In vitro percutaneous penetration of silver nanoparticles in pig and human skin.

In this study, the effects of surface charge, dose, and cosmetic vehicle on the penetration of silver nanoparticles (AgNPs) into pig and human skin were compared. AgNPs (20 nm) with varying surface-charges (polyethylene glycol (PEG; neutral), citrate (CIT; negative), and branched polyethylenimine (bPEI; positive) were dosed onto skin in in vitro diffusion cells using an aqueous solution and an oil-in-water emulsion formulation. Samples were analyzed by inductively coupled plasma mass spectroscopy (ICP-MS) and transmission electron microscope (TEM) to assess AgNP skin penetration. The results showed that neutral and positive AgNPs penetrate human skin when applied in a high dose aqueous solution and less with the emulsion vehicle. A mass balance percutaneous penetration study in human skin found the majority of AgNPs were washed from the skin or remained mostly in the stratum corneum (3.4% of the applied dose for AgbPEI and 1.7% for AgPEG). Very little silver was found in the epidermis (1.2% AgbPEI and 0.3% AgPEG) and dermis (0.1% AgbPEI and none detected for AgPEG). These results indicate low dermal penetration of AgNPs that is not greatly affected by surface coating charge. The results will facilitate dermal exposure assessments by better understanding how nanoparticle properties affect skin absorption of nanoparticles found in personal care products.

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.

The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network's nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal's genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.

Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Quality and sensory acceptability of a chilled functional apple ready-dessert.

An apple and dairy based ready-dessert with an added prebiotic was stored and chill temperatures and number of quality attributes were monitored during chill (4 °C) storage for 30 days. All ready-desserts were thermally processed by sous vide (P (90) > 10 min). The stability of the dairy component in ready-desserts was monitored by measuring volatile free fatty acids. Changes in these components were more evident in prebiotic-enriched samples compared to controls. However, no significant differences were observed over storage in control and prebiotic-enriched ready-desserts. This was supported by sensory analysis that showed no significant changes over storage in control or prebiotic-enriched samples. Of the other quality parameters, the addition of prebiotic inclusions resulted in lower L and b values and dry matter (p < 0.05), while increasing (p < 0.05) soluble solids content compared to control samples. Fluctuations in some of the quality parameters were also observed over storage. Rheological characteristics, i.e. flow behaviour (n), consistency index (K), storage (G'), loss (G″) and complex (G*) moduli were unaffected by prebiotic inclusion. However, storage affected the rheological characteristics of ready-desserts. A decrease (p < 0.05) in flow behaviour (n) led to concomitant increases in consistency index (K) and complex modulus (G*) values in control samples.

Human Mitochondrial Control Region and mtGenome: Design and Forensic Validation of NGS Multiplexes, Sequencing and Analytical Software.

Forensic mitochondrial DNA (mtDNA) analysis conducted using next-generation sequencing (NGS), also known as massively parallel sequencing (MPS), as compared to Sanger-type sequencing brings modern advantages, such as deep coverage per base (herein referred to as read depth per base pair (bp)), simultaneous sequencing of multiple samples (libraries) and increased operational efficiencies. This report describes the design and developmental validation, according to forensic quality assurance standards, of end-to-end workflows for two multiplexes, comprised of ForenSeq mtDNA control region and mtDNA whole-genome kits the MiSeq FGxTM instrument and ForenSeq universal analysis software (UAS) 2.0/2.1. Polymerase chain reaction (PCR) enrichment and a tiled amplicon approach target small, overlapping amplicons (60-150 bp and 60-209 bp for the control region and mtGenome, respectively). The system provides convenient access to data files that can be used outside of the UAS if desired. Studies assessed a range of environmental and situational variables, including but not limited to buccal samples, rootless hairs, dental and skeletal remains, concordance of control region typing between the two multiplexes and as compared to orthogonal data, assorted sensitivity studies, two-person DNA mixtures and PCR-based performance testing. Limitations of the system and implementation considerations are discussed. Data indicated that the two mtDNA multiplexes, MiSeq FGx and ForenSeq software, meet or exceed forensic DNA quality assurance (QA) guidelines with robust, reproducible performance on samples of various quantities and qualities.

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.

The pathway to the closed-loop artificial pancreas: research and commercial perspectives.

BACKGROUND: Over the past decades, insulin pumps (CSII) and continuous glucose monitoring (CGM) systems have been combined in sensor augmented pump therapy. In addition, artificial pancreas (AP) research has progressed to clinical studies, using combinations of commercially available devices. OBJECTIVE: Sensor augmented pump therapy has been evaluated in a number of clinical trials. These studies have been designed to show glycemic outcomes. The low glucose suspend (LGS) feature of the Medtronic Paradigm Veo (Medtronic MiniMed, Northridge, CA) pump allows CGM to suspend insulin delivery if preset hypoglycemic thresholds are achieved. Evaluation of the AP has been conducted to show effect on time in target, and has involved a variety of algorithms, pumps and CGM systems. RESULTS: Multiple studies have shown that more time is spent in the target range for glucose levels and that there is less hypoglycemia with sensor augmented pump, LGS and early AP platforms. CONCLUSIONS: Current research shows that progress has been made in the iterative steps required to develop the AP.

Correction: Effects of providing manuscript editing through a combination of in-house and external editing services in an academic hospital.

[This corrects the article DOI: 10.1371/journal.pone.0219567.].

Effects of providing manuscript editing through a combination of in-house and external editing services in an academic hospital.

BACKGROUND: English editing services are effective for improving manuscript quality as well as providing learning opportunities for non-native English-speaking authors. Herein, we describe the effects of a combined system of in-house and external editing services for handling large volumes of editing requests and providing personalized editing service in academic hospitals. METHODS: We established the Scientific Publications Team (SPT), an in-house editing team in Asan Medical Center in Seoul, Korea. The SPT is composed of two professional editors who manage editing requests sent to external companies while also providing one-on-one in-house editing services. We gathered author satisfaction data from 936 surveys between July 2017 and December 2018 and analyzed the number of editing requests and research publications by segmented regression analysis of interrupted time series data. RESULTS: The SPT processed 3931 editing requests in 2017-2018, which was a marked increase compared with prior to its establishment (P = 0.0097). The authors were generally satisfied with the quality of editing services from both in-house and external editors. Upon conducting regular quality control, overall author satisfaction with one external company gradually increased over the course of one year (P for trend = 0.086). Author satisfaction survey results revealed that overall satisfaction of editing service was most strongly correlated with how well the edits conformed to the authors' intentions (R = 0.796), and was only weakly correlated with quick turnaround time (R = 0.355). We also observed a significant increase in the trend of the number of research publications (P = 0.0007) at one year after the establishment of the SPT. CONCLUSION: Providing a combination of in-house and external editing services resulted in high author satisfaction and subsequent hospital-wide increases in manuscript writing and publication. Our model system may be adapted in academic hospitals to better address the editing needs of non-native English-speaking researchers.

The predicted probability of having positive non-sentinel lymph nodes in patients who received neoadjuvant chemotherapy for large operable breast cancer.

The accuracy of the nomogram in women with positive sentinel nodes following neoadjuvant chemotherapy (NCT) is unknown. The aim of this study was to evaluate the accuracy of the nomogram in patients receiving NCT. Between December 1999 and December 2005, we identified 233 patients who had a positive sentinel lymph node biopsy (SLNB) and complete axillary lymph node dissection at Magee-Womens Hospital of University of Pittsburgh Medical Center. Thirty-two patients (14%) had presented with clinically N0 breast cancer (BC) for which NCT was administered. The computerised BC nomogram was used to calculate the probability of non-sentinel node metastases utilising tumour size before NCT and after NCT for the same patient. The discrimination of the nomogram was assessed by calculating the area under (AUC) the receiver operating characteristic curve (ROC). The median patient age was 51.5 (range: 39-66) years in the NCT group of patients. Twelve patients (37%) had positive axillary non-sentinel lymph nodes (NSLNs). The nomogram was first validated in our institution for 201 patients without NCT and the predicted accuracy of the nomogram by the AUC was 0.73. The area under the ROC was identical regardless of whether pre- or posttreatment tumour size was used to determine predicted probability of NSLN metastases (0.66). The predictive accuracy of the nomogram was found to have less power for patients receiving NCT (0.66) than the non-NCT group of patients.

C. elegans Development and Activity Test detects mammalian developmental neurotoxins.

Due to the high cost and long duration of traditional testing methods for developmental neurotoxicity (DNT), only a small fraction of chemicals that humans are exposed to have been assessed for DNT activity. In order to ensure public safety, human-predictive methods for DNT detection that are faster and less resource intensive are urgently required. Using Caenorhabditis elegans, a novel worm Development and Activity test (wDAT) has been designed that uses a relatively inexpensive small-animal activity tracker and takes less than 4 days to complete. The wDAT was able to detect both developmental delay and hyperactivity for arsenic, lead, and mercury, heavy metals that are known human developmental neurotoxins and have been associated with hyperactivity in children. Lithium was also tested as a control developmental toxin that is not considered a mammalian neurotoxin. With the wDAT, lithium induced developmental delay but not hyperactivity. This initial assessment of a new assay for DNT detection indicates that the wDAT has potential for detecting at least some types of mammalian developmental neurotoxins. A planned 20-compound validation study will clarify the utility of the wDAT for predicitive toxicology.

Automated Overnight Closed-Loop Control Using a Proportional-Integral-Derivative Algorithm with Insulin Feedback in Children and Adolescents with Type 1 Diabetes at Diabetes Camp.

OBJECTIVE: This study determined the feasibility and efficacy of an automated proportional-integral-derivative with insulin feedback (PID-IFB) controller in overnight closed-loop (OCL) control of children and adolescents with type 1 diabetes over multiple days in a diabetes camp setting. RESEARCH DESIGN AND METHODS: The Medtronic (Northridge, CA) Android™ (Google, Mountain View, CA)-based PID-IFB system consists of the Medtronic Minimed Revel™ 2.0 pump and Enlite™ sensor, a control algorithm residing on an Android phone, a translator, and remote monitoring capabilities. An inpatient study was completed for 16 participants to determine feasibility. For the camp study, subjects with type 1 diabetes were randomized to either OCL or sensor-augmented pump therapy (control conditions) per night for up to 6 nights at diabetes camp. RESULTS: During the camp study, 21 subjects completed 50 OCL nights and 52 control nights. Based on intention to treat, the median time spent in range, from 70 to 150 mg/dL, was greater during OCL at 66.4% (n = 55) versus 50.6% (n = 52) during the control period (P = 0.004). A per-protocol analysis allowed for assessment of algorithm performance with the median percentage time in range, 70-150 mg/dL, being 75.5% (n = 37) for OCL versus 47.6% (n = 32) for the control period (P < 0.001). There was less time spent in the hypoglycemic ranges <60 mg/dL and <70 mg/dL during OCL compared with the control period (P = 0.003 and P < 0.001, respectively). CONCLUSIONS: The PID-IFB controller is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.

Differential diagnosis of intractable lateral knee pain with progressive symptoms: a case problem.

This case study of an active 22 year old female who sustained a traumatic incident to the right knee focuses on the differential diagnostic process. Although early subjective complaints, clinical presentation, and diagnostic testing results were commensurate with internal derangement of the knee, appropriate medical and surgical management failed to halt the progression of pain and subsequent onset of neurological symptoms. Electrodiagnostic testing conducted 10 months post initial injury produced a definitive diagnosis of an irritative lesion of the right peroneal nerve in the region of the fibular neck. A fibular tunnel release and peroneal nerve decompression was subsequently performed after which complete symptom resolution was achieved, allowing return to full functional activities.

Regulation of Mg2+ homeostasis by insulin in perfused rat livers and isolated hepatocytes.

Several recent studies demonstrate that adrenergic receptor stimulation evokes marked changes in Mg2+ homeostasis. As insulin counter-regulates many of the metabolic consequences of adrenergic receptor stimulation, we evaluated the potential influence of insulin on Mg2+ movements in response to adrenergic stimulation. The data demonstrate that insulin is able to block the Mg2+ efflux from perfused rat livers stimulated by isoproterenol or 8-Br-cAMP, but has little or no effect on epinephrine or phenylephrine induced Mg2+ efflux. Thus, evidence is provided demonstrating that there are redundant adrenergic pathways regulating Mg2+ efflux from liver tissue. One of these pathways, the beta-adrenergic component, is selectively blocked by insulin. Furthermore, these findings may provide a cellular explanation for hypomagnesemia associated with diabetes.

Surgery for benign esophageal stricture.

The long-term results of five different operations for benign lower esophageal reflux stricture, carried out over the 5 year period 1973 to 1977, are presented and evaluated. The 94 patients, 51 women and 43 men (mean age 61 years), underwent one of the following procedures: I, transthoracic Nissen fundoplication (26 patients); II, Bingham gastroplasty (20 patients); III, colon interposition (17 patients); IV, jejunal interposition (10 patients); and V, jejunal bypass (21 patients). Residual dysphagia (mean follow-up period 62 months) was significantly less in groups III, IV, and V (p less than 0.05), the more radical procedures, 87% of the patients having no dysphagic symptoms. This observation was corroborated by the greatly reduced (one sixth) number of postoperative dilatations required and also by the reduced need for reoperation. Only the colon interposition group, however, had an acceptable operative mortality (0%). The Bingham gastroplasty group also had a 0% operative mortality but achieved less good functional results, only 55% of patients having no dysphagic symptoms. Further analysis of functional results showed groups III, IV, and V to be superior regardless of the preoperative grade of stricture. The pros and cons of surgical antireflux procedures coupled with dilatation versus radical procedures to excise the stricture are presented. We conclude that, for an established benign stricture of the lower esophagus, colon interposition may offer the best long-term relief from dysphagia, with very low operative mortality.

Acquired ventricular septal defect.

The past 9 years' experience with ventricular septal rupture complicating myocardial infarction has been reviewed. Thirty-six patients were treated surgically, with 10 early deaths (28%) and one late death, for an 8 year actuarial survival rate of 63%. The mortality was highest for those defects which followed inferior infarction, 38% compared with 13% following anterior infarction. The infarction-operation interval also greatly influenced mortality; under 2 weeks, 43%; over 2 weeks, 18%. Concomitant coronary artery bypass grafts (13 patients) or left ventricular aneurysmectomy (14 patients) did not carry an increased mortality. Of 17 patients who presented with cardiogenic shock, eight died (47%). The intra-aortic balloon pump (IABP) was used in 16 patients (44%) and helped greatly in the management of the critically ill. With an estimated 17 acquired septal defects occurring each year in persons under 65 years of age in Wessex, awareness of this complication and of the favorable outcome of operation is essential among those who treat the aftereffects of myocardial infarction.

A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

OBJECTIVES: To compare the clinical- and cost-effectiveness of minimally invasive direct coronary artery bypass grafting (MIDCAB) and percutaneous transluminal coronary angioplasty (PTCA) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery (LAD). DESIGN: Multi-centre randomised trial without blinding. The computer-generated sequence of randomised assignments was stratified by centre, allocated participants in blocks and was concealed using a centralised telephone facility. SETTING: Four tertiary cardiothoracic surgery centres in England. PARTICIPANTS: Patients with ischaemic heart disease with at least 50% proximal stenosis of the LAD, suitable for either PTCA or MIDCAB, and with no significant disease in another vessel. INTERVENTIONS: Patients randomised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure. Patients randomised to MIDCAB had general anaesthetic. The chest was opened through an 8-10-cm left anterior thoracotomy. The ribs were retracted and the left internal thoracic artery (LITA) harvested. The pericardium was opened in the line of the LAD to confirm the feasibility of operation. The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD. All operators were experienced in carrying out MIDCAB. MAIN OUTCOME MEASURES: The primary outcome measure was survival free from cardiac-related events. Relevant events were death, myocardial infarction, repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up. Secondary outcome measures were complications, functional outcome, disease-specific and generic quality of life, health and social services resource use and their costs. RESULTS: A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001. Of the 1091 patients with proximal stenosis of the LAD, 127 were eligible and consented to take part; 100 were randomised and the remaining 27 consented to follow-up. All randomised participants were included in an intention-to-treat analysis of survival free from cardiac-related events, which found a non-significant benefit from MIDCAB. Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2% for MIDCAB and PTCA, respectively. There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life. The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA, respectively. The costs of resources used during 1 year of follow-up were 1033 British pounds and 843 British pounds, respectively. CONCLUSIONS: The study found no evidence that MIDCAB was more effective than PTCA. The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA. Given these findings, it is unlikely that MIDCAB represents a cost-effective use of resources in the reference population. Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB. At the same time, cardiologists are treating more patients with multi-vessel disease by PTCA. Future primary research should focus on this comparison. Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review.

Quantification of hemoglobin A2 and identification of hemoglobin variants using a fully automated hemoglobin analyzer.

The DIAMAT Analyser System is a fully automated high performance liquid chromatographic (HPLC) instrument originally designed for the quantification of glycated hemoglobin (HbA1c). Buffers were developed for the separation and quantification of hemoglobin A2 on the DIAMAT. Also studied were the retention patterns of various hemoglobin variants on the DIAMAT using the buffers developed for the hemoglobin A2 quantification.

Dietary carrot results in diminished ovarian progesterone secretion, whereas a metabolite, retinoic acid, stimulates progesterone secretion in the in vitro perfused rabbit ovary.

OBJECTIVE: To determine the effects of dietary carrots and retinoic acid on P secretion in the in vitro perfused rabbit ovary. DESIGN: Controlled experiment. SETTING: Laboratory. SUBJECTS: Sexually mature New Zealand white rabbits. INTERVENTION(S): Experiments were done in vitro using an isolated rabbit ovarian perfusion system after acute feeding of carrots or with in vitro exposure to retinoic acid. MAIN OUTCOME MEASURE(S): Progesterone and E2 were measured in aliquots taken from arterial and venous cannulas. RESULT(S): Progesterone secretion during the in vitro perfusion of six ovaries is significantly diminished after the acute feeding of carrots. Human chorionic gonadotropin-induced P secretion also is significantly reduced. Progesterone secretion during in vitro perfusion on day 1 of pseudopregnancy was significantly increased in the perfusate samples from ovaries taken from rabbits not acutely fed carrots but that were exposed to retinoic acid. Progesterone secretion was increased but only marginally significant on day 11 of pseudopregnancy in perfusate samples from ovaries exposed to retinoic acid. CONCLUSION(S): Rabbit ovarian P secretion may be modified by carrots and carotene metabolites. This effect on steroid secretion may contribute to the relationship between hypercarotenemia and alterations in menstrual function.