraoperatively and occasionally for diagnostic purposes. Therefore, the ability to interpret these specimens remains critical. Previous studies have suggested a high specificity but low sensitivity as a limitation. The objective of the current study was to further explore the use and performance of ovarian cyst FNA for diagnosing malignancy at the study institution.

METHODS

The electronic database was searched from 1998 through 2016 for ovarian cyst fluid cytology specimens; any concurrent or follow-up surgical pathology; and clinical information including patient age, radiology findings, and procedure type. Test performance was calculated using the surgical pathology diagnosis as the gold standard.

RESULTS

A total of 459 ovarian cyst FNA specimens had the following diagnoses: 416 (90.6%) were diagnosed as benign, 32 (7.0%) as atypical, 4 (0.9%) as suspicious, and 7 (1.5%) as malignant. Overall, 300 specimens (65.4%) had a corresponding surgical pathology specimen. On follow-up, the rate of malignancy (including borderline neoplasms) for benign FNA was 10 of 264 specimens (3.8%), that for atypical FNA was 0 of 24 specimens (0%), that for suspicious FNA was 5 of 5 specimens (100%), and that for malignant FNA was 7 of 7 specimens (100%). Test sensitivity was 54.0% and test specificity was 100%. The positive predictive value was 1.00 and the negative predictive value was 0.97, with a disease (malignancy) prevalence of 7.33%.

CONCLUSIONS

Ovarian cyst fluid cytology is highly specific and moderately sensitive for the detection of ovarian malignancies. A negative FNA is reassuring for patients with a low pretest probability of malignancy. Cancer (Cancer Cytopathol) 2017. © 2017 American Cancer Society.

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Identification of distinct cytomorphologic features in the diagnosis of NIFTP at the time of preoperative FNA: Implications for patient management

BACKGROUND

A major reclassification occurred with the redesignation of noninvasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its indolent nature. The aim of this study was to determine whether distinct cytomorphologic features could be identified on preoperative fine-needle aspiration (FNA) when NIFTP cases were compared with invasive follicular variant of papillary thyroid carcinoma (FVPTC) subtypes.

METHODS

Thyroid resection cases with the diagnosis of FVPTC from 2012 to 2016 were reclassified as NIFTP, invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC), and invasive FVPTC subtypes. Corresponding FNA specimens were retrieved and retrospectively reviewed. A univariate analysis using Fisher's exact test was performed to determine any differences in the frequencies of various cytomorphologic features among NIFTP, IEFVPTC, and FVPTC cases. A multivariate analysis was performed to identify any independent salient features that would be helpful in differentiating NIFTP from its invasive counterparts.

RESULTS

The study population consisted of 93 cases, including 51 cases of NIFTP, 21 cases of IEFVPTC, and 21 cases of infiltrative FVPTC. Demographics such as age, sex, and tumor size were comparable across the 3 groups. A predominantly microfollicular pattern, an absence of nuclear pseudo-inclusions, and less frequent nuclear elongations and grooves were significantly more likely to be associated with NIFTP versus its invasive counterparts. The absence of nuclear pseudo-inclusions and the presence of a microfollicular pattern were the only independent predictors of a NIFTP diagnosis.

CONCLUSIONS

This study demonstrates that NIFTP cases have distinguishing cytomorphologic characteristics in comparison with invasive FVPTC cases. Therefore, a preoperative cytologic evaluation provides clues that can aid in the distinction between NIFTP and its invasive counterparts. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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A pattern-based risk-stratification scheme for salivary gland cytology: A multi-institutional, interobserver variability study to determine applicability

BACKGROUND

Salivary gland aspiration cytology is useful in the preoperative management of patients but remains challenging, because of the extensive morphologic overlap of some tumors limits the ability to always determine the presence of malignancy. In response to this challenge, there has been increasing drive to develop a risk-based categorization scheme for salivary gland aspirates. Herein, the authors examine the interobserver variability of 1 such pattern and risk-based system.

METHODS

Select smears and cell-block sections of 50 salivary gland aspirates from 2 large academic centers were digitally imaged. These scanned slides were independently and blindly reviewed by 4 cytopathologists, and each aspirate was assigned to 1 of the proposed pattern-based categories if it was considered neoplastic by the observer. Interobserver agreement was scored and aggregated risks of malignancy were calculated for cases with available surgical follow-up.

RESULTS

In total, 42 samples (84%) were considered neoplastic by at least 2 observers and were scored for interobserver agreement: 10 of 42 (23.8%) had uniform agreement, 14 of 42 (33.3%) had majority agreement, and 5 of 42 (11.9%) had divided agreement. Only 9 of 42 samples (21.4%) had minimal agreement, and 4 of 42 (9.5%) had no agreement. Condensation of similar categories was able to improve interobserver agreement and still maintain stratified risk of malignancy.

CONCLUSIONS

The proposed pattern-based risk-stratification scheme, which could be implemented with the forthcoming Milan System, has good overall interobserver agreement and successfully stratifies the risk of malignancy. Some simplification is possible to make the system easier to use and improve interobserver agreement while maintaining stratification of risk. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Continuous Glucose Monitoring in Patients With Type 2 Diabetes

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Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women A Phase 2 Randomized Trial

Background:

Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP).

Objective:

To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection.

Design:

Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114)

Setting:

12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group.

Participants:

HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days.

Intervention:

MVC only, MVC–emtricitabine (FTC), MVC–tenofovir disoproxil fumarate (TDF), and TDF–FTC (control).

Measurements:

At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment.

Results:

Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC–FTC), 9 (MVC–TDF), and 8 (TDF–FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC–TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.

Limitations:

Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy.

Conclusion:

Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF–FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study.

Primary Funding Source:

National Institutes of Health.

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Venous Thrombosis and Cancer: What Would Dr. Trousseau Teach Today?

In their systematic review, van Es and colleagues conclude that although extensive screening of patients with unprovoked venous thromboembolism (VTE) may detect more cancer than a limited approach, whether that translates into improved patient outcomes remains unclear. The editorialists discuss the results of the review in light of the historical context of Trousseau's observations about VTE and cancer 150 years ago.

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Screening for Occult Cancer in Patients With Unprovoked Venous Thromboembolism A Systematic Review and Meta-analysis of Individual Patient Data

Background:

Screening for cancer in patients with unprovoked venous thromboembolism (VTE) often is considered, but clinicians need precise data on cancer prevalence, risk factors, and the effect of different types of screening strategies.

Purpose:

To estimate the prevalence of occult cancer in patients with unprovoked VTE, including in subgroups of different ages or those that have had different types of screening.

Data Sources:

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to 19 January 2016.

Study Selection:

Prospective studies evaluating cancer screening strategies in adults with unprovoked VTE that began enrolling patients after 1 January 2000 and had at least 12 months of follow-up.

Data Extraction:

2 investigators independently reviewed abstracts and full-text articles and independently assessed risk of bias.

Data Synthesis:

10 eligible studies were identified. Individual data were obtained for all 2316 patients. Mean age was 60 years; 58% of patients received extensive screening. The 12-month period prevalence of cancer after VTE diagnosis was 5.2% (95% CI, 4.1% to 6.5%). The point prevalence of cancer was higher in patients who had extensive screening than in those who had more limited screening initially (odds ratio [OR], 2.0 [CI, 1.2 to 3.4]) but not at 12 months (OR, 1.4 [CI, 0.89 to 2.1]). Cancer prevalence increased linearly with age and was 7-fold higher in patients aged 50 years or older than in younger patients (OR, 7.1 [CI, 3.1 to 16]).

Limitation:

Variation in patient characteristics and extensive screening strategies; unavailability of long-term mortality data.

Conclusion:

Occult cancer is detected in 1 in 20 patients within a year of receiving a diagnosis of unprovoked VTE. Older age is associated with a higher cancer prevalence. Although an extensive screening strategy initially may detect more cancer cases than limited screening, whether this translates into improved patient outcomes remains unclear.

Primary Funding Source:

None. (PROSPERO: CRD42016033371)

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Re-analysis of All-Cause Mortality in the U.S. Preventive Services Task Force 2016 Evidence Report on Colorectal Cancer Screening

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Continuous Glucose Monitoring in Patients With Type 2 Diabetes Receiving Insulin Injections: Does This Mean Continuous Glucose Monitoring for Everyone?

Beck and colleagues report a 24-week, randomized controlled trial of continuous glucose monitoring (CGM) in patients with type 2 diabetes treated with insulin. The editorialists discuss the findings, what we know about the benefits of CGM in patients with type 1 diabetes, and the potential role of CGM in selected patients with type 2 diabetes.

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Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections A Randomized Trial

Background:

Continuous glucose monitoring (CGM), which studies have shown is beneficial for adults with type 1 diabetes, has not been well-evaluated in those with type 2 diabetes receiving insulin.

Objective:

To determine the effectiveness of CGM in adults with type 2 diabetes receiving multiple daily injections of insulin.

Design:

Randomized clinical trial. (The protocol also included a type 1 diabetes cohort in a parallel trial and subsequent second trial.) (ClinicalTrials.gov: NCT02282397)

Setting:

25 endocrinology practices in North America.

Patients:

158 adults who had had type 2 diabetes for a median of 17 years (interquartile range, 11 to 23 years). Participants were aged 35 to 79 years (mean, 60 years [SD, 10]), were receiving multiple daily injections of insulin, and had hemoglobin A_1c (HbA_1c) levels of 7.5% to 9.9% (mean, 8.5%).

Intervention:

Random assignment to CGM (n = 79) or usual care (control group, n = 79).

Measurements:

The primary outcome was HbA_1c reduction at 24 weeks.

Results:

Mean HbA_1c levels decreased to 7.7% in the CGM group and 8.0% in the control group at 24 weeks (adjusted difference in mean change, −0.3% [95% CI, −0.5% to 0.0%]; P = 0.022). The groups did not differ meaningfully in CGM-measured hypoglycemia or quality-of-life outcomes. The CGM group averaged 6.7 days (SD, 0.9) of CGM use per week.

Limitation:

6-month follow-up.

Conclusion:

A high percentage of adults who received multiple daily insulin injections for type 2 diabetes used CGM on a daily or near-daily basis for 24 weeks and had improved glycemic control. Because few insulin-treated patients with type 2 diabetes currently use CGM, these results support an additional management method that may benefit these patients.

Primary Funding Source:

Dexcom.

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Top EMS Game Changers – #9: Electronic Patient Care Reports

ePCRs allow virtually limitless information extraction through automated data storage and retrieval

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Top EMS Game Changers – #9: Electronic Patient Care Reports

Electronic PCRs, now used by roughly three quarters of U.S. EMS agencies, were pretty far from commonplace in 1995 when I started my first two paramedic jobs. One of those positions was administrative; I was responsible for keeping manual records of day-to-day patient encounters by ALS providers in our county. Creating, sorting and sometimes tabulating paper reports was no fun. I'd gotten into ...

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Association of IL-27 rs153109 and rs17855750 Polymorphisms with Risk and Response to Therapy in Acute Lymphoblastic Leukemia

Abstract

Interleukin (IL)-27 is a cytokine with important anti-cancer activity. This study has evaluated the effects of IL-27 rs153109 and rs17855750 single nucleotide polymorphisms (SNPs) on risk of acute lymphoblastic leukemia (ALL) development, as well as their impact on prognosis and patient survival. A total of 200 patients and 210 healthy subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism. We observed a higher frequency of rs153109 AG and rs17855750 TG genotypes and allele G in patients compared to controls (p < 0.001). Combined G variant genotypes (AG + GG and TG + GG) also conferred significantly greater risk of ALL. There was a significant correlation between the genotypes of both SNPs with event-free survival (EFS). Patients with GG genotypes of both SNPs and those of rs153109 AG and rs17855750 TG had a shorter EFS than patients with rs153109 AA and rs17855750 TT genotypes (p ≤ 0.035). Combined G variant genotypes for both SNPs showed poorer response to therapy in all patients (p < 0.027) as well as B-ALL (rs153109, p < 0.001) and T-ALL (rs153109, p = 0.048) patients. In multivariate analysis, rs153109 combined G variant genotype was associated with shorter EFS (relative risk = 9.7, p = 0.026). Among those who relapsed, 87.1% had the rs153109 AG genotype and 77.4% had the rs17855750 TG genotype (p < 0.01). Patients had higher IL-27 serum levels compared to controls, but this did not differ between genotypes. In conclusion, the association of IL-27 rs153109 and rs17855750 polymorphisms with risk of ALL development and their impact on EFS suggested an important role for this cytokine in biology and response to ALL therapy.

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Concurrent assessment of calpain and caspase3 activities in brains of mice with acetaminophen-induced acute hepatic encephalopathy

Abstract

To develop pharmacological therapy for acute hepatic encephalopathy (AHE), understanding the molecular basis for cell injury is essential. Excitotoxic neural cell injury mediated by calpain as a post- receptor mechanism has been proposed as a player in neuronal injury in AHE. Concurrent assessment of Calpain and Caspase3 activities in the brain of AHE mice in acetaminophen- induced mourine model was performed. After induction of AHE by acetaminophen in mice, the model was confirmed by histopathological, biochemical and behavioural studies. The brains were removed, western blot analysis was done and the relative activity of calpain and caspase was estimated and compared to control group calpain but not caspase 3 activity was significantly increased in the AHE group compared to the control brains. Experimentally, this finding is the first to report. Increased calpain activity in liver has been previously reported. To translate both finding it can be suggested that calpain inhibition can be an investigational intervention in saving lives in AHE. To confirm the results, besides more advanced toxicodynamic studies on acetaminophen, the results should be confirmed in other models of AHE in future.

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Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4

Here, we present a protocol to induce paralysis and opticospinal inflammation by transfer of aquaporin-4 (AQP4)-specific T cells from AQP4-/- mice into WT mice. In addition, we demonstrate how to use serial optical coherence tomography to monitor visual system dysfunction.

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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation

The method described here is a new vesicle isolation protocol, which allows for the purification of the cellular compartments where exogenous antigens are processed by endoplasmic reticulum-associated degradation in cross-presentation.

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Freiburg Neuropathology Case Conference

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Ileectomy-induced Bile Overaccumulation in Mouse Intestine

Small intestine-dependent bile acid reabsorption and feedback inhibition of hepatic bile acid synthesis is important for systemic homeostasis and health. In this study, we describe a mouse model for ileal resection to evaluate ileectomy-induced bile malabsorption, overaccumulation, and toxicity in mouse intestine.

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Highlights from the 2017 St. Gallen Breast Cancer Consensus

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The value of advanced MRI techniques in the assessment of cervical cancer: a review

Abstract

Objectives

To assess the value of new magnetic resonance imaging (MRI) techniques in cervical cancer.

Methods

We searched PubMed and MEDLINE and reviewed articles published from 1990 to 2016 to identify studies that used MRI techniques, such as diffusion weighted imaging (DWI), intravoxel incoherent motion (IVIM) and dynamic contrast enhancement (DCE) MRI, to assess parametric invasion, to detect lymph node metastases, tumour subtype and grading, and to detect and predict tumour recurrence.

Results

Seventy-nine studies were included. The additional use of DWI improved the accuracy and sensitivity of the evaluation of parametrial extension. Most studies reported improved detection of nodal metastases. Functional MRI techniques have the potential to assess tumour subtypes and tumour grade differentiation, and they showed additional value in detecting and predicting treatment response. Limitations included a lack of technical standardisation, which limits reproducibility.

Conclusions

New advanced MRI techniques allow improved analysis of tumour biology and the tumour microenvironment. They can improve TNM staging and show promise for tumour classification and for assessing the risk of tumour recurrence. They may be helpful for developing optimised and personalised therapy for patients with cervical cancer.

Teaching points

• Conventional MRI plays a key role in the evaluation of cervical cancer.

• DWI improves tumour delineation and detection of nodal metastases in cervical cancer.

• Advanced MRI techniques show promise regarding histological grading and subtype differentiation.

• Tumour ADC is a potential biomarker for response to treatment.

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People Favor Highly-Reviewed Products, Even When They Shouldn’t

When we're trying to decide which cell phone case to buy or which hotel room to book, we often rely on the ratings and reviews of others to help us choose. But new research suggests that we tend to use this information in ways that can actually work to our disadvantage.

The findings, published in Psychological Science, a journal of the Association for Psychological Science, indicate that people tend to favor a product that has more reviews, even when it has the same low rating as an alternative product.

"It's extremely common for websites and apps to display the average score of a product along with the number of reviews. Our research suggests that, in some cases, people might take this information and make systematically bad decisions with it," says researcher Derek Powell of Stanford University, lead author on the study.

"We found that people were biased toward choosing to purchase more popular products and that this sometimes led them to make very poor decisions," he explains.

As opportunities to buy products and services online multiply, we have greater access than ever before to huge amounts of first-hand information about users' experiences.

"We wanted to examine how people use this wealth of information when they make decisions, and specifically how they weigh information about other people's decisions with information about the outcomes of those decisions," says Powell.

Looking at actual products available on Amazon.com, Powell and colleagues Jingqi Yu (Indiana University Bloomington), Melissa DeWolf, and Keith Holyoak (University of California, Los Angeles) found no relationship between the number of reviews a product had and its average rating. In other words, real-world data show that a large number of reviews is not a reliable indicator of a product's quality.

With this in mind, the researchers wanted to see how people would actually use review and rating information when choosing a product. In one online experiment, 132 adult participants looked at a series of phone cases, presented in pairs. The participants saw an average user rating and total number of reviews for each phone case and indicated which case in each pair they would buy.

Across various combinations of average rating and number of reviews, participants routinely chose the option with more reviews. This bias was so strong that they often favored the more-reviewed phone case even when both of the options had low ratings, effectively choosing the product that was, in statistical terms, more likely to be low quality.

A second online experiment that followed the same design and procedure produced similar results.

"By examining a large dataset of reviews from Amazon.com, we were able to build a statistical model of how people should choose products. We found that, faced with a choice between two low-scoring products, one with many reviews and one with few, the statistics say we should actually go for the product with few reviews, since there's more of a chance it's not really so bad," Powell explains. "But participants in our studies did just the opposite: They went for the more popular product, despite the fact that they should've been even more certain it was of low quality."

The researchers found that this pattern of results fit closely with a statistical model based on social inference. That is, people seem to use the number of reviews as shorthand for a product's popularity, independent from the product's average rating.

According to Powell, these findings have direct implications for both retailers and consumers:

"Consumers try to use information about other people's experiences to make good choices, and retailers have an incentive to steer consumers toward products they will be satisfied with," he says. "Our data suggest that retailers might need to rethink how reviews are presented and consumers might need to do more to educate themselves about how to use reviews to guide their choices."

All data, code, and materials have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure is available online. This article has received badges for Open Data and Open Materials.

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5 things to know about EMS chaplains

It's no secret that EMS providers have a dangerous job. While we want every responder to return home safely after a shift, sadly it doesn't always happen. In the event of a sudden death, seriously injured responder or line of duty death, an EMS chaplain provides both counseling to responders and other department members. EMS providers often help people on the worst day of their life. In the ...

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EMS Innovations: #9 Electronic Patient Care Reports

Electronic PCRs, now used by roughly three quarters of U.S. EMS agencies, were pretty far from commonplace in 1995 when I started my first two paramedic jobs. One of those positions was administrative; I was responsible for keeping manual records of day-to-day patient encounters by ALS providers in our county. Creating, sorting and sometimes tabulating paper reports was no fun. I'd gotten into ...

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EMCrit Podcast 206 – ApOx, ENDAO, & PreOx Update

ApOx & PreOx Update

EMCrit by Scott Weingart.

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EMS Innovations: #9 Electronic Patient Care Reports

ePCRs allow virtually limitless information extraction through automated data storage and retrieval

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Bottlenose Dolphin (Tursiops truncatus) Spermatozoa: Collection, Cryopreservation, and Heterologous In Vitro Fertilization

Here, we present protocols that have been successfully used for dolphin spermatozoa collection, cryopreservation, and heterologous IVF performance using bovine oocytes.

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NCI Program Supports Small Businesses to Advance Cancer Research Innovation – A Q&A with Michael Weingarten

NCI's Small Business Innovation Research Program recently issued contract solicitations to spur the development of new cancer-related therapies and technologies, including seven opportunities specific to the Cancer Moonshot.

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Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

Abstract

Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic (HG; glucotoxic) conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

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Information

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Insufficient sleep: Enhanced risk-seeking relates to low local sleep intensity

Abstract

Objectives: Chronic sleep restriction is highly prevalent in modern society and is in its clinical form, insufficient sleep syndrome, one of the most prevalent diagnoses in clinical sleep laboratories, with substantial negative impact on health and community burden. It reflects every-day sleep loss better than acute sleep deprivation, but its effects and particularly the underlying mechanisms remain largely unknown for a variety of critical cognitive domains, as for example risky decision-making.

Methods: We assessed financial risk-taking behavior after 7 consecutive nights of sleep restriction and after one night of acute sleep deprivation compared to a regular sleep condition in a within-subject design. We further investigated potential underlying mechanisms of sleep loss induced changes in behavior by high-density electroencephalography recordings during restricted sleep.

Results: We show that chronic sleep restriction increases risk-seeking, while this was not observed after acute sleep deprivation. This increase was subjectively not noticed and was related to locally lower values of slow wave energy during preceding sleep, an electrophysiological marker of sleep intensity and restoration, in electrodes over the right prefrontal cortex.

Interpretation: This study provides for the first time evidence that insufficient sleep restoration over circumscribed cortical areas leads to aberrant behavior. In chronically sleep restricted subjects, low slow wave sleep intensity over the right prefrontal cortex - which has been shown to be linked to risk behavior – may lead to increased and subjectively unnoticed risk-seeking. This article is protected by copyright. All rights reserved.

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Quality Indicators for Sentinel Lymph Node Biopsy in Breast Cancer: Applicability and Clinical Relevance in a Non-screened Population

Abstract

Quality Indicators for Sentinel Lymph Node Biopsy in Breast Cancer: Applicability and Clinical Relevance in a Non-screened Population: sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as standard of care for management of early breast cancer. This study assessed our SLNB program against 11 published quality indicators (QIs). All breast cancer patients who underwent SLNB in our centre from June 2013–Dec 2015 were included. Clinical, pathological and follow-up data were extracted from the institutional REDCap data system. Analysis was done with SPSS 23. Following validation, 234 patients had SLNB, always performed along with primary surgery. Identification rate was 95.3% and > 1 SLN was identified in 72% of patients. SLNB positivity was 33%, of these, 100% underwent ALND. Overall 91% of QI eligible patients underwent SLNB. No ineligible patients (T4) underwent SLNB. For the patients who had radio colloid, injection criteria were met for 100%. Pathological evaluation and reporting criteria were met for 100% of patients. There were no axillary recurrences in a median follow-up of 2 years. 7.6% patients had SLN negative on frozen section but positive on final histology. 7.2% of patients with clinical negative nodes had pN2 disease in final histopathology report after surgery. Sixty percent of patients who had completion ALND had only positive SLN. This study supports the applicability of published QI of SLNB in a non-screened cohort of early breast cancer patients. Although QI were useful, modification based on patient characteristics and resource availability may be needed. These indicators can be used as audit tools to improve the overall accuracy of the procedure.

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Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia

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Green Tea Consumption - A Potential Chemopreventive Measure for Hepatocellular Carcinoma?

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Metal Thio- and Selenophosphates as Multifunctional van der Waals Layered Materials

Since the discovery of Dirac physics in graphene, research in 2D materials has exploded with the aim of finding new materials and harnessing their unique and tunable electronic and optical properties. The follow-on work on 2D dielectrics and semiconductors has led to the emergence and development of hexagonal boron nitride, black phosphorus, and transition metal disulfides. However, the spectrum of good insulating materials is still very narrow. Likewise, 2D materials exhibiting correlated phenomena such as superconductivity, magnetism, and ferroelectricity have yet to be developed or discovered. These properties will significantly enrich the spectrum of functional 2D materials, particularly in the case of high phase-transition temperatures. They will also advance a fascinating fundamental frontier of size and proximity effects on correlated ground states. Here, a broad family of layered metal thio(seleno)phosphate materials that are moderate- to wide-bandgap semiconductors with incipient ionic conductivity and a host of ferroic properties are reviewed. It is argued that this material class has the potential to merge the sought-after properties of complex oxides with electronic functions of 2D and quasi-2D electronic materials, as well as to create new avenues for both applied and fundamental materials research in structural and magnetic correlations.

Metal thiophosphates (MTPs) are a class of cleavable insulating materials with a common P₂S₆ structural framework. They span a very wide variety of transition metal cations, thus exhibiting ferroelectricity, magnetism, and optoelectronic properties, as well as rich solid state chemistry that can combine various properties within a single bulk, quasi-2D, or prospectively 2D crystal. In this respect, MTP compounds can be viewed as a layered analog to complex oxides.

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1D Coordination Polymer Nanofibers for Low-Temperature Photothermal Therapy

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) usually requires hyperthermia to >50 °C for effective tumor ablation, which can potentially induce inflammatory disease and heating damage of normal organs nearby, while tumor lesions without sufficient heating (e.g., the internal part) may survive after treatment. Achieving effective tumor killing under relatively low temperatures is thus critical toward successful clinical use of PTT. Herein, we design a simple strategy to fabricate poly(ethylene glycol) (PEG)-modified one-dimensional nanoscale coordination polymers (1D-NCPs) with intrinsic biodegradability, large surface area, pH-responsive behaviors, and versatile theranostic functions. With NCPs consisting of Mn2+/indocyanine green (ICG) as the example, Mn-ICG@pHis-PEG display efficient pH-responsive tumor retention after systemic administration and then load Gambogic acid (GA), a natural inhibitor of heat-shock protein 90 (Hsp90) that plays an essential role for cells to resist heating-induced damage. Such Mn-ICG@pHis-PEG/GA under a mild NIR-triggered heating is able to induce effective apoptosis of tumor cells, realizing low-temperature PTT (~43 °C) with excellent tumor destruction efficacy. This work not only develops a facile approach to fabricate PEGylated 1D-NCPs with tumor-specific pH responsiveness and theranostic functionalities, but also presents a unique low-temperature PTT strategy to kill cancer in a highly effective and minimally invasive manner.

A one-dimensional (1D) PEGylated nanoscale coordination polymer (NCPs) is fabricated via a one-step method. After loading gambogic acid (GA), such Mn-ICG@pHis-PEG/GA displays efficient pH-responsive tumor retention after systemic administration. Owing to the GA-induced down-regulation of Hsp90 to overcome the thermal-resistance of tumor cells, highly effective in vivo destruction of tumors is relized with Mn-ICG@pHis-PEG/GA under low-temperature PTT at 43 °C.

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Forming Sticky Droplets from Slippery Polymer Zwitterions

Polymer zwitterions are generally regarded as hydrophilic and repellant or "slippery" materials. Here, a case is described in which the polymer zwitterion structure is tailored to decrease water solubility, stabilize emulsion droplets, and promote interdroplet adhesion. Harnessing the upper critical solution temperature of sulfonium- and ammonium-based polymer zwitterions in water, adhesive droplets are prepared by adding organic solvent to an aqueous polymer solution at elevated temperature, followed by agitation to induce emulsification. Droplet aggregation is observed as the mixture cools. Variation of salt concentration, temperature, polymer concentration, and polymer structure modulates these interdroplet interactions, resulting in distinct changes in emulsion stability and fluidity. Under attractive conditions, emulsions encapsulating 50–75% oil undergo gelation. By contrast, emulsions prepared under conditions where droplets are nonadhesive remain fluid and, for oil fractions exceeding 0.6, coalescence is observed. The uniquely reactive nature of the selected zwitterions allows their in situ modification and affords a route to chemically trigger deaggregation and droplet dispersion. Finally, experiments performed in a microfluidic device, in which droplets are formed under conditions that either promote or suppress adhesion, confirm the salt-responsive character of these emulsions and the persistence of adhesive interdroplet interactions under flow.

Dipole–dipole interactions of polymer zwitterions promote adhesion between emulsion droplets, which exhibit responsiveness to both environmental and chemical triggers. Oil-in-water emulsions stabilized by polymer zwitterions become adhesive and gel under conditions where the polymers are insoluble in the aqueous phase. These interdroplet interactions are modulated by temperature, salt concentration, polymer concentration, zwitterion type, and reactions conducted at the oil–water interface.

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Extraordinary Thermoelectric Performance Realized in n-Type PbTe through Multiphase Nanostructure Engineering

Lead telluride has long been realized as an ideal p-type thermoelectric material at an intermediate temperature range; however, its commercial applications are largely restricted by its n-type counterpart that exhibits relatively inferior thermoelectric performance. This major limitation is largely solved here, where it is reported that a record-high ZT value of ≈1.83 can be achieved at 773 K in n-type PbTe-4%InSb composites. This significant enhancement in thermoelectric performance is attributed to the incorporation of InSb into the PbTe matrix resulting in multiphase nanostructures that can simultaneously modulate the electrical and thermal transport. On one hand, the multiphase energy barriers between nanophases and matrix can boost the power factor in the entire temperature range via significant enhancement of the Seebeck coefficient and moderately reducing the carrier mobility. On the other hand, the strengthened interface scattering at the intensive phase boundaries yields an extremely low lattice thermal conductivity. This strategy of constructing multiphase nanostructures can also be highly applicable in enhancing the performance of other state-of-the-art thermoelectric systems.

A new strategy of constructing multiphase nanostructures can enhance the thermoelectric power factor and reduce the lattice thermal conductivity simultaneously. Through this strategy, it is reported that a record-high ZT value of ≈1.83 can be achieved at 773 K in n-type PbTe-4%InSb composites. Furthermore, the mechanisms introducing multiphase nanostructures are also highly applicable in other thermoelectric systems.

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Room Temperature Electrochemical Sintering of Zn Microparticles and Its Use in Printable Conducting Inks for Bioresorbable Electronics

This study describes a conductive ink formulation that exploits electrochemical sintering of Zn microparticles in aqueous solutions at room temperature. This material system has relevance to emerging classes of biologically and environmentally degradable electronic devices. The sintering process involves dissolution of a surface passivation layer of zinc oxide in CH₃COOH/H₂O and subsequent self-exchange of Zn and Zn²⁺ at the Zn/H₂O interface. The chemical specificity associated with the Zn metal and the CH₃COOH/H₂O solution is critically important, as revealed by studies of other material combinations. The resulting electrochemistry establishes the basis for a remarkably simple procedure for printing highly conductive (3 × 10⁵ S m⁻¹) features in degradable materials at ambient conditions over large areas, with key advantages over strategies based on liquid phase (fusion) sintering that requires both oxide-free metal surfaces and high temperature conditions. Demonstrations include printed magnetic loop antennas for near-field communication devices.

This study describes a conductive ink formulation that exploits electrochemical sintering of Zn microparticles in aqueous solutions at room temperature, with relevance to emerging classes of biologically and environmentally degradable electronic devices. The resulting electrochemistry establishes the basis for a remarkably simple procedure for printing highly conductive features in degradable materials at ambient conditions over large areas.

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A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers

A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of β-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing β-lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects.

A cascade amplification release nanoparticle is constructed by loading β-lapachone and a reactive-oxygen-species-responsive doxorubicin (DOX) prodrug in polymeric nanoparticles. The selective cascade amplification release of β-lapachone and DOX in cancer cells remarkably increases the selectivity of chemotherapy and overcomes the multidrug resistance (MDR) in cancer cells, producing a remarkably enhanced therapeutic efficacy against MDR tumors with minimal side effects.

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A 1D Vanadium Dioxide Nanochannel Constructed via Electric-Field-Induced Ion Transport and its Superior Metal–Insulator Transition

Nanoscale manipulation of materials' physicochemical properties offers distinguished possibility to the development of novel electronic devices with ultrasmall dimension, fast operation speed, and low energy consumption characteristics. This is especially important as the present semiconductor manufacturing technique is approaching the end of miniaturization campaign in the near future. Here, a superior metal–insulator transition (MIT) of a 1D VO₂ nanochannel constructed through an electric-field-induced oxygen ion migration process in V₂O₅ thin film is reported for the first time. A sharp and reliable MIT transition with a steep turn-on voltage slope of <0.5 mV dec⁻¹, fast switching speed of 17 ns, low energy consumption of 8 pJ, and low variability of <4.3% is demonstrated in the VO₂ nanochannel device. High-resolution transmission electron microscopy observation and theoretical computation verify that the superior electrical properties of the present device can be ascribed to the electroformation of nanoscale VO₂ nanochannel in V₂O₅ thin films. More importantly, the incorporation of the present device into a Pt/HfO₂/Pt/VO₂/Pt 1S1R unit can ensure the correct reading of the HfO₂ memory continuously for 10⁷ cycles, therefore demonstrating its great possibility as a reliable selector in high-density crossbar memory arrays.

A 1D vanadium dioxide nanochannel is constructed via electric-field-induced ion transport and related solid-state redox reaction in V₂O₅ thin film. A superior metal–insulator transition of VO₂ with sharp transition, fast switching speed, low energy consumption, and excellent reproducibility is demonstrated. The VO₂ nanostructure can act as a promising candidate for the selector element in high-density crossbar memory arrays.

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Si Complies with GaN to Overcome Thermal Mismatches for the Heteroepitaxy of Thick GaN on Si

Heteroepitaxial growth of lattice mismatched materials has advanced through the epitaxy of thin coherently strained layers, the strain sharing in virtual and nanoscale substrates, and the growth of thick films with intermediate strain-relaxed buffer layers. However, the thermal mismatch is not completely resolved in highly mismatched systems such as in GaN-on-Si. Here, geometrical effects and surface faceting to dilate thermal stresses at the surface of selectively grown epitaxial GaN layers on Si are exploited. The growth of thick (19 µm), crack-free, and pure GaN layers on Si with the lowest threading dislocation density of 1.1 × 10⁷ cm⁻² achieved to date in GaN-on-Si is demonstrated. With these advances, the first vertical GaN metal–insulator–semiconductor field-effect transistors on Si substrates with low leakage currents and high on/off ratios paving the way for a cost-effective high power device paradigm on an Si CMOS platform are demonstrated

Thick (19 µm), crack-free, and pure GaN-on-Si is achieved by strain engineering and metal–organic chemical vapor deposition. A record-low threading dislocation density of 1.1 × 10⁷ cm⁻² and vertical trench-gate normally off metal–insulator–semiconductor field-effect transistor are achieved for the first time in GaN-on-Si.

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“What” and “where” was when? Memory for the temporal order of episodic events in children

Abstract

In the past, researchers have shown that the individual components of episodic memory (i.e "what," "where," and "when") may emerge at different points in development. Specifically, while children as young as three can accurately report the "what" and "where" of an event, they struggle to accurately report when the event occurred. One explanation for children's difficulty in reporting when an event took place is a rudimentary understanding, and ability to use, temporal terms. In the current experiment, we employed a physical timeline to aid children's reporting of the order in which a series of episodic events occurred. Overall, while 4-, 5-, and 6-year olds performed above chance, 3-year olds did not. Our findings suggest that 3-year olds' limited ability to produce temporal terms may not be the rate-limiting step preventing them from identifying when events occurred in their recent past.

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Prenatal programming of postnatal plasticity for externalizing behavior: Testing an integrated developmental model of genetic and temperamental sensitivity to the environment

Abstract

Although both gene- and temperament-environment interactions contribute to the development of youth externalizing problems, it is unclear how these factors jointly affect environmental sensitivity over time. In a 7-year longitudinal study of 232 children (aged 5–10) with and without ADHD, we employed moderated mediation to test a developmentally sensitive mechanistic model of genetic and temperamental sensitivity to prenatal and postnatal environmental factors. Birth weight, a global measure of the prenatal environment, moderated predictions of child negative emotionality from a composite of dopaminergic polymorphisms (i.e., DRD4 and DAT1), such that birth weight inversely predicted negative emotionality only for children with genetic plasticity. Negative emotionality, in turn, predicted externalizing behavior 4–5 years later, beyond genetic and postnatal parenting effects. Finally, birth weight moderated the indirect effect of dopaminergic genotypes on externalizing problems through negative emotionality, partially supporting a prenatal programming model. We discuss theoretical and empirical implications for models of environmental sensitivity.

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Simultaneous monitoring of maternal and fetal heart rate variability during labor in relation with fetal gender

Abstract

Male gender is considered a risk factor for several adverse perinatal outcomes. Fetal gender effect on fetal heart rate (FHR) has been subject of several studies with contradictory results. The importance of maternal heart rate (MHR) monitoring during labor has also been investigated, but less is known about the effect of fetal gender on MHR. The aim of this study is to simultaneously assess maternal and FHR variability during labor in relation with fetal gender. Simultaneous MHR and FHR recordings were obtained from 44 singleton term pregnancies during the last 2 hr of labor (H_1,H₂). Heart rate tracings were analyzed using linear (time- and frequency-domain) and nonlinear indices. Both linear and nonlinear components were considered in assessing FHR and MHR interaction, including cross-sample entropy (cross-SampEn). Mothers carrying male fetuses (n = 22) had significantly higher values for linear indices related with MHR average and variability and sympatho-vagal balance, while the opposite occurred in the high-frequency component and most nonlinear indices. Significant differences in FHR were only observed in H₁ with higher entropy values in female fetuses. Assessing the differences between FHR and MHR, statistically significant differences were obtained in most nonlinear indices between genders. A significantly higher cross-SampEn was observed in mothers carrying female fetuses (n = 22), denoting lower synchrony or similarity between MHR and FHR. The variability of MHR and the synchrony/similarity between MHR and FHR vary with respect to fetal gender during labor. These findings suggest that fetal gender needs to be taken into account when simultaneously monitoring MHR and FHR.

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The intersensory redundancy hypothesis: Extending the principle of unimodal facilitation to prenatal development

Abstract

Selective attention to different properties of stimulation provides the foundation for perception, learning, and memory. The Intersensory Redundancy Hypothesis (IRH) proposes that early in development information presented redundantly across two or more modalities (multimodal) selectively recruits attention to and enhances perceptual learning of amodal properties, whereas information presented to a single sense modality (unimodal) enhances perceptual learning of modality-specific properties. The present study is the first to assess this principle of unimodal facilitation in non-human animals in prenatal development. We assessed bobwhite quail embryos' prenatal detection of pitch, a modality-specific property, under conditions of unimodal and bimodal (synchronous or asynchronous) exposure. Chicks exposed to prenatal unimodal auditory stimulation or asynchronous bimodal (audiovisual) stimulation preferred the familiarized maternal call over a novel pitch-modified maternal call following hatching, whereas chicks exposed to redundant (synchronous) audiovisual stimulation failed to prefer the familiar call over the pitch-modified call. These results provide further evidence that selective attention is recruited to specific stimulus properties of events in early development and that these biases are evident even during the prenatal period.

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Associations Between Environmental Resources and the “Wanting” and “Liking” of Male Song in Female Songbirds

Abstract

Reproductive success requires animals to adjust social and sexual behaviors in response to changes in environmental resources. In many species, males produce courtship signals to attract females; however, not all females are attracted by these signals. One possible explanation for this is that environmental resources alter neural mechanisms underlying motivation and reward in females so that male courtship is attractive when conditions are most favorable for an individual to breed. Here, we first introduce resource-dependent breeding behaviors of female songbirds. We then review studies that show associations between neural systems underlying motivation and reward, female responses to male courtship stimuli, and environmental resources necessary for breeding success (e.g., in female starlings, a nest cavity). Overall, we review evidence supporting the working hypotheses that (1) dopamine underlies sexually-motivated female responses to male courtship stimuli (i.e., song), (2) opioids underlie reward induced in females by hearing male courtship song, and (3) these systems are possibly modified by resources such that male courtship song is only attractive and rewarding to females with access to limited environmental resources essential for breeding success.

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Quantitative Evaluation of the Compressed L5 and S1 Nerve Roots in Unilateral Lumbar Disc Herniation by Using Diffusion Tensor Imaging

Abstract

Background and Purpose

Nerve root compression by lumbar disc herniation (LDH) induces a series of clinical symptoms, seriously affecting the patient's life and work. The purpose of this study is to investigate microstructural changes and fiber bundle abnormalities of the compressed L5 and S1 nerve roots in young patients with unilateral LDH by using diffusion tensor imaging (DTI).

Methods

Forty young patients with unilateral LDH and 17 healthy volunteers participated in the study, and 33 patients received follow-up DTI examination after one month of conservative treatment. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and trace weight (TraceW) values of the L5 and S1 nerve roots were measured on FA maps.

Results

The mean FA, ADC and TraceW values of the affected nerve roots were 0.259 ± 0.047, 1.79 ± 0.252 and 0.076 ± 0.025, respectively. Compared to the contralateral side and volunteers, the affected nerve roots showed a decreased FA (P < 0.01), an increased ADC (P < 0.01) and TraceW (P < 0.05). The compression severity had a moderately negative correlation with FA (r = −0.646, P < 0.01) and positive correlation with ADC (r = 0.408, P < 0.01) but not with TraceW (r = 0.298, P = 0.06). For 33 patients with follow-up study after conservative treatment, FA (0.286 ± 0.06) and ADC (1.630 ± 0.046) in the affected nerve roots showed an increasing and a decreasing trend, respectively. Moreover, FA values (14 cases; 0.246 ± 0.015, P = 0.213) in the severe compression group had no significant changes between initial and follow-up data.

Conclusions

DTI is able to assess microstructural abnormalities of the compressed nerve roots and has potentially practical value for prognostic evaluation after treatment in patients with LDH.

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Septic abortion presenting as a right lower trapezius abscess secondary to Bacteroides fragilis bacteraemia

A 43-year-old Japanese woman was evaluated in the outpatient department for right shoulder pain and fever, which began 5 days earlier. MRI of the right shoulder revealed a high-intensity area deep in the right trapezius muscle. Aspiration revealed purulent fluid, and Gram staining of the fluid showed Gram-negative bacilli. The patient was also found to be profoundly anaemic and to have a positive urine pregnancy test. On admission, we initiated intravenous ampicillin–sulbactam and aztreonam. She underwent dilatation and curettage for septic abortion and surgical drainage of the right shoulder abscess. Bacteroides fragilis was isolated from the blood, uterine aspiration and abscess samples. On hospital day 4, a whole-body CT scan revealed no other abscesses, and ampicillin–sulbactam was continued for 28 days. The patient was discharged on hospital day 29. Gram staining is an important tool for evaluating infectious aetiologies.

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Herpes simplex transmission to chest and face through autoinoculation in an infant

A 4-month-old female infant presented with a vesicular lesion on her left hand present since 1 day. A few days prior to presentation, she had a similar lesion on the lower lip. Two days after presentation, she returned with new lesions on her thorax and upper eyelid. PCR of the vesicle was positive for herpes simplex virus type 1. The transmission to her chest and face probably resulted from autoinoculation, caused by rubbing of the hand on other parts of the body. Transmission of herpes simplex through skin-to-skin contact is a common route of infection in people engaging in contact sports. Antiviral therapy was started because of the extensiveness and expansion of lesions and risk of developing herpetic keratitis. The patient completely recovered. This case shows that in an otherwise healthy infant, multiple herpetic skin lesions were not due to disseminated infection, but through autoinoculation.

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Novel use of rituximab in macrophage activation syndrome secondary to systemic lupus erythematosus

Macrophage activation syndrome (MAS) is a rare disease characterised by aberrant immune hyperactivation of T lymphocytes and macrophages driven by cytokine dysfunction. The HLH-2004 protocol is commonly used for the treatment of MAS, but significant toxicities are associated. We describe a case of MAS secondary to systemic lupus erythematosus in a young female that responded well to rituximab in lieu of etoposide. She continues to be in remission 1 year following the completion of rituximab infusion and is maintained on hydroxychloroquine. This case highlights the need for further research on the use of rituximab and other available biologics in the setting of MAS in order to help guide further alternative treatment decisions.

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