Dopamine and beta-band oscillations differentially link to striatal value and motor control.

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson's disease and related neurodegenerative disorders.

Imaging of sleep-disordered breathing in adults.

Sleep-disordered breathing (SDB) is a term that includes several chronic conditions in which partial or complete cessation of breathing occurs multiple times throughout the night. Central sleep apnoea (CSA) is uncommon and defined by the episodic cessation of airflow without respiratory effort. Lesions involving the respiratory centre in the brainstem or the origin of the phrenic nerve from the mid-cervical cord are the commonest structural causes of CSA; magnetic resonance imaging (MRI) will demonstrate the lesion and frequently suggest the likely aetiology. In contrast, obstructive sleep apnoea (OSA) is defined as upper airway obstruction despite ongoing respiratory effort. Repetitive episodes of narrowing or closure of the upper airway are the predominant cause leading to snoring and OSA, respectively. OSA affects 33-40% of the adult population and is associated with multiple adverse health consequences, including a significantly increased risk of serious morbidity and mortality. The incidence is increasing proportionally to the worldwide rise in obesity. Imaging, performed primarily without the involvement of radiologists, has been integral to understanding the anatomical basis of SDB and especially OSA. This article will review the pathophysiology, imaging findings, and sequelae of these common conditions. The role of imaging both in suggesting the incidental diagnoses of SDB and in the investigation of these conditions when the diagnosis is suspected or has been established are also discussed.

Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.

Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the etiology of pathologies including peritonitis, endometriosis, and metastatic cancer; thus, understanding the factors that govern their behavior is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover, and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single-cell RNA sequencing revealed marked dimorphisms in gene expression between male and female peritoneal macrophages that was, in part, explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2 -/- mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow, whereas others are reliant on local microenvironment signals. We demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious diseases.

Oxidation of cis-Diamminediacetato PtII with Hydrogen Peroxide Can Give Rise to Two Isomeric PtIV Products.

The oxidation of cis-[Pt(NH3 )2 (OAc)2 ] with H2 O2 yields a mixture of two isomers: ctc-[Pt(NH3 )2 (OH)2 (OAc)2 ] and ctc-[Pt(NH3 )2 (OH)(OAc)(OH)(OAc)]. Following modification with 4-phenylbutyric (PhB) anhydride, two isomers were separated and characterized; the symmetric ctc-[Pt(NH3 )2 (PhB)2 (OAc)2 ] (1) and the nonsymmetric ctc-[Pt(NH3 )2 (PhB)(OAc)(PhB)(OAc)] (2). They differ in their log P values and despite having similar cellular uptake and similar DNA platination levels, the symmetric ctc-[Pt(NH3 )2 (OH)2 (OAc)2 ] is more than 4-fold more potent than the nonsymmetric isomer in a panel of 4 cancer cell lines.

Captive Psittacine Birds in Ontario, Canada: a 19-Year Retrospective Study of the Causes of Morbidity and Mortality.

Psittacines (e.g. parrots, macaws and cockatoos) are common companion animals that are also kept in zoos and private breeding collections. Despite this popularity, long-term, comprehensive studies of diagnostic data from captive psittacines are rare. This study was conducted to assess trends in disease prevalence and to describe causes of morbidity and mortality in psittacines submitted for post-mortem examination to the veterinary hospital and diagnostic laboratory at the University of Guelph, Ontario, Canada. Post-mortem reports of 1,850 psittacines from 1998 to 2017 were assessed and included 110 species from 45 genera. Birds were often diagnosed with infectious disease processes (n = 823; 44.5%), including viral (n = 428; 23.1%), bacterial (n = 284; 15.4%) and fungal (n = 161; 8.7%). Non-infectious disease processes (n = 1,076; 58.2%) were most commonly degenerative (n = 465; 25.1%), metabolic (n = 392; 21.2%) or haemodynamic (n = 270; 14.6%). Exploratory statistical analyses, used to guide further research, revealed significant correlations and associations among disease processes and genera, age categories and sex. This 19-year retrospective study is the first to be conducted in Canada for psittacine birds and provides a broad overview of disease prevalence that can be used as a baseline to inform other studies addressing common and uncommon diseases affecting these birds in the future.

Saccharomyces cerevisiae boulardii CNCM I-1079 affects health, growth, and fecal microbiota in milk-fed veal calves.

The objective of this study was to investigate the effect of one specific strain of yeast, Saccharomyces cerevisiae boulardii CNCM I-1079 (SCB), on the growth performance, health, and fecal bacterial profile of veal calves. A total of 84 animals were enrolled in an experiment at a commercial veal farm for a total of 7 wk. Calves were fed twice a day with a milk replacer meal during the entire experiment and were randomly assigned to receive daily either SCB supplementation (10 × 109 cfu/d) or a placebo (CON). Individual feed intake and body weight were monitored on a daily and weekly basis, respectively. Fecal samples were collected at arrival to the veal facility (wk 0) and additional samples were taken on d 14 (wk 2) and d 49 (wk 7). These samples were subjected to 16S rRNA gene amplicon sequencing using Illumina MiSeq (Illumina Inc., San Diego, CA) to examine the bacterial profiles and real-time quantitative PCR to quantify Saccharomyces cerevisiae and specific bacterial groups. The significant increase of S. cerevisiae in the feces of SCB calves at wk 2 and 7 compared with wk 0 (respectively 1.7 × 107, 1.2 × 107, and 2.2 × 105 copy number of S. cerevisiae/g of feces) indicates a good survival of that yeast strain along the gastrointestinal tract. Supplementation of SCB did not improve overall growth performance with regard to average daily gain (ADG), final body weight, and feed intake. Nevertheless, a total of 69.1% of nonsupplemented calves had diarrhea and 28.6% experienced severe diarrhea, whereas 50.0% of the calves supplemented with SCB had diarrhea and 9.5% experienced severe diarrhea. With respect to antibiotic use, 89.7% of the diarrheic calves recorded in the CON group were treated, whereas only 66.7% of the SCB diarrheic calves received an antibiotic. In addition, diarrheic calves supplemented with SCB maintained an ADG similar to nondiarrheic animals, whereas the CON diarrheic calves had a significantly lower ADG in comparison with nondiarrheic CON calves. Fecalibacterium was the most predominant bacterial genus in fecal samples of nondiarrheic and diarrheic calves supplemented with SCB, whereas fecal microbiota was predominated by Collinsella in diarrheic calves from the CON group. Live yeast supplementation in milk replacer led to a decrease of diarrhea in milk-fed veal calves and the fecal microbiota of diarrheic calves maintained a healthy community similar to nondiarrheic animals, with Fecalibacterium being the predominant genus.

Skipping breakfast and non-high-density lipoprotein cholesterol level in school children: a preliminary analysis.

OBJECTIVE: The objective of the study is to examine whether the increased levels of non-high-density lipoprotein cholesterol (non-HDL-c) are associated with skipping breakfast among school children. STUDY DESIGN: A cross-sectional survey was conducted among 539 school children aged 8-12 years from the Niagara Region of Canada. METHODS: Non-fasting finger blood was taken for total cholesterol (total-c) and HDL-c measurements. Non-HDL-c was calculated as the difference between total-c and HDL-c. The information of skipping breakfast in a week was obtained from a questionnaire, which was categorized into three groups, i.e., none, 1-3 times and 4 + times. Demographic information and other related variables were described by the three breakfast-skipping groups. RESULTS: Approximately 44% of children (n = 182) reported skipping breakfast. There were significant differences between the three groups in the means of total-c, non-HDL-c, body mass index, waist circumference, proportions of overall health excellent, eating dinner with parent and skipping breakfast that affects learning (P < 0.05). The number of days of skipping breakfast was weakly correlated to the level of non-HDL-c (r = 0.145, P < 0.0001). Multiple regression results indicated that every one more time of skipping breakfast would increase approximately 0.05 mmol/L level of non-HDL-c (P < 0.01), on average, after adjusting for those aforementioned potential confounding variables. The adjusted mean levels of non-HDL-c were 2.77, 2.94 and 3.07 mmol/L for none, skipping 1-3 times and skipping 4 + times of breakfast, respectively; the mean differences between none and the other two groups were statistical significant (P < 0.05). CONCLUSION: Non-HDL-c levels is positively associated with the number of skipping breakfast among school children, and further research is needed to confirm this relationship.

Amorphous Silicon with Extremely Low Absorption: Beating Thermal Noise in Gravitational Astronomy.

Amorphous silicon has ideal properties for many applications in fundamental research and industry. However, the optical absorption is often unacceptably high, particularly for gravitational-wave detection. We report a novel ion-beam deposition method for fabricating amorphous silicon with unprecedentedly low unpaired electron-spin density and optical absorption, the spin limit on absorption being surpassed for the first time. At low unpaired electron density, the absorption is no longer correlated with electron spins, but with the electronic mobility gap. Compared to standard ion-beam deposition, the absorption at 1550 nm is lower by a factor of ≈100. This breakthrough shows that amorphous silicon could be exploited as an extreme performance optical coating in near-infrared applications, and it represents an important proof of concept for future gravitational-wave detectors.

Baseline characteristics and outcomes of children with cancer in the English-speaking Caribbean: A multinational retrospective cohort.

BACKGROUND: English-speaking Caribbean (ESC) childhood cancer outcomes are unknown. PROCEDURE: Through the SickKids-Caribbean Initiative (SCI), we established a multicenter childhood cancer database across seven centers in six ESC countries. Data managers entered patient demographics, disease, treatment, and outcome data. Data collection commenced in 2013, with retrospective collection to 2011 and subsequent prospective collection. RESULTS: A total of 367 children were diagnosed between 2011 and 2015 with a median age of 5.7 years (interquartile range 2.9-10.6 years). One hundred thirty (35.4%) patients were diagnosed with leukemia, 30 (8.2%) with lymphoma, and 149 (40.6%) with solid tumors. A relative paucity of children with brain tumors was seen (N = 58, 15.8%). Two-year event-free survival (EFS) for the cohort was 48.5% ± 3.2%; 2-year overall survival (OS) was 55.1% ± 3.1%. Children with acute lymphoblastic leukemia (ALL) and Wilms tumor (WT) experienced better 2-year EFS (62.1% ± 6.4% and 66.7% ± 10.1%), while dismal outcomes were seen in children with acute myeloid leukemia (AML; 22.7 ± 9.6%), rhabdomyosarcoma (21.0% ± 17.0%), and medulloblastoma (21.4% ± 17.8%). Of 108 deaths with known cause, 58 (53.7%) were attributed to disease and 50 (46.3%) to treatment complications. Death within 60 days of diagnosis was relatively common in acute leukemia [13/98 (13.3%) ALL, 8/26 (30.8%) AML]. Despite this, traditional prognosticators adversely impacted outcome in ALL, including higher age, higher white blood cell count, and T-cell lineage. CONCLUSIONS: ESC childhood cancer outcomes are significantly inferior to high-income country outcomes. Based on these data, interventions for improving supportive care and modifying treatment protocols are under way. Continued data collection will allow evaluation of interventions and ensure maximal outcome improvements.

Bimorph material/structure designs for high sensitivity flexible surface acoustic wave temperature sensors.

A fundamental challenge for surface acoustic wave (SAW) temperature sensors is the detection of small temperature changes on non-planar, often curved, surfaces. In this work, we present a new design methodology for SAW devices based on flexible substrate and bimorph material/structures, which can maximize the temperature coefficient of frequency (TCF). We performed finite element analysis simulations and obtained theoretical TCF values for SAW sensors made of ZnO thin films (~5 µm thick) coated aluminum (Al) foil and Al plate substrates with thicknesses varied from 1 to 1600 µm. Based on the simulation results, SAW devices with selected Al foil or plate thicknesses were fabricated. The experimentally measured TCF values were in excellent agreements with the simulation results. A normalized wavelength parameter (e.g., the ratio between wavelength and sample thickness, λ/h) was applied to successfully describe changes in the TCF values, and the TCF readings of the ZnO/Al SAW devices showed dramatic increases when the normalized wavelength λ/h was larger than 1. Using this design approach, we obtained the highest reported TCF value of -760 ppm/K for a SAW device made of ZnO thin film coated on Al foils (50 µm thick), thereby enabling low cost temperature sensor applications to be realized on flexible substrates.

Radiographic study to assess the reliability of the Gillies approach for biopsy of the superficial temporal artery.

Biopsy of the superficial temporal artery is often used in the diagnosis of giant cell arteritis, but at traditional sites there is a risk of injury to the facial nerve. Recently the Gillies incision has been suggested as an alternative means of access for the biopsy, but the anatomical basis of this has not been fully elucidated. We therefore undertook a radiographic review of 150 patients, and examining 300 vessels, to find out. Our results indicated that there is considerable variability in the position of the bifurcation of the superficial temporal artery, and so a Gillies approach may not be reliable, particularly if access to the bifurcation is required.

Probiotic supplementation and associated infant gut microbiome and health: a cautionary retrospective clinical comparison.

While probiotics are a multi-billion dollar industry, there is little evidence to show that supplementing infants provides any health benefits. We conducted an observational study where 35 of 86 participating mothers self-administered probiotics during breastfeeding, as well as directly to their infants. The primary objective was to determine if probiotic exposure influenced the infants' fecal microbiome while the secondary objective assessed associated changes to the mothers' breast milk immunity and infant health. Analysis of infant fecal microbiome throughout the first 6 months of life revealed that probiotics were associated with higher abundances of Bifidobacterium at week 1 only. Short-chain fatty acid production and predicted metagenomic functions of the microbial communities were not altered. While probiotics did not alter breast milk immune markers, fecal sIgA responses were higher among probiotic supplemented infants. Surprisingly, this was not associated with better health outcomes, as the probiotic cohort had higher incidences of mucosal-associated illnesses as toddlers. This retrospective clinical comparison suggests that probiotic exposure during infancy has limited effects on gut microbial composition yet is associated with increased infection later in life. These correlative findings caution against probiotic supplementation during infancy until rigorous controlled follow-up studies determining their safety and efficacy have occurred.

NLRP3 as a potentially novel biomarker for the management of osteoarthritis.

Osteoarthritis (OA) was previously thought of as 'wear and tear' as humans age, however there is increasing evidence to support an inflammatory theory. The nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) inflammasome has been implicated in the pathogenesis of a number of arthritic disorders, producing proinflammatory cytokines and degradative enzymes such as Interleukin-1 beta (IL-1ß), Tumour necrosis factor alpha (TNF-α) and Matrix metalloproteinase-3 (MMP-3) which drive cartilage degeneration and synovial inflammation. This review aims to summarise the evidence of NLRP3 involvement in OA. Currently, treatment options focus on management of the disease and to date there is no cure. The development of novel biomarkers for OA could improve diagnosis, treatment and management. Importantly, this review provides detail on the involvement of the NLRP3 inflammasome in OA pathology and how its members could act as potential biomarkers to assist clinical decisions.

Surfactants and their role in wound cleansing and biofilm management.

Surfactants are widely used as detergents, emulsifiers, wetting agents, foaming agents and dispersants in the cosmetics, hygiene, food and oil industries. Their use in a clinical setting is also common, particularly within the field of wound care. Many wound cleansers contain surfactants and subsequently there is available data that shows the growing potential of these wound cleansers in the enhancement of wound closure. The presence of microorganisms in wounds has been recognised as a significant factor that delay healing. In complex or chronic wounds that are complicated by biofilms, persistent inflammation or the production of non-viable tissue and slough, the use of surfactants has been shown to aid in the removal of these barriers to wound healing. The use of concentrated surfactant(poloxamer) based wound dressings represent an important component of wound management. Consequently, this article will discuss the effect of clinically used surfactants, with specific focus on a concentrated poloxamer for use against wound biofilm.

Thin high numerical aperture metalens.

We designed, fabricated, and characterized a thin metalens in an amorphous silicon film of diameter 30 µm, focal length equal to the incident wavelength 633 nm. The lens is capable of simultaneously manipulating the state of polarization and phase of incident light. The lens converts a linearly polarized beam into radially polarized light, producing a subwavelength focus. When illuminated with a linearly polarized Gaussian beam, the lens produces a focal spot whose size at full-width half-maximum intensity is 0.49λ and 0.55λ (λ is incident wavelength). The experimental results are in good agreement with the numerical simulation, with the simulated focal spot measuring 0.46λ and 0.52λ. This focal spot is less than all other focal spots obtained using metalenses.

The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines.

Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR. Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding. In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co-administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance. The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.

Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This guideline is endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper summarises the current imaging modalities in use for head and neck cancer evaluation. It highlights their role in the management with recommendations on modality choice for each cancer subsite. Recommendations • Offer appropriate radiological imaging, based on tumour extent, site and local expertise, to stage tumours and plan treatment for patients diagnosed with head and neck cancer. (G) • Consider positron emission tomography combined with computed tomography (PET-CT) imaging if conventional cross-sectional imaging identifies no primary site. (R) • Offer PET-CT imaging 12 weeks after non-surgical treatment to detect residual disease. (R).

A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.