Expression of fibroblast growth factor 13 (Fgf13) mRNA in bovine antral follicles and corpora lutea

Recent studies have suggested a paracrine role for several fibroblast growth factors (FGFs) in the regulation of follicle and luteal development. Fgf13 is a non-secreted FGF that has been previously localized to the developing gonads, but it is not known if it is expressed in the adult ovary. The objective of the present study was to determine the expression pattern of Fgf13 mRNA in the bovine ovary. Fgf13 mRNA expression was examined by semiquantitative RT-PCR using Gapdh as the internal control gene in theca and granulosa cells, corpora lutea (CL) and oocytes collected from abattoir ovaries. Follicles were grouped according to estradiol content (<5, 5-20, >20-100 and >100 ng/ml) and size (5-7, 8-10 and >10 mm diameter). CL samples were morphologically classified into four developmental stages. Fgf13 mRNA expression was assessed in pools containing 50 oocytes aspirated from follicles larger than 4 mm in diameter. ANOVA was used to test for the main effects of follicle size group, and estradiol concentration group in granulosa and theca cells, and to test the effect of CL developmental stage on Fgf13 mRNA abundance. Fgf13 mRNA was detected in the CL and in somatic follicle cells, but not in oocytes. Thecal Fgf13 expression increased with increasing follicle diameter but did not change with intrafollicular estradiol concentrations. No evidence of developmental regulation of Fgf13 mRNA expression was observed in granulosa cells and CL. The present data demonstrate for the first time the expression of an intracellular FGF in the bovine ovary and suggests that Fgf13 mRNA is upregulated in bovine theca cells during antral follicle growth.(AU)

HIV exposure and its association with paediatric ICU outcomes in children admitted with severe pneumonia at Chris Hani Baragwanath Academic Hospital, South Africa

Background. Pneumonia is one of the leading causes of under-5 death in South Africa and accounts for a substantial burden of paediatric intensive care unit (PICU) admissions. However, little is known about PICU outcomes in HIV-exposed uninfected (HIV-EU) children with pneumonia, despite the growing size of this vulnerable population. Objectives. To determine whether HIV exposure without infection is an independent risk factor for mortality and morbidity in children admitted to PICU with pneumonia. Methods. This retrospective review included all patients with pneumonia admitted to the PICU at Chris Hani Baragwanath Academic Hospital between 1 January 2013 and 31 December 2014. Patients were classified as HIV-unexposed (HIV-U), HIV-EU and HIV-infected. Medical records were reviewed to determine survival to PICU discharge, duration of PICU admission and duration of mechanical ventilation. Survival analysis was used to determine the association between HIV infection/exposure with mortality, and linear regression was used to examine the association with length of stay and duration of mechanical ventilation. This study included 107 patients: 54 were HIV-U; 28 were HIV-EU; 23 HIV-positive; and 2 had an unknown HIV status. Results. Overall, 84% (n=90) survived to PICU discharge, with no difference in survival based on HIV infection or exposure. Both HIV-EU and HIV-U children had significantly shorter PICU admissions and fewer days of mechanical ventilation compared with HIV-infected children (p=0.011 and p=0.004, respectively). Conclusion. HIV-EU children behaved similarly to HIV-U children in terms of mortality, duration of PICU admission and length of mechanical ventilation. HIV infection was associated with prolonged length of mechanical ventilation and ICU stay but not increased mortality.

Improved Λp Elastic Scattering Cross Sections between 0.9 and 2.0 GeV/c as a Main Ingredient of the Neutron Star Equation of State.

Strange matter is believed to exist in the cores of neutron stars based on simple kinematics. If this is true, then hyperon-nucleon interactions will play a significant part in the neutron star equation of state. Yet, compared to other elastic scattering processes, there is very little data on Λ-N scattering. This experiment utilized the CEBAF Large Acceptance Spectrometer (CLAS) detector to study the Λp→Λp elastic scattering cross section in the incident Λ momentum range 0.9-2.0 GeV/c. These are the first data on this reaction since the 1970s. The new cross sections have significantly better accuracy and precision than the existing world data, and the techniques developed here can also be used in future experiments.

Vanishing congenital lung malformations: What is the incidence of true regression?

BACKGROUND: A congenital lung malformation (CLM) that is diagnosed on prenatal ultrasound exam may subsequently become undetectable on later scans, a "vanishing" CLM. OBJECTIVE: The purpose of our study is to characterize the prenatal natural history and postnatal outcomes of "vanishing" lesions treated at our institution. METHODS: We performed a retrospective chart review of 107 patients diagnosed prenatally with CLM at our institution. Comparisons were made using Kruskal-Wallis or t-test for continuous variables and Fisher's exact test or Chi-Square test for categorical variables. Multivariable analysis using logistic regression was performed. RESULTS: Of the 104 patients, 59 (56.7%) had lesions that became sonographically undetectable on serial ultrasound scans. Patients with lesions that vanished prenatally tended to need less Neonatal Intensive Care Unit (NICU) admission at birth (persistent CLM: 54.8%vs vanished CLM: 28.8%), decreased need for supplemental O2 at birth (persistent CLM: 31.0%vs vanished CLM: 11.9%), and decreased delay in feeds (persistent CLM: 26.2%vs vanished CLM: 8.5%) compared to those with persistent CLM. After multivariate analysis controlling for maternal steroid administration and sex, admission to NICU maintained a slight statistical significance, with patients in the vanishing CLM group 2.5 times less likely to be admitted to the NICU. None of our patients whose lesions vanished prenatally required mechanical ventilation. Eighty-six patients underwent postnatal computed tomography (CT) chest. Only 2 patients had lesions that regressed on postnatal CT. CONCLUSION: Lesions that vanish on prenatal imaging may be associated with improved clinical outcomes. The rate of true regression at our institution was as low as 2.3%.

Non-Gaussian Mechanical Motion via Single and Multiphonon Subtraction from a Thermal State.

Quantum optical measurement techniques offer a rich avenue for quantum control of mechanical oscillators via cavity optomechanics. In particular, a powerful yet little explored combination utilizes optical measurements to perform heralded non-Gaussian mechanical state preparation followed by tomography to determine the mechanical phase-space distribution. Here, we experimentally perform heralded single-phonon and multiphonon subtraction via photon counting to a laser-cooled mechanical thermal state with a Brillouin optomechanical system at room temperature and use optical heterodyne detection to measure the s-parametrized Wigner distribution of the non-Gaussian mechanical states generated. The techniques developed here advance the state of the art for optics-based tomography of mechanical states and will be useful for a broad range of applied and fundamental studies that utilize mechanical quantum-state engineering and tomography.

Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression.

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine's antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

Shedding light on predicting and controlling emission chromaticity in multicomponent photoluminescent systems.

Predictable colour tuning in multicomponent photoluminescent (PL) systems is achieved using mixtures of simultaneously emitting organic molecules. By mitigating the potential for energy transfer through the control of concentration, the resulting emission chromaticity of five dichromic PL systems is approximated as a linear combination of the emitting components and their corresponding brightness (χ i , ϕ i , and I ex,i ). Despite being limited to dilute solutions (10-6 M), colour tuning within these systems was controlled by (1) varying the composition of the components and (2) exploiting the differences in the components' excitation intensities at common wavelengths. Using this approach, white light emission (WLE) was realized using a pre-determined mixture of red, green, and blue emitting organic molecules. Based on these results, materials and devices with built-in or programmable emission colour can be achieved, including highly sought-after WLE.

Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats.

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 µg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 µA, 90 µs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3ß and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3ß and phospho-mTOR in the IL and vHIP regions of the mood network.

A Multicentre UK Study of Outcomes for Locally Advanced Sinonasal Squamous Cell Carcinoma Treated with Adjuvant or Definitive Intensity-modulated Radiotherapy.

AIMS: Sinonasal malignancies are rare; the most common histological subtype is squamous cell carcinoma (SCC). No randomised trial data exist to guide treatment decisions, with options including surgery, radiotherapy and chemotherapy. The role and sequence of a primary non-surgical approach in this disease remains uncertain. The aim of this study was to present treatment outcomes for a multicentre population of patients with locally advanced, stage IVa/b sinonasal SCC treated with radical-intent intensity-modulated radiotherapy, either definitively or postoperatively. MATERIALS AND METHODS: Consecutively treated patients with locally advanced, stage IVa/b sinonasal SCC at four UK oncology centres between January 2012 and December 2017 were retrospectively identified. Descriptive statistics and survival analyses were carried out. Univariable Cox regression analysis was carried out to evaluate the relationship between patient, disease and treatment factors and survival outcomes. RESULTS: In total, 56 patients with sinonasal SCC were included (70% maxillary sinus, 21% nasal cavity, 9% ethmoid/frontal sinus). Forty-one patients (73%) were treated by surgery/adjuvant (chemo)radiotherapy and 15 (27%) by definitive (chemo)radiotherapy. The median duration of follow-up was 3.8 years (interquartile range 2.0-4.7 years). Estimates for 5-year overall survival and progression-free survival were 30.2% and 24.2%, respectively. Local, regional and distant treatment failures were seen in 33%, 33% and 16% of patients, respectively. Univariable analysis revealed inferior progression-free survival for patients treated with neck dissection (hazard ratio 2.6, 95% confidence interval 1.2-6.1, P = 0.022) but no other significant association between the studied factors and survival outcomes. CONCLUSION: We show poor survival outcomes and high rates of locoregional treatment failure for patients with locally advanced stage IVa/b sinonasal SCC. There is a need to investigate improved treatments for this group of patients.

Hospital-onset COVID-19 infection surveillance systems: a systematic review.

Hospital-onset COVID-19 infections (HOCIs) are associated with excess morbidity and mortality in patients and healthcare workers. The aim of this review was to explore and describe the current literature in HOCI surveillance. Medline, EMBASE, the Cochrane Database of Systematic Reviews, the Cochrane Register of Controlled Trials, and MedRxiv were searched up to 30 November 2020 using broad search criteria. Articles of HOCI surveillance systems were included. Data describing HOCI definitions, HOCI incidence, types of HOCI identification surveillance systems, and level of system implementation were extracted. A total of 292 citations were identified. Nine studies on HOCI surveillance were included. Six studies reported on the proportion of HOCI among hospitalized COVID-19 patients, which ranged from 0 to 15.2%. Six studies provided HOCI case definitions. Standardized national definitions provided by the UK and US governments were identified. Four studies included healthcare workers in the surveillance. One study articulated a multimodal strategy of infection prevention and control practices including HOCI surveillance. All identified HOCI surveillance systems were implemented at institutional level, with eight studies focusing on all hospital inpatients and one study focusing on patients in the emergency department. Multiple types of surveillance were identified. Four studies reported automated surveillance, of which one included real-time analysis, and one included genomic data. Overall, the study quality was limited by the observational nature with short follow-up periods. In conclusion, HOCI case definitions and surveillance methods were developed pragmatically. Whilst standardized case definitions and surveillance systems are ideal for integration with existing routine surveillance activities and adoption in different settings, we acknowledged the difficulties in establishing such standards in the short-term.

A Predictive Model for Reactive Tube Feeding in Head and Neck Cancer Patients Undergoing Definitive (Chemo) Radiotherapy.

AIMS: Careful management of a patient's nutritional status during and after treatment for head and neck squamous cell cancers (HNSCC) is crucial for optimal outcomes. The aim of this study was to develop a model for stratifying a patient's risk of requiring reactive enteral feeding through a nasogastric tube during radiotherapy for HNSCC, based on clinical and treatment-related factors. MATERIALS AND METHODS: A cohort of consecutive patients treated with definitive (chemo)radiotherapy for HNSCC between January 2016 and January 2018 was identified in the institutional electronic database for retrospective analysis. Patients requiring enteral feeding pretreatment were excluded. Clinical and treatment data were obtained from prospectively recorded electronic clinical notes and planning software. RESULTS: Baseline patient characteristics and tumour-related parameters were captured for 225 patients. Based on the results of the univariate analysis and using a stepwise backwards selection process, clinical and dosimetric variables were selected to optimise a clinically predictive multivariate model, fitted using logistic regression. The parameters found to affect the probability, P, of requiring a nasogastric feeding tube for >4 weeks in our clinical multivariate model were: tumour site, tumour stage (early T0/1/2 stage versus advanced T3/T4 stage), chemotherapy drug (none versus any drug) and mean dose to the contralateral parotid gland. A scoring model using the regression coefficients of the selected variables in the clinical multivariate model achieved an area under the curve (AUC) of 0.745 (95% confidence interval 0.678-0.812), indicating good discriminative performance. Internal validation of the model involved splitting the dataset 80:20 into training and test datasets 10 times and assessing differences in AUC of the model fitted to these. CONCLUSIONS: We developed an easy-to-use prediction model based on both clinical and dosimetric parameters, which, once externally validated, can lead to more personalised treatment planning and inform clinical decision-making on the appropriateness of prophylactic versus reactive enteral feeding.

Advances in neurochemical measurements: A review of biomarkers and devices for the development of closed-loop deep brain stimulation systems.

Neurochemical recording techniques have expanded our understanding of the pathophysiology of neurological disorders, as well as the mechanisms of action of treatment modalities like deep brain stimulation (DBS). DBS is used to treat diseases such as Parkinson's disease, Tourette syndrome, and obsessive-compulsive disorder, among others. Although DBS is effective at alleviating symptoms related to these diseases and improving the quality of life of these patients, the mechanism of action of DBS is currently not fully understood. A leading hypothesis is that DBS modulates the electrical field potential by modifying neuronal firing frequencies to non-pathological rates thus providing therapeutic relief. To address this gap in knowledge, recent advances in electrochemical sensing techniques have given insight into the importance of neurotransmitters, such as dopamine, serotonin, glutamate, and adenosine, in disease pathophysiology. These studies have also highlighted their potential use in tandem with electrophysiology to serve as biomarkers in disease diagnosis and progression monitoring, as well as characterize response to treatment. Here, we provide an overview of disease-relevant neurotransmitters and their roles and implications as biomarkers, as well as innovations to the biosensors used to record these biomarkers. Furthermore, we discuss currently available neurochemical and electrophysiological recording devices, and discuss their viability to be implemented into the development of a closed-loop DBS system.

Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder.

INTRODUCTION: A key mechanism of lithium is the inhibition of glycogen synthase kinase-3ß (GSK3ß) and activation of mammalian target of rapamycin (mTOR), two contributors to insulin signaling. We explored the relationship between these markers and clinical response to lithium in bipolar disorder (BD). METHODS: Thirty-four subjects with BD who had been taking lithium for ≥2 years and had a maintenance lithium Alda score defined as either high (≥7; n = 20) or low (≤2; n = 14) were included in the study. Baseline protein expression of GSK3ß and mTOR (total and phosphorylated (p)) was obtained from a buffy coat. Peripheral blood mononuclear cells (PBMCs) from a subset of each group (n = 11) were stimulated with insulin (10 µg) and change in protein expression was determined using Western blot. RESULTS: In buffy coat samples, significantly higher levels of pmTOR were present in subjects with an Alda score ≤2 (lithium non-responsive), relative to those with scores ≥7 (lithium-responsive). No differences were observed for pGSK3ß. In contrast, functional PBMC responses to 5 min of insulin stimulation demonstrated robust increases in pGSK3ß (87.05 ± 43.41%) and pmTOR (105.7 ± 66.48%) in the lithium responsive group only. This contrasted observed decreases in pGSK3ß (34.08 ± 16.12%) and pmTOR (37.84 ± 14.39%) 5 mins post-insulin in non-responders. CONCLUSIONS: Dynamic increases in pmTOR and pGSK3ß post-insulin stimulation may reflect an immunometabolic state that facilitates lithium response. Further prospective analyses are needed to replicate and extend these preliminary findings and further investigate the role of insulin signaling in lithium response in BD.