Sensory development in children: research in taste and olfaction.
Taste and smell are considered important influences on food selection and intake. However, the exact nature of the effects of chemical sensory function on dietary habits is still unclear. Future research concerning this interaction should facilitate the development of optimal dietary guidelines concerning the palatability of foods for children. At present, however, some broad generalizations about sensory development and food acceptance can be made. First, sweet preference appears innate, and thus addition of sweet substances is almost certain to increase the palatability of foods. Conversely, aversions to bitterness appear from a very early age, and thus bitter flavors are likely to decrease palatability. Third, saltiness may be aversive or neutral to infants, with adult patterns of salt preference not appearing until about age 2. Fourth, odors, including volatile flavors like cherry, which are perceived via the olfactory receptors, cannot be expected to have much impact on children until about age 5. Even though children can detect such odors, their likes and dislikes are attenuated. Finally, young children probably find strong or irritative sensations in the mouth, e.g., from carbonation or pepper, to be aversive.


Light Chain-Only Immunotactoid Glomerulopathy: A Case Report.
The monotypic variant of immunotactoid glomerulopathy (ITG), strongly associated with low-grade lymphoproliferative disorders, is characterized histologically by glomerulonephritis and microtubular deposits of monoclonal immunoglobulin G (IgG). We report a patient with high-risk κ light chain multiple myeloma who presented with acute kidney injury, hematuria, proteinuria, and hypocomplementemia. Kidney biopsy revealed immunotactoid glomerulopathy concomitant with κ light chain myeloma cast nephropathy. The glomerular microtubular deposits stained for κ light chain and C3 only. Proteomic analysis of glomeruli and atypical casts detected κ light chain constant domain and a single VL variability subgroup (IGKV3) in both glomeruli and casts (without γ, α, or μ heavy chain or λ light chain). C3, C5, C6, C7, and C9 were detected in glomeruli. No autoantibodies against alternative pathway of complement proteins were detected. Despite clone-directed chemotherapy, the patient remained on dialysis treatment. For this light chain-only variant of immunotactoid glomerulopathy, pathogenesis potentially involves activation of the alternative pathway of complement by a nephrotoxic κ light chain.


Elongation of the trachea during neck extension in children: implications of the safety of endotracheal tubes.
During neck extension, the changes in distance between endotracheal tube (ETT) tip and carina may not be equal to the changes in distance between vocal cords and ETT tip because of tracheal elongation. These distances are directly related to extubation risk. Using a fiberoptic bronchoscope, the distance between ETT tip and carina was measured in the neutral position after full extension of the neck in 25 children (2-8 yr old) scheduled for elective surgery under general anesthesia. The tracheal length was then measured in the neutral position and after full extension. The distance between vocal cords and ETT tip was calculated as the tracheal length minus the distance between ETT tip and carina. After full extension, the tracheal length (7.97 +/- 0.85 cm) was increased by 0.95 +/- 0.43 cm, and the change in distance between vocal cords and ETT tip was -1.08 +/- 0.47 cm, whereas the change in distance between ETT tip and carina was 2.02 +/- 0.58 cm. These results suggest that neck extension actually displaces the ETT tip to the vocal cords, increasing the risk of tracheal extubation in older children, although the actual displacement of ETT tip to vocal cords is reduced by tracheal lengthening. The distance between endotracheal tube tip and vocal cords is directly related to the risk of exubation. Despite tracheal elongation, neck extension actually displaced the endotracheal tube tip to the vocal cords in older children.


Design and Delivery of Real-Time Adherence Data to Men Who Have Sex with Men Using Antiretroviral Pre-exposure Prophylaxis via an Ingestible Electronic Sensor.
Once daily tenofovir/emtricitabine when used for pre-exposure prophylaxis (PrEP) is effective in preventing HIV acquisition but requires consistent medication adherence. The use of ingestible technologies to monitor PrEP adherence can assist in understanding the impact of behavioral interventions. Digital pill systems (DPS) utilize an ingestible radiofrequency emitter integrated onto a gelatin capsule, which permits direct, real-time measurement of medication adherence. DPS monitoring may lead to discovery of nascent episodes of PrEP nonadherence and allow delivery of interventions that prevent the onset of sustained nonadherence. Yet, the acceptance and potential use of DPS in high-risk men who have sex with men (MSM; i.e., those who engage in condomless sex and use substances) is unknown. In this investigation, we conducted individual, semi-structured qualitative interviews with 30 MSM with self-reported non-alcohol substance use to understand their responses to the DPS, willingness and perceived barriers to its use, and their perceptions of its potential utility. We also sought to describe how MSM would potentially interact with a messaging system integrated into the DPS. We identified major themes around improved confidence of PrEP adherence patterns, safety of ingestible radiofrequency sensors, and design optimization of the DPS. They also expressed willingness to interact with messaging contingent on DPS recorded ingestion patterns. These data demonstrate that MSM who use substances find the DPS to be an acceptable method to measure and record PrEP adherence.


Depression, menopause and estrogens: is there a correlation?
Women have a higher incidence of depression than men. The lifetime incidence of endogenous depression in women is twice the incidence in males. Because depression in the elderly is an important public health concern, an eventual correlation between menopause and depression is of practical importance. The relevant literature is reviewed. There are suggestive data that estrogen deficiency may increase the susceptibility for depression. Furthermore, here is suggestive evidence from observational studies and a limited number of randomized, controlled trials that estrogen therapy after menopause improves mood and cognition. However, the clinical relevance of estrogen administration is unproved. There are weak data that estrogens might be considered for mild depressive symptoms attributed to hot flushes, sleep disturbances, or other climacteric symptoms. No hard data exist to indicate whether estrogen could be used as adjunct therapy for other depressive disorders during the menopausal transition or postmenopausal period, but newer findings suggest that estrogens may improve the effect of serotonin reuptake inhibitors.


Progressive Schnyder's corneal dystrophy.
Schnyder's crystalline dystrophy is a central anterior bilateral corneal dystrophy characterized by the deposition of crystals composed of cholesterol and other lipids. This condition classically is described as nonprogressive after childhood, but a series of recent studies following patients over time has challenged this teaching. The authors present a family pedigree including a patient first reported in 1954 and followed for 25 years with dramatic progression of the corneal condition in a dense, discoid pattern of crystals. Best-corrected visual acuity decreased from 20/30 to 20/80 in both eyes. This patient now has three children, all with typical corneal involvement. Ocular pathologic examination performed on corneal biopsies submitted for light and electron microscopy demonstrated cholesterol deposition consistent with a diagnosis of Schnyder's. Schnyder's corneal dystrophy may progress significantly over time. The characterization of this condition as stationary may need to be reconsidered.


Subunit composition affects formation and stabilization of o/w emulsions by 11S seed storage protein cruciferin.
The 11S globulin cruciferin is the major storage protein in Brassicaceae/Cruciferae seeds and exists as a hexamer in its natural configuration. Arabidopsis thaliana cruciferin is composed of CRUA, CRUB and CRUC subunits. Wild type (WT) cruciferin and cruciferins composed only of identical CRUA, CRUB and CRUC subunits were examined for their ability to form and stabilize oil-in-water (o/w) emulsions. All proteins (0.9% at pH 7.4 and 2.0), except CRUC, formed stable canola oil or triolein emulsions with a dispersed phase volume fraction of 22-23%. A fine emulsion was formed by CRUB at pH 7.4 with droplet sizes of 6.8 and 8.6 μm for canola oil and triolein, respectively. The presence of 0.5 M NaCl reduced the level of adsorbed protein and protein load at the interface at pH 7.4, and resulted in emulsions that were less stable. Emulsions of CRUA and CRUB (pH 7.4, zero ionic strength, canola oil or triolein) had higher stability than emulsions with WT cruciferin up to 15 days after formation. CRUC formed a stable emulsion only at pH 2.0. The low solubility, low surface hydrophobicity and compact structure of the CRUC protein may contribute to its inferior emulsifying properties at neutral pH; however, acidic pH-induced dissociation of the hexameric assembly improved these properties. The abundance and exposure of hydrophobic residues in the hypervariable regions, extended loop regions, and solvent exposed surfaces of cruciferin are critical factors affecting o/w interface stabilization.


Prolactin-induced stimulation of rat renal adenylate cyclase and autoradiographic localization to the distal nephron.
Prolactin was shown to activate adenylate cyclase in broken cellular enzyme preparations from rat renal medulla. Likewise, vasopresin was effective on this enzyme system. Parathyroid hormone was similarly active in the renal cortex. The simultaneous administration of vasopressin and prolactin to medullary kidney slices did not result in an additive effect in stimulating medullary adenyl cyclase. Audioradiographic techniques revealed a selective and prolonged localization of intravenously injected 125I-prolactin to the thick limb of the loop of Henle, the distal tubule and the collecting duct. It is concluded that prolactin activates medullary adenylate cyclase, and may do so by occupying ADH receptors.


Processing efficiency in pediatric cancer survivors: A review and operationalization for outcomes research and clinical utility.
Childhood cancer and cancer-related treatments disrupt brain development and maturation, placing survivors at risk for cognitive late effects. Given that assessment tools vary widely across researchers and clinicians, it has been daunting to identify distinct patterns in outcomes across diverse cancer types and to implement systematic neurocognitive screening tools. This review aims to operationalize processing efficiency skill impairment-or inefficient neural processing as measured by working memory and processing speed abilities-as a worthwhile avenue for continued study within the context of childhood cancer. A comprehensive literature review was conducted to examine the existing research on cognitive late effects and biopsychosocial risk factors in order to conceptualize processing efficiency skill trends in childhood cancer survivors. While a frequently reported pattern of neurobiological (white matter) and cognitive (working memory and processing speed) disruption is consistent with processing efficiency skill impairment, these weaknesses have not yet been fully operationalized in this population. We offer a theoretical model that highlights the impacts of a host of biological and environmental factors on the underlying neurobiological substrates of cancer survivors that precede and may even predict long-term cognitive outcomes and functional abilities following treatment. The unified construct of processing efficiency may be useful in assessing and communicating neurocognitive skills in both outcomes research and clinical practice. Deficits in processing efficiency may serve as a possible indicator of cognitive late effects and functional outcomes due to the unique relationship between processing efficiency skills and neurobiological disruption following cancer treatment. Continued research along these lines is crucial for advancing childhood cancer outcomes research and improving quality of life for survivors.


Analysis of CT and MR imaging features of the brain in patients with hydrogen sulfide poisoning based on clinical symptom grading.
To retrospectively analyze CT and MR imaging features of the brain in patients with hydrogen sulfide poisoning based on clinical symptom grading and to investigate their correlations with clinical symptoms and patients' prognosis. A retrospective analysis was performed of CT and MR imaging data of the brain in 40 patients with hydrogen sulfide poisoning in our hospital. There were four main imaging manifestations. Patients were clinically graded according to the central nervous system symptom scores of the Poisoning Severity Score (PSS) and staged according to the gas inhalation time segment. Based on clinical symptom grading, the frequencies and proportions of four imaging signs that occurred in each group were counted, their development trends were analyzed, and the correlations of imaging features with clinical grading and prognosis were calculated. Forty patients were divided into minor, moderate and severe clinical grades and classified into four stages. In patients with minor and moderate clinical grading, only one patient suffered from generalized brain edema at stage 1, with a good prognosis. Patients with severe clinical grade showed the highest probability of presenting with the four imaging signs. The imaging signs were correlated with the severe clinical grade and a poor prognosis (P = 0.000, R = 0.828; P = 0.000, R = 0.858). In patients with the severe clinical grade, generalized brain edema and symmetrical hypodensity/abnormal signals in the bilateral basal ganglia and around the lateral ventricles were the main findings and were shown to persist. The presence of imaging signs can assist in the clinically effective evaluation of clinical symptom grade.


Reducing clinical inertia in hypertension treatment: a pragmatic randomized controlled trial.
Clinical inertia is a major contributor to poor blood pressure (BP) control. The authors tested the effectiveness of an intervention targeting physician, patient, and office system factors with regard to outcomes of clinical inertia and BP control. A total of 591 adult primary care patients with elevated BP (mean systolic BP ≥ 140 mm Hg or mean diastolic BP ≥ 90 mm Hg) were randomized to intervention or usual care. An outreach coordinator raised patient and provider awareness of unmet BP goals, arranged BP-focused primary care clinic visits, and furnished providers with treatment decision support. The intervention reduced clinical inertia (-29% vs -11%, P=.001). Nonetheless, change in BP did not differ between intervention and usual care (-10.1/-4.1 mm Hg vs -9.1/-4.5 mm Hg, P=.50 and 0.71 for systolic and diastolic BP, respectively). Future primary care-focused interventions might benefit from the use of specific medication titration protocols, treatment adherence support, and more sustained patient follow-up visits.


Improvement of chronic neurotic excoriations with oral doxepin therapy.
Two patients with 6- to 7-year histories of neurotic excoriations refractory to the usual dermatologic management were referred for evaluation. Both had symptoms and signs of depression associated with the onset and persistence of the skin condition. Doxepin, a tricyclic antidepressant therapy with potent antihistamine properties, was used in oral doses of 30-75 mg daily for our patients. This therapy resulted in symptomatic and clinical improvement in both patients within several weeks. This limited report of apparent benefit of doxepin in two patients with neurotic excoriations and depression offers a potential therapy in the management of this challenging clinical problem.


Computer-aided design of customized foot orthoses: reproducibility and effect of method used to obtain foot shape.
To determine, for a number of techniques used to obtain foot shape based around plaster casting, foam box impressions, and 3-dimensional scanning, (1) the effect the technique has on the overall reproducibility of custom foot orthoses (FOs) in terms of inter- and intracaster reliability and (2) the reproducibility of FO design by using computer-aided design (CAD) software in terms of inter- and intra-CAD operator reliability for all these techniques. Cross-sectional study. University laboratory. Convenience sample of individuals (N=22) with noncavus foot types. Not applicable. Parameters of the FO design (length, width at forefoot, width at rearfoot, and peak medial arch height), the forefoot to rearfoot angle of the foot shape, and overall volume match between device designs. For intra- and intercaster reliability of the different methods of obtaining the foot shape, all methods fell below the reproducibility quality threshold for the medial arch height of the device, and volume matching was <80% for all methods. The more experienced CAD operator was able to achieve excellent reliability (intraclass correlation coefficients >0.75) for all variables with the exception of forefoot to rearfoot angle, with overall volume matches of >87% of the devices. None of the techniques for obtaining foot shape met all the criteria for excellent reproducibility, with the peak arch height being particularly variable. Additional variability is added at the CAD stage of the FO design process, although with adequate operator experience good to excellent reproducibility may be achieved at this stage. Taking only basic linear or angular measurement parameters from the device may fail to fully capture the variability in FO design.


RC-element analysis for low-pass filter and analog differentiator circuits using a programmable calculator.
A program written for the Texas Instrument TI-59 programmable calculator is presented. The program will calculate for any biologically important time constant the RC-elements of a second order low pass filter and an analog differentiating amplifier, which are used in biomechanical measuring equipment to study the force of contraction of muscle tissue under various conditions i.e. electrical or chemical stimulation.


Pharmacokinetics and tolerance of a single twelve-tablet dose of trimethoprim (960 mg)-sulfamethoxazole (4,800 mg).
To evaluate the potential usefulness of a single large oral dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of uncomplicated genitourinary gonorrhea, the pharmacokinetics of a 12-tablet dose containing 960 mg of TMP and 4,800 mg of SMZ were studied in 15 male volunteers, and the tolerance of this regimen was compared to that of a placebo in a double-blind crossover study. Both TMP and SMZ were rapidly absorbed. Peak mean serum concentrations (+/- standard deviation) of TMP, total SMZ, and free SMZ were 9.2 +/- 2.2, 259.4 +/- 40.9, and 233.7 +/- 33.6 mug/ml, respectively. Elimination half-lives were 16.7, 14.6, and 12.9 h, respectively. When results were compared to data from similar studies after smaller doses, peak mean serum concentrations were proportional to dose, but elimination half-lives were longer after larger doses. Urinary concentrations of TMP, total SMZ, and free SMZ were many-fold higher than serum concentrations. Percents recovery (+/- standard deviation) in urine were 60.6 +/- 10.6, 80.2 +/- 7.8, and 37.4 +/- 6.5%, respectively, during the 48 h after administration. The incidence of severe headache and of objective transient oliguria was significantly higher after TMP-SMZ than after placebo. Although the observed serum concentrations of TMP and SMZ surpassed concentrations necessary to inhibit clinical isolates of Neisseria gonorrhoeae in vitro for longer than 24 h, the adverse reactions associated with a 12-tablet dose of TMP-SMZ would preclude the clinical usefulness of such a therapeutic regimen.


Activating AMP-activated protein kinase without AMP.
Though once believed to be regulated exclusively by the cellular energy state, AMPK has now been shown to be activated by a calcium-dependent signaling pathway.


Drug characteristics derived from kinetic modeling: combined 11C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A.
Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs. Displacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1(11C-UCB-J, displacement), K1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of 11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug), KD(11C-UCB-J), fP(drug), fP(11C-UCB-J, displacement), fP(11C-UCB-J, post-dose), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values. The proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with 11C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lower bound of the ratio BRV K1/LEV K1 was ~ 7. Under appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.


Carrier detection for Sanfilippo A syndrome.
Leukocytes from 21 obligate carriers in 12 Sanfilippo A families and 49 normal controls were assayed for heparan sulphamidase (EC 22.214.171.124) at 55 degrees C. At this assay temperature the results show an absolute distinction between heterozygous carriers and the normal controls.


Endoscopic application of polysaccharide powder for hemostasis in anticoagulated pigs (with video).
Acute GI bleeding remains a clinical problem of daily importance. Increasing numbers of patients with compromised coagulation challenge the established methods of endoscopic hemostasis. Therefore, new powders for the treatment of GI bleeding have been developed. To clarify the efficacy of a newly available anticoagulant powder in stopping hemorrhage. A randomized prospective comparative study regarding the potential of an endoscopically applicable polysaccharide powder in pigs receiving antithrombotic medication. A professional veterinary animal laboratory. Twenty-two pigs were anticoagulated with heparin (n = 8), aspirin (n = 8), or no antithrombotic medication (n = 6), in a randomized order. A bleeding ulcer with continuous bleeding (Forrest I b) was established in the stomach. Endoscopic hemostasis was performed using the powder. Time to hemostasis and the amount of powder used were recorded. Follow-up occurred for 3 days, final hemoglobin measurement, followed by autopsy with control for post-interventional bleeding. Endoscopic hemostasis was successful in all cases. Post-interventional bleeding was not recorded. Animal study, artificial superficial bleeding source. Polysaccharide powder is able to stop active bleeding from Forrest I b lesions in pigs receiving antithrombotic therapy.


Overexpression of the Severe Acute Respiratory Syndrome Coronavirus-2 Receptor, Angiotensin-Converting Enzyme 2, in Diabetic Kidney Disease: Implications for Kidney Injury in Novel Coronavirus Disease 2019.
Diabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS). The expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq). Mean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25). Increased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.


Ecology of SO2 resistance : V. effects of volcanic SO2 on native Hawaiian plants.
Plant species reflected SO2-stress gradients that existed with increased distance from Hawaiian volcano vents which emit SO2. These changes relate, in part at least, to species differences in stomatal responses to SO2. The sensitive leaves do not close their stomata when exposed to elevated atmospheric SO2 concentrations.


The clinical significance of marginal and velamentous insertion of the cord.
The claims that marginal and velamentous insertion of the cord are associated with a high incidence of abortion, low birth weight, premature delivery, fetal malformation, fetal hypoxia and intrauterine fetal death have been investigated. A study of 1000 cases has failed to demonstrate any such association.


Gas-Phase Hydrogen/Deuterium Scrambling in Negative-Ion Mode Tandem Mass Spectrometry.
Hydrogen/deuterium exchange coupled with mass spectrometry (HDX MS) has become a powerful method to characterize protein conformational dynamics. Workflows typically utilize pepsin digestion prior to MS analysis to yield peptide level structural resolution. Tandem mass spectrometry (MS/MS) can potentially facilitate determination of site-specific deuteration to single-residue resolution. However, to be effective, MS/MS activation must minimize the occurrence of gas-phase intramolecular randomization of solution-generated deuterium labels. While significant work has focused on understanding this process in positive-ion mode, little is known about hydrogen/deuterium (H/D) scrambling processes in negative-ion mode. Here, we utilize selectively deuterated model peptides to investigate the extent of intramolecular H/D scrambling upon several negative-ion mode MS/MS techniques, including negative-ion collision-induced dissociation (nCID), electron detachment dissociation (EDD), negative-ion free radical-initiated peptide sequencing (nFRIPS), and negative-ion electron capture dissociation (niECD). H/D scrambling was extensive in deprotonated peptides upon nCID and nFRIPS. In fact, the energetics required to induce dissociation in nCID are sufficient to allow histidine C-2 and Cβ hydrogen atoms to participate in the scrambling process. EDD and niECD demonstrated moderate H/D scrambling with niECD being superior in terms of minimizing hydrogen migration, achieving ~ 30% scrambling levels for small c-type fragment ions. We believe the observed scrambling is likely due to activation during ionization and ion transport rather than during the niECD event itself.


Lactobacillus rhamnosus GG Regulates Host IFN-I Through the RIG-I Signalling Pathway to Inhibit Herpes Simplex Virus Type 2 Infection.
Numerous recent studies have demonstrated that the commensal microbiota plays an important role in host immunity against infections. During the infection process, viruses can exhibit substantial and close interactions with the commensal microbiota. However, the associated mechanism remains largely unknown. Therefore, in this study, we explored the specific mechanisms by which the commensal microbiota modulates host immunity against viral infections. We found that the expression levels of type I interferon (IFN-I) and antiviral priming were significantly downregulated following the depletion of the commensal microbiota due to treatment with broad-spectrum antibiotics (ABX). In addition, we confirmed a unique molecular mechanism underlying the induction of IFN-I mediated by the commensal microbiota. In vivo and in vitro experiments confirmed that Lactobacillus rhamnosus GG (LGG) can suppress herpes simplex virus type 2 (HSV-2) infection by inducing IFN-I expression via the retinoic acid-inducible gene-I (RIG-I) signalling pathway. Therefore, the commensal microbiota-induced production of IFN-I provides a potential therapeutic approach to combat viral infections. Altogether, understanding the complexity and the molecular aspects linking the commensal microbiota to health will help provide the basis for novel therapies already being developed.


CHEK2 is not a Li-Fraumeni syndrome gene: time to update public resources.
The gene-disease relationship for CHEK2 remains listed as 'Li-Fraumeni syndrome 2' in public resources such as OMIM and MONDO, despite published evidence to the contrary, causing frustration among Li-Fraumeni syndrome (LFS) clinical experts. Here, we compared personal cancer characteristics of 2095 CHEK2 and 248 TP53 pathogenic variant carriers undergoing multigene panel testing at Ambry Genetics against 15 135 individuals with no known pathogenic variant. Our results from a within-cohort logistic regression approach highlight obvious differences between clinical presentation of TP53 and CHEK2 pathogenic variant carriers, with no evidence of CHEK2 being associated with any of the TP53-related core LFS cancers. These findings emphasise the need to replace 'Li-Fraumeni syndrome 2' as the CHEK2-associated disease name, thereby limiting potential confusion.


The contributions of ammonia oxidizing bacteria and archaea to nitrification-dependent N2O emission in alkaline and neutral purple soils.
Nitrification is believed to be one of the primary processes of N2O emission in the agroecological system, which is controlled by soil microbes and mainly regulated by soil pH, oxygen content and NH4+ availability. Previous studies have proved that the relative contributions of ammonia oxidizing bacteria (AOB) and archaea (AOA) to N2O production were varied with soil pH, however, there is still no consensus on the regulating mechanism of nitrification-derived N2O production by soil pH. In this study, 1-octyne (a selective inhibitor of AOB) and acetylene (an inhibitor of AOB and AOA) were used in a microcosm incubation experiment to differentiate the relative contribution of AOA and AOB to N2O emissions in a neutral (pH = 6.75) and an alkaline (pH = 8.35) soils. We found that the amendment of ammonium (NH4+) observably stimulated the production of both AOA and AOB-related N2O and increased the ammonia monooxygenase (AMO) gene abundances of AOA and AOB in the two test soils. Among which, AOB dominated the process of ammonia oxidation in the alkaline soil, contributing 70.8% of N2O production derived from nitrification. By contrast, the contribution of AOA and AOB accounted for about one-third of nitrification-related N2O in acidic soil, respectively. The results indicated that pH was a key factor to change abundance and activity of AOA and AOB, which led to the differentiation of derivation of N2O production in purple soils. We speculate that both NH4+ content and soil pH mediated specialization of ammonia-oxidizing microorganisms together; and both specialization results and N2O yield led to the different N2O emission characteristics in purple soils. These results may help inform the development of N2O reduction strategies in the future.


Pathogenic mechanisms in Huntington's disease.
Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder presenting in midlife. Multiple pathogenic mechanisms which hypothesise how the expanded CAG repeat causes manifest disease have been suggested since the mutation was first detected. These mechanisms include events that operate at both the gene and protein levels. It has been proposed that somatic instability of the CAG repeat could underlie the striatal-specific pathology observed in HD, although how this occurs and what consequences this has in the disease state remain unknown. The form in which the Htt protein exists within the cell has been extensively studied in terms of both its role in aggregate formation and its cellular processing. Protein-protein interactions, post-translational modifications and protein cleavage have all been suggested to contribute to HD pathogenesis. The potential downstream effects of the mutant Htt protein are also noted here. In particular, the adverse effect of the mutant Htt protein on cellular protein degradation, subcellular transport and transcription are explored, and its role in energy metabolism and excitotoxicity investigated. Elucidating the mechanisms at work in HD pathogenesis and determining when they occur in relation to disease is an important step in the pathway to therapeutic interventions.


Agent-based methods facilitate integrative science in cancer.
In this opinion, we highlight agent-based modeling as a key tool for exploration of cell-cell and cell-environment interactions that drive cancer progression, therapeutic resistance, and metastasis. These biological phenomena are particularly suited to be captured at the cell-scale resolution possible only within agent-based or individual-based mathematical models. These modeling approaches complement experimental work (in vitro and in vivo systems) through parameterization and data extrapolation but also feed forward to drive new experiments that test model-generated predictions.


Ingested Foreign Body Imaging Using Point-of-Care Ultrasonography: A Case Series.
The ingestion of foreign bodies is a common problem in the pediatric population. Emergent treatment of ingested foreign bodies is dependent on the type of foreign body ingested, patient symptoms, timing of ingestion, and the location of the foreign body. Although X-ray and computed tomography are the imaging techniques used most often to assess for foreign bodies, ultrasonography, which lacks ionizing radiation, may also be useful. This case series describes 8 cases of gastrointestinal tract foreign bodies and the utility of point-of-care ultrasonography for their real-time evaluation.


Lead concentrations in breast milk at various stages of lactation.
A total of 164 breast-milk samples from Thai mothers in different stages of lactation, from one day to over nine months postpartum, and 35 samples of infant milk formulas commercially available were analyzed for their lead concentrations using atomic absorption spectrophotometry. The mean lead concentration in breast milk was 0.0846 +/- 0.0332 microgram per ml which is in the low range and is safe for infants, whereas the mean lead concentration in commercial infant mild formulas was 0.1587 +/- 0.0232 microgram per ml which can become a potential health hazard to infants.


Transradial versus transfemoral intervention for acute myocardial infarction: a propensity score-adjusted and -matched analysis from the REAL (REgistro regionale AngiopLastiche dell'Emilia-Romagna) multicenter registry.
This study sought to assess whether transradial intervention, by minimizing access-site bleeding and vascular events, improves outcomes in patients with ST-segment elevation myocardial infarction compared with the transfemoral approach. Bleeding and consequent blood product transfusions have been causally associated with a higher mortality rate in patients with myocardial infarction undergoing coronary angioplasty. We identified all adults undergoing percutaneous intervention for acute myocardial infarction in Emilia-Romagna, a region in the north of Italy of 4 million residents, between January 1, 2003, and July 30, 2009, at 12 referral hospitals using a region-mandated database of percutaneous coronary intervention procedures. Differences in the risk of death at 2 years between patients undergoing transfemoral versus transradial intervention, assessed on an intention-to-treat basis, were determined from vital statistics records and compared based on propensity score adjustment and matching. A total of 11,068 patients were treated for acute myocardial infarction (8,000 via transfemoral and 3,068 via transradial route). According to analysis of matched pairs, the 2-year, risk-adjusted mortality rates were lower for the transradial than for the transfemoral group (8.8% vs. 11.4%; p = 0.0250). The rate of vascular complications requiring surgery or need for blood transfusion were also significantly decreased in the transradial group (1.1% vs. 2.5%, p = 0.0052). In patients undergoing angioplasty for acute myocardial infarction, transradial treatment is associated with decreased 2-year mortality rates and a reduction in the need for vascular surgery and/or blood transfusion compared with transfemoral intervention.


[The treatment of tongue squamous cell with N0].
To evaluate the validity of selective surgery for the N(0) neck in squamous cell carcinoma of the mobile tongue. 116 patients with N(0) neck of the mobile tongue cancer who underwent comprehensive RND and 5 patients who had a selective RND were reviewed retrospectively. According to the suggestion of division of neck level, 7 patients had metastasis at level I; 21, level II; 10, level III, 1 case for level IV or V each. There were 5 cases with level III involvement as a first echelon of metastasis which was peculiar for the neck metastasis of mobile tongue. For N(0) neck of the mobile tongue cancer, a neck dissection of level I-III or level I-IV is more than enough.


Prognostic Significance of Uric Acid Levels in Ischemic Stroke Patients.
The importance and function of serum uric acid (UA) levels in patients with cardiovascular disease or stroke are unclear. We sought to evaluate the appropriate UA levels for stroke patients and the association between endogenous UA levels and clinical outcomes in acute ischemic stroke (AIS) patients, particularly regarding the possible interaction between gender and UA levels with respect to AIS prognosis. We examined 303 patients who had an onset of ischemic stroke within 48 h. Of those, 101 patients received thrombolytic treatment. Serum UA (μmol/L) levels were measured the second morning after admission. Patient prognosis was evaluated 90 days after clinical onset by modified Rankin Scale. Patients were divided into four groups according to serum UA quartiles. A binary multivariate logistic regression model was used to assess clinical relevance in regard to functional outcome and endogenous UA levels. Analysis of subgroups by gender and normal glomerular filtration rate were also been done. Poor functional outcome was associated with older age, history of atrial fibrillation, or higher baseline National Institutes of Health Stroke Scale scores. After adjustment for potential confounders, patients with higher UA levels (>380 μmol/L) or lower UA levels (≤250 μmol/L) were 2-3 times more likely to have a poor outcome (OR 2.95, 95% CI 1.14-7.61; OR 2.78, 95% CI 1.02-7.58, respectively) compared to the baseline group (UA level 316-380 μmol/L). The same results were observed in thrombolyzed patients. Patients with high and low UA levels were 9-18 times more likely to having poor outcomes compared to the baseline group (UA level: 316-380 μmol/L; OR 18.50, 95% CI: 2.041-167.67; OR 9.66, 95% CI 1.42-65.88, respectively). In men, patients with high UA levels were 6 times more likely to have poor outcomes compared to the baseline group (UA level: 279-334 μmol/L; OR 6.10, 95% CI 1.62-22.93). However, female patients with UA level 271-337 μmol/L were seven times more likely to perform badly compared to the baseline group (UA level >337 μmol/L, OR 7.06, 95% CI 1.00-49.81). Serum UA levels in an appropriate range were associated with better outcome in patients with AIS but may be harmful when too high or too low. The association of UA levels with AIS prognosis differed in male and female patients, which highlights the necessity of stratifying by gender in investigations of cerebrovascular risk factors.


A 3-Dimensional-Printed Hand Model for Home-Based Acquisition of Fracture Fixation Skills Without Fluoroscopy.
To design a low cost ($40), realistic and fluoroscopy-free percutaneous Kirschner wire hand fracture fixation training instrument kit for home-based skill acquisition during the COVID-19 pandemic. A 3D-printed hand was designed from a computed tomography scan of a healthy hand. These data were used to create replaceable hand and wrist bones and reusable silicone molds for a replica of the soft tissue envelope. The model is currently being integrated into the simulation curriculum at 2 integrated plastic surgery residency programs for training in percutaneous wire fixation of hand fractures. Brown University, Warren Alpert Medical School of Brown University. Department of Surgery, Division of Plastic and Reconstructive Surgery. Large academic quaternary referral institution. Yale University, Yale School of Medicine. Department of Surgery, Division of Plastic and Reconstructive Surgery. Large academic quaternary referral institution. PGY 1-4 plastic surgery residents preparing to meet ACGME Accreditation for Graduate Medical Education hand surgery specific milestones. A realistic and durable 3D model with interchangeable bones allows trainees to practice the key motor skills necessary for successful fixation of hand and wrist fractures with K-wires in a home-based setting. A low cost, realistic and durable 3D hand model with interchangeable bones allows easy integration into any home-based hand surgery curriculum. With 3D printers and programming becoming more prevalent and affordable, such models offer a means of low-cost and safe instruction of residents in fracture fixation with no harm to patients.


Paradoxical fall in proteinuria during pregnancy in an LCAT-deficient patient-A case report.
A 29-year-old lady was diagnosed with lecithin:cholesterol acyltransferase (LCAT) deficiency having presented with bilateral corneal clouding, severely reduced high density lipoproteins cholesterol, and proteinuria. She is a compound heterozygote with two LCAT gene mutations, one of which is novel, c.321C>A in exon 3. Surprisingly, the level of proteinuria significantly improved during pregnancy, despite stopping the angiotensin-converting enzyme inhibitor. However, LCAT concentration and activity remained identical during pregnancy and postpartum. Her pregnancy was complicated by rising triglyceride levels from the second trimester requiring treatment with omega-3 fatty acid and fenofibrate. In the last trimester, a further complication arose when she became hypertensive and proteinuria worsened. She was diagnosed with pre-eclampsia and had an emergency cesarean section at 39 weeks delivering a healthy baby. This case adds to the knowledge of the pathophysiology of LCAT deficiency during pregnancy and will be useful in future patient management.


Supporting nurse mentor development: An exploration of developmental constellations in nursing mentorship practice.
Supervised practice as a mentor is currently an integral component of nurse mentor education. However, workplace education literature tends to focus on dyadic mentor-student relationships rather than developmental relationships between colleagues. This paper explores the supportive relationships of nurses undertaking a mentorship qualification, using the novel technique of constellation development to determine the nature of workplace support for this group. Semi-structured interviews were conducted with three recently qualified nurse mentors. All participants developed a mentorship constellation identifying colleagues significant to their own learning in practice. These significant others were also interviewed alongside practice education, and nurse education leads. Constellations were analysed in relation to network size, breadth, strength of relationships, and attributes of individuals. Findings suggest that dyadic forms of supervisory mentorship may not offer the range of skills and attributes that developing mentors require. Redundancy of mentorship attributes within the constellation (overlapping attributes between members) may counteract problems caused when one mentor attempts to fulfil all mentorship roles. Wider nursing teams are well placed to provide the support and supervision required by mentors in training. Where wider and stronger networks were not available to mentorship students, mentorship learning was at risk.


Choice of base at silent codon site 3 is not selectively neutral in eucaryotic structural genes: it maintains excess short runs of weak and strong hydrogen bonding bases.
On the average in the coding sequences of 30 eucaryotic structural genes the weak hydrogen bonding, W, (A or T) or strong hydrogen bonding, S, (C or G) base in codon site 3 was chosen to be unlike its neighbors on both sides up to two sites away. This preference produced the nonrandom excess of runs W and S of length one and two and the deficit of long runs observed earlier (Blaisdell 1982). The neighbors in the different codon, 3' to codon site 3, were as important in determining the choice as were the neighbors 5' in the same codon. Every amino acid except methionine and tryptophan, of least frequent occurrence, permits choice of W or S. The persistence of this preference could explain the observation that the rate of substitution of codon site 3 in functional genes is considerably less than in synonymous pseudo genes.


Improvement in survival after excision of primary tumor in stage III neuroblastoma.
Fifty-eight patients with stage III neuroblastoma (according to the Childrens Cancer Study Group) underwent 86 operative procedures. Initial diagnostic or therapeutic operations were followed by chemotherapy and radiation therapy, and second- or third-look procedures were performed on patients whose tumors showed evidence of clinical response. Complete resection was obtained during the initial procedure in 12 patients, during the second operation in 12 others, and at the time of the third procedure in two additional children. Twenty of these 26 patients have survived with no evidence of disease for a median duration of greater than 3 years since initiation of therapy. Only nine of the 32 patients in whom complete tumor excision could not be accomplished are still alive. The chemotherapy and radiation therapy employed in this protocol may have enhanced resectability in many patients. The site of the primary tumor does not seem to influence ease of resectability or outcome in this group. The "favorable" prognostic factors of patient age and histopathology of the tumor do not necessarily predict that the tumor will be resectable. While patients with complete resection at the time of the second operation had an outcome superior to those with incomplete resections, the influence of the inherent tumor biology or other selection factors on the eventual tumor resectability in these patients is not known. Extensive operative procedures were required to completely resect stage III tumors, and a moderate complication rate may be anticipated. However, this may be justifiable if complete tumor resection can be achieved and ultimate patient survival possibly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)


EyeRIS: a general-purpose system for eye-movement-contingent display control.
In experimental studies of visual performance, the need often emerges to modify the stimulus according to the eye movements performed by the subject. The eye-movement-contingent display (EMCD) methodology enables accurate control of the position and motion of the stimulus on the retina. EMCD procedures have been used successfully in many areas of vision science, including studies of visual attention or eye movements and physiological characterization of neuronal response properties. Unfortunately, the difficulty of real-time programming and the unavailability of flexible and economical systems that can be easily adapted to the diversity of experimental needs and laboratory setups have prevented the widespread use of EMCD control. This article describes EyeRIS, a general-purpose system for performing EMCD experiments on a Windows computer. Based on a digital signal processor with analog and digital interfaces, this integrated hardware and software system is responsible for sampling and processing oculomotor signals and subject responses and for modifying the stimulus displayed on a CRT according to a gaze-contingent procedure specified by the experimenter. EyeRIS is designed to update the stimulus with a delay of only 10 msec. To thoroughly evaluate EyeRIS's performance, this study was designed to (1) examine the response of the system in a number of EMCD procedures and computational benchmarking tests; (2) compare the accuracy of implementation of one particular EMCD procedure, retinal stabilization, with that produced by a standard tool used for this task; and (3) examine EyeRIS's performance in one of the many EMCD procedures that cannot be executed by means of any other currently available device.


Endoscopic hepatic resection and endoscopic radiofrequency ablation as initial treatments for hepatocellular carcinoma within the Milan criteria.
The indication of endoscopic (laparoscopic and thoracoscopic) hepatic resection (HR) has been expanded in the past decade because of its low invasiveness. However, the indications of endoscopic HR and radiofrequency ablation (RFA) have not yet been determined. Among the 906 patients hospitalized for the initial treatment of hepatocellular carcinoma (HCC) between 2000 and 2017, 77 underwent endoscopic partial HR (E-pHR), and 94 underwent endoscopic RFA (E-RFA). We compared the short- and long-term outcomes between the E-pHR and E-RFA groups. The patients in the E-RFA group were characterized primarily by an impaired liver function. Among the patients with liver damage B or C, the overall survival (OS) in the E-pHR group was significantly worse than in the E-RFA group (3-year OS: 36% vs. 82%, p = 0.003). E-RFA may be recommended for the initial treatment of HCC in patients with a severely impaired liver function. However, E-pHR should be avoided as the initial treatment of HCC in such patients.


Decreased expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in basal cell carcinomas.
Thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor is associated with tumor angiogenesis. We evaluated the TP mRNA and protein expression in basal cell carcinomas (BCC) and in various skin tumors including numerous BCC histological simulants. Immunohistochemistry was performed on 99 paraffin sections of formalin-fixed skin tumors using monoclonal antibodies (mAb) against TP. TP mRNA levels were measured by real time RT-PCR in whole BCCs (wBCC) and laser capture microdissected (LCM) BCC tumor cells. TP immunostaining was negative in all BCC variants and in most of the benign trichogeneic tumors studied. By contrast, TP was constantly immunodetected in actinic keratosis (AK), squamous cell carcinomas (SCC), syringomatous carcinomas (SC), basosquamous carcinomas (BSC) and melanomas. TP mRNA levels were low and statistically not different in wBCC and normal skin but were strongly downregulated in LCM-BCC as compared with LCM-normal epidermis. We concluded that (i) anti-TP mAb is an useful marker to differentiate BCC from AK, SCC, BSC and SC but not from trichoblastic tumors, (ii) the lack of TP protein expression in BCC tumoral cells is linked to transcriptional regulatory mechanisms, (iii) the low TP mRNA levels in whole BCC may be related to the low intra-tumoral microvessel density, the slow growth and the very low metastatic potential of these tumors.


[Risk factors leading to failure in myringoplasty: a case-control study].
To determine the risk factors associated with myringoplasty failure among the study population, a case-control study was carried out in 2 tertiary hospital centers. Patients undergoing tympanic membrane perforation or atelectasis within 3 to 6 months following surgery were considered as cases, otherwise, they were considered to be controls. Patients having undergone any type of ossiculoplasty were excluded. Seventy cases and 210 controls were included, a sample size calculated for the following variables: inflammation at time of surgery, place and size of the tympanic membrane perforation, presence of tympanosclerosis, presence of cholesteatoma, and surgical technique. Odds ratio was calculated as main association measure, a stratified analysis was performed to rule out possible confusion factors. No significant differences were found between the 2 groups respect to the variables for which the sample was calculated. Although in total group the addition of a modified radical mastoidectomy showed better operative results (95 % CI OR = 0.13-0.72; P=.002), in isolated tympanic membrane perforation this association it was loosed (95 % CI OR = 0.06-7.44; P=.81). Results in this study suggest that the variables for which the sample size was calculated are not associated with myringoplasty failure in this population.


The solution structure of the oxidized bovine microsomal cytochrome b(5) mutant V61H.
Using 1488 NOE constraints, 19 stereo-specific assignments, 13 pairs of H-bond constraints, and 140 pseudo-contact shift constraints, a family of 35 structures of bovine microsomal cytochrome b(5) mutant V61H has been obtained through the program PSEUDYANA. The family has been further refined by restrained energy minimization to give a family of final structures. The RMSD values of final structures with respect to the average structure are 0.45+/-0.11 and 0.96+/-0.10A for backbone and heavy atoms, respectively. The final Deltachi(ax) and Deltachi(rh) values are 2.34 x 10(-32) and -0.67 x 10(-32)m(3), respectively. The comparisons between the solution structures of mutant V61H and WT cytochrome b(5), and X-ray structure of the mutant V61H show that the global folding of the molecule in solution is unchanged and the side-chain of His61 deviates from the heme pocket and extends into the solvent like in its crystal structure. However, the helices around the heme pocket undergo outward global displacement while their local conformations are well maintained. Meanwhile, the heme ring shows a little off the heme pocket, which accounts for the lower stability of the mutant. Additionally, the axial ligand rings counterclockwise rotate around His39 N-Fe axis due to the mutation, which is confirmed by variation of the hyperfine shifts of the heme protons of V61H compared to those of WT cytochrome b(5).


Mechanisms and abuse liability of the anti-histamine dimenhydrinate.
The over-the-counter anti-emetic dimenhydrinate (DMH) (Gravol or Dramamine) has been reported to be abused for non-medicinal purposes. Street drug users abuse DMH for the acute effects of euphoric sensations and hallucinations, while psychiatric patients abuse DMH for its anxiolytic or anti-cholinergic effects. DMH is an H(1) histamine receptor antagonist, but it interacts either directly or indirectly with other neurotransimitter systems, including those using acetylcholine, serotonin, norepinephrine, dopamine, opioids or adenosine. Animal behavioural studies, such as self-administration, conditioned place preference, drug discrimination, and modulation of operant responding, show that anti-histamines have abuse potential. Further support comes from reports of acute and chronic abuse of DMH by humans. Collectively, results confirm the abuse liability of DMH.


Pharmacological interventions in aging and age-associated disorders: potentials of propargylamines for human use.
Past studies including our own have confirmed that chronic administration of deprenyl can prolong life spans of at least four different animal species. Pretreatment with the drug for several weeks increases activities of superoxide dismutase (SOD) and catalase (CAT) in selective brain regions. An up-regulation of antioxidant enzyme activities can also be induced in organs such as the heart, kidney, spleen, and adrenal gland, and all are accompanied by an increase in mRNA levels for SODs in these organs. The effect of deprenyl on enzyme activities has a dose-effect relationship of a typical inverted U shape. A similar inverted U shape also has emerged for the drug's effect on survival of animals. An apparent parallelism observed between these two effects of the drug seems to support our contention that the up-regulation of antioxidant enzymes is at least partially responsible for the life-prolonging effect on animals. Further, when a clinically applied dose of the drug for patients with Parkinson's disease was given to monkeys, SOD and CAT activities were increased in striatum of these monkeys, which suggests potential for the drug's applicability to humans. The drug was also found to increase concentrations of cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the above rat organs. Together with past reports demonstrating that deprenyl increases natural killer (NK) cell functions and interferon-gamma, and prevents the occurrence of malignant tumors in rodents and dogs, the mobilization of these humoral factors may therefore be included as possible mechanisms of action of deprenyl for its diverse antiaging and life-prolonging effects. The potentials of propargylamines, (-)deprenyl in particular, for human use as antiaging drugs remain worthy of exploration in the future.


Characterization of Arsenic Biotransformation by a Typical Bryophyte Physcomitrella patens.
Arsenic (As) is a ubiquitous environmental toxin that has created catastrophic human health and environmental problems around world. Physcomitrella patens is a potential model plant for the study of environmental monitoring, which exists in all kinds of ecosystems. In this study, arsenic metabolism was investigated by this moss. When supplied with different levels of arsenate (50, 100, 200 µmol/L) for a 4-week period, the total arsenic concentrations were up to 231.4-565.4 mg/kg DW in this moss. Arsenite concentration increased with increasing external arsenate concentrations, the proportion was up to 25.1-36.8% of the total As. An arsenate reductase, PpACR2, was identified and functionally characterized. Heterologous expression of PpACR2 in an As(V)-sensitive strain WC3110 (ΔarsC) of Escherichia coli conferred As(V) resistance. Purified PpACR2 protein exhibited the arsenate reductase activity. Given its powerful As accumulation ability, the bryophyte could be exploited in bioremediation of As-contaminated environments.


Experimental immune complex glomerulonephritis in dogs receiving cationized bovine serum albumin.
Eight 16-week-old dogs were used to induce immune complex glomerulonephritis by daily intravenous injections of 120 mg highly cationized bovine serum albumin (pI9.5). Of four control dogs, two received unmodified native anionic bovine serum albumin (pI 4.5) while the other two received only phosphate buffered saline. The renal glomeruli were examined by light, electron (transmission and scanning) and immunofluorescence microscopy at intervals from five to 11 weeks after the start of the injections. Animals receiving cationic antigen all developed generalised diffuse granular deposits of IgG and C3 along the capillary walls; these were detected as early as five weeks and continued until the termination of the experiment at 11 weeks. Ultrastructural studies revealed many electron dense deposits along the subepithelial regions of the glomerular basement membrane. The experimental disease resembled in many respects naturally occurring membranous nephropathy, the most common form of immune complex glomerulonephritis in dogs.


Symbiosis within Symbiosis: Evolving Nitrogen-Fixing Legume Symbionts.
Bacterial accessory genes are genomic symbionts with an evolutionary history and future that is different from that of their hosts. Packages of accessory genes move from strain to strain and confer important adaptations, such as interaction with eukaryotes. The ability to fix nitrogen with legumes is a remarkable example of a complex trait spread by horizontal transfer of a few key symbiotic genes, converting soil bacteria into legume symbionts. Rhizobia belong to hundreds of species restricted to a dozen genera of the Alphaproteobacteria and Betaproteobacteria, suggesting infrequent successful transfer between genera but frequent successful transfer within genera. Here we review the genetic and environmental conditions and selective forces that have shaped evolution of this complex symbiotic trait.


Environmental drivers of the first major animal extinction across the Ediacaran White Sea-Nama transition.
The Ediacara Biota-the oldest communities of complex, macroscopic fossils-consists of three temporally distinct assemblages: the Avalon (ca. 575-560 Ma), White Sea (ca. 560-550 Ma), and Nama (ca. 550-539 Ma). Generic diversity varies among assemblages, with a notable decline at the transition from White Sea to Nama. Preservation and sampling biases, biotic replacement, and environmental perturbation have been proposed as potential mechanisms for this drop in diversity. Here, we compile a global database of the Ediacara Biota, specifically targeting taphonomic and paleoecological characters, to test these hypotheses. Major ecological shifts in feeding mode, life habit, and tiering level accompany an increase in generic richness between the Avalon and White Sea assemblages. We find that ∼80% of White Sea taxa are absent from the Nama interval, comparable to loss during Phanerozoic mass extinctions. The paleolatitudes, depositional environments, and preservational modes that characterize the White Sea assemblage are well represented in the Nama, indicating that this decline is not the result of sampling bias. Counter to expectations of the biotic replacement model, there are minimal ecological differences between these two assemblages. However, taxa that disappear exhibit a variety of morphological and behavioral characters consistent with an environmentally driven extinction event. The preferential survival of taxa with high surface area relative to volume may suggest that this was related to reduced global oceanic oxygen availability. Thus, our data support a link between Ediacaran biotic turnover and environmental change, similar to other major mass extinctions in the geologic record.


Multidrug-resistant and extensively drug-resistant tuberculosis in multi-ethnic region, Xinjiang Uygur Autonomous Region, China.
The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has emerged as a global threat. Xinjiang is a multi-ethnic region and suffered second highest incidence of TB in China. However, epidemiological information on MDR and XDR TB is scarcely investigated. A prospective study was conducted to analyze the prevalence of MDR and XDR TB and the differences of drug resistance TB between Chinese Han and other nationalities population at Chest Hospital of Xinjiang Uygur Autonomous Region, China. We performed in vitro drug susceptibility testing of Mycobacterium tuberculosis to first- and second-line anti-tuberculosis drugs for all 1893 culture confirmed positive TB cases that were diagnosed between June 2009 and June 2011. Totally 1117 (59.0%, 95% CI, 56.8%-61.2%) clinical isolates were resistant to ≥1 first-line drugs; the prevalence of MDR TB was 13.2% (95% CI, 11.7%-14.7%), of which, 77 (30.8%; 95% CI, 25.0%-36.6%) and 31 (12.8%; 95% CI, 8.6%-17.0%) isolates were pre-XDR and XDR TB respectively. Among the MDR/XDR TB, Chinese Han patients were significantly less likely to be younger with an odds ratio 0.42 for age 20-29 years and 0.52 for age 40-49 years; P(trend) = 0.004), and Chinese Han patients has a lower prevalence of XDR TB (9.6%) than all the other nationality (14.9%). The burden of drug resistance TB cases is sizeable, which highlights an urgent need to reinforce the control, detection and treatment strategies for drug resistance TB. However, the difference of MDR and XDR TB between Chinese Han and other nationalities was not observed.


Sleep architecture in Sheehan's syndrome before and 6 months after growth hormone replacement therapy.
To characterize the sleep parameters in patients with growth hormone (GH) deficiency in Sheehan's syndrome adults and to assess the effects of 6-month GH replacement therapy (GHRT). Twenty-two women with Sheehan's syndrome, (mean age; 49.1+/-2.2 years), and 12 women with similar age (mean age; 51.3+/-3.8 years) and body mass index as control subjects were included in the study. Under baseline conditions, women received adequate hormone replacement therapy for all hormonal deficiencies other than GH. Twelve patients received recombinant GH (Genotropin; Pfizer Stockholm, Sweden) (treatment group) and eight patients received placebo (placebo group) for 6 months. Two patients had only baseline evaluation and were not followed up prospectively. Two polysomnography (PSG) recordings were performed on the patients group, one in the baseline period and the other at the sixth month of treatment (either GH or placebo). Control group had only baseline PSG. GH deficient females with Sheehan's syndrome have more NREM (95.9+/-1.5% and 88.6+/-0.9%, respectively; p<0.05), particularly in stage 4 sleep (11.4+/-1.9% and 4.9+/-1.6, respectively; p<0.05), less REM sleep (4.2+/-1.5% and 11.4+/-0.9, respectively; p<0.05) and also less sleep efficiency (69.7+/-3.4% and 81.1+/-2.8%, respectively; p<0.05) when compared to healthy controls. After 6 months of GHRT there was no significant difference in sleep parameters. GH deficiency has sleep disturbing effects on Sheehan's syndrome patients under baseline conditions.


Efficacy of Traditional Chinese Medicine, Maxingshigan-Weijing in the management of COVID-19 patients with severe acute respiratory syndrome: A structured summary of a study protocol for a randomized controlled trial.
We aimed to test our expectation that additional administration of Traditional Chinese medicine (TCM), maxingshigan-weijing decoction, is more effective in the management of COVID-19 patients compared to those treated with routine supportive care alone. This is a multicenter, open-label 2-arm (1:1 ratio) randomized controlled trial. Patients will be recruited from 3 hospitals in Wenzhou China: the First Affiliated Hospital of Wenzhou Medical University, the Second Affiliated Hospital of Wenzhou Medical University and Wenzhou Center Hospital. The inclusion and exclusion criteria are as follows: Inclusion criteria 1. Participants are 18-85 years of age, either male or female. 2. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3. Symptomatic. Mild (mild clinical symptoms without signs of pneumonia in chest X-ray) and Moderate (fever or respiratory symptom with signs of pneumonia in chest X-ray) . 1. Signed the informed consent before treatment. 2. Agreed not to enroll in any other clinical trials. 3. Inpatients Exclusion criteria 1. < 18 or > 85 years old. 2. Pregnancy and lactation. 3. Serious heart, liver, kidney and hematopoietic system diseases, abnormal liver or kidney function. 4. Suffering from other known virus pneumonia. 5. Allergic to Chinese herbal medicine or suffering from allergies. 6. Critical patients (respiratory failure treated by mechanical ventilation or shock or multiple organ failure). Patients in the control group will receive routine supportive clinically care including the therapies of anti-viral, anti-bacterial and ameliorating the related symptoms, while patients in TCM group will be asked to take maxingshigan-weijing decoction (composed of 14 Chinese herbal medicines), orally 200 mL 2 times daily, for 14 consecutive days in addition to routine supportive care as mentioned above. Maxingshigan-weijing decoction consists of 10 g of Herba Ephedra (Mahuang), 10 g of Amygdalus Communis Vas (Xingren), 45 g of Gypsum Fibrosum (Shigao), 30 g of Rhizoma phragmitis (Lugen), 20 g of Peach kernel (Taoren), 20 g of Winter Melon kernel (Dongguaren), 30 g of Trichosanthes Kirilowii Maxim (Gualou), 12 g of Pericarpium Citri Reticulatae (Chenpi), 12 g of Rhizoma Pinelliae (Jiangbanxia), 12 g of caulis bambusae in taeniis (Zhuru), 30 g of semen lepidii (Tingliz), 15 g of semen lepidii (Shichangpu), 10 g of curcuma zedoary (ezhu) and 5 g of Radix Glycyrrhizae (Gancao). The primary outcome will be the number of days until the clinical symptom of fever improves in the first 14 days of treatment following randomisation. Fever will be defined as an improvement when the temperature is less than 37°C. Secondary outcomes will be TCM Syndrome Scores, the time it takes until individuals have negative test results for SARS-CoV-2 nucleic acid, the proportion of cases with chest X-ray improvements and the rate of symptom (fever, cough, malaise, shortness of breath) recovery. TCM Syndrome Scoring System is a checklist covering 4 main, 7 secondary and 13 accompanying items. The 4 main items consisting of fever, cough, malaise and shortness of breath, use a four-point scale (0, 2, 4 and 6) depending on the severity; the 7 secondary items including dysphoria, diarrhea, pharyngalgia, expectoration, muscular soreness, nasal obstruction and rhinorrhoea use 0-3-point scale; the 13 accompanying items contain chest pain, headache, aversion to cold, dizziness, nausea and vomiting, anorexia, abdominal distension, dry mouth, anxiety, spontaneous sweating, insomnia, wheezing and blood tinged sputum, and each item is rated on 0-1 scale ( 0 stands for asymptomatic, 1 stands for symptomatic ). The total scores sum up to a range from 0 to 58, with higher scores indicating more severe levels of disease. Minimization method will be used, balancing the two arms for pneumonia severity. Patients are randomized (1:1 ratio) to each group. Clinical researchers will get a random sequence number which is automatically generated by a random number generator (IBM Corp., Armonk, NY, USA), and sequentially number them in an opaque envelope. Researchers will open random allocation envelopes and assign participants accordingly. Eligible patients will be randomly divided into a routine supportive care group and a routine supportive care plus oral administration of traditional Chinese medicine group, with 70 patients in each group. This is an open-label study. The statistical analysis will be carried out by the Professor of Statistics at Wenzhou Medical University, who is blinded to patient allocation. The previous study reported the efficacy of TCM for COVID-19 and H1N1 influenza patients, the median survival time in the TCM group is estimated as 3 days; this time will be 1.5 times longer in the control group. Accordingly, Kaplan-Meier method and log-rank test will be used. And assuming a statistical power of 70% (one-sided type-1 error of α = 5%, β = 30%) and a rate of withdrawal and loss to follow-up of 10%, we plan to include 140 participants in both groups ( TCM group = 70, control group = 70). The trial protocol is Version 2.0, October 14, 2020. Recruitment began March, 2020, and is anticipated to be completed by December 31, 2020. Chinese Clinical Trial Registry, ChiCTR2000030759 . Registered on 13 March 2020. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


A donor-acceptor molecular dyad showing multiple electronic energy-transfer processes in crystalline and amorphous states.
Singlet-singlet, singlet-triplet, and triplet-triplet energy transfer takes place within single crystals and amorphous solid-state solutions of a molecular dyad comprising boron dipyrromethene and oligo-thiophene subunits. The crystal and sublimed thin-films are strongly fluorescent.


Bio-mineralized self-healing recycled aggregate concrete for sustainable infrastructure.
Various carriers have been investigated by researchers to introduce bacteria inside the concrete however, factors such as local availability, cost and long-term protection of bacterial cells have barred the application of this contemporary technology in the construction industry. In the present study, bacteria were immobilized via recycled coarse aggregate (RCA) and virgin fine aggregate (FA) besides direct induction to preserve natural resources and emulate sustainability. The application of RCA in substitution of virgin coarse aggregate is dropping anthropogenic emissions, minimizing energy consumption and managing construction waste effectively. Vegetative cells of Bacillus subtilis bacterium were incorporated in RCA through vacuum impregnation to boost crack healing efficiency. Crack healing efficiency was studied by quantifying the crack healing widths and percentage of strength regained after pre-cracking at 3,7 and 28 days. Similarly, mechanical properties were gauged via compressive and split tensile strengths at specified intervals while healing precipitate was characterized using analytical means. Results of experimental work revealed that specimens having RCA and 50% virgin FA as bacteria immobilizers exhibited the most efficient crack healing remedy by healing crack widths up to 1.1 mm and recovering 85% of compressive strength. Specimens containing RCA exclusively displayed a maximum of 0.7 mm crack healing widths and 76% strength recovery while direct incorporation of bacteria lagged behind with 0.6 mm crack healing width having 69% strength recovery. Likewise, synergetic formulation and direct induction depicted increase in compressive strength of 4% and 6% respectively while exclusive RCA formulation decreased the compressive strength up to 3% Moreover, field-emission scanning electron microscopy (FE-SEM), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD) and X-ray fluorescent (XRF) characterized the crack healing precipitate as bio-mineralized calcite crystals.


The promises and perils of non-invasive brain stimulation.
Non-invasive brain stimulation promises innovative experimental possibilities for psychology and neuroscience as well as new therapeutic and palliative measures in medicine. Because of its good risk-benefit ratio, non-invasiveness and reversibility as well as its low effort and cost it has good chances of becoming a widespread tool in science, medicine and even in lay use. While most issues in medical and research ethics such as informed consent, safety, and potential for misuse can be handled with manageable effort, the real promise of brain stimulation does raise one prominent moral worry: it may lay the foundation of reliable, precise and stable manipulations of the mind. This article addresses this worry and concludes that it is not the possibility of manipulation, but the shift in our understanding of our mind which stands in need of careful consideration.


Modulation of insulin like growth factor I (IGF-I) binding sites on erythrocytes by IGF-I treatment in patients with Laron syndrome (LS).
The in vivo regulation of IGF-I binding sites was evaluated using erythrocytes (RBC) from 8 patients with Laron syndrome (LS), before and after IGF-I treatment (120-150 micrograms/kg/day s.c.). Basal fasting IGF-I averaged 20.48 +/- 2.06 nmol/l (mean +/- S.E.M.) in the control group as compared to 4.72 +/- 0.84 nmol/l in the 8 LS patients (P = 0.0001). After 1 week of IGF-I treatment serum IGF-I levels increased to 6.53 +/- 1.58 nmol/l (a mean difference of 1.81 +/- 0.95, P = 0.05) and after 1 month of treatment to 14.37 +/- 4.56 nmol/l (a mean difference of 9.37 +/- 4.42, P = 0.03). Concomitantly, we found a significant decrease in the number of high affinity IGF-I binding sites, from 5.74 +/- 0.86 sites/cell (mean +/- S.E.M.) in the non-treated state to 2.29 +/- 0.64 sites/cell and 2.17 +/- 0.53 sites/cell after 1 week and 1 month of treatment, respectively (a mean difference of -3.44 +/- 0.94, P = 0.004 and -3.58 +/- 0.79, P = 0.002, respectively), values similar to those found in the control group. These data demonstrate that replacement treatment of LS patients with IGF-I down regulates its specific receptors. We propose IGF-I binding to RBC as a test to determine the responsiveness of patients considered for long term IGF-I treatment.


Food Insecurity: Is Leagility a Potential Remedy?
In the wake of the COVID-19 pandemic, and Ukraine-Russian conflict, both significant geo-political and socio-economic shocks to the global food system and food insecurity has risen across the world. One potential remedy to reduce the level of food insecurity is to move from a lean just-in-time food system to one where there is more resilience through greater agility both in routine supply operations and also in the event of an emergency situation. The aim of this critical perspectives paper was to firstly reflect on the concepts of lean, agility, and 'leagility'. Then, this study considered the ability of individual organisations and the whole food system to be resilient, adaptive, enable the elimination of waste, reduce inefficiency, and assure the consistent delivery to market requirements in terms of both volume, safety, and quality. Promoting the concept of leagility together with advocating resilient, sustainable practices that embed buffer and adaptive capacity, this paper positions that increasing digitalisation and improving business continuity planning can ensure effective operationalisation of supply chains under both normal and crisis situations, ultimately reducing the risk of food insecurity at personal, household, and community levels.


Disposable immunosensors for C-reactive protein based on carbon nanotubes field effect transistors.
Label-free immunosensors based on single-walled carbon nanotubes field effect transistor (NTFET) devices were developed for the detection of C-reactive protein (CRP) which is currently the best validated inflammatory biomarker associated with cardiovascular diseases. The immunoreaction principle consists in the direct adsorption of CRP specific antibodies (anti-CRP) to single-walled carbon nanotubes (SWCNTs) networks. Such anti-CRP are the molecular receptors of CRP antigens which, in turn, can be detected by the developed NTFET devices in a linear dynamic range of 10(-4)-10(2) μg/mL. Thus, typical values of CRP (in blood serum) for healthy persons (<1 μg/mL), and higher levels (>5 μg/mL) corresponding to pathological states, can be both detected with the NTFET immunosensors, becoming an advantageous alternative as the basis for the development of analytical instrumentation for assessment of risk of occurrence of cardiovascular diseases. A log-log linear regression was applied to the experimental data with a correlation coefficient of r=0.9962 (p<0.001), and there is no statistical difference (from ANOVA) between individual NTFET devices (p=0.9582), demonstrating acceptable reproducibility. According to the experimental results, the estimate of detection limit (LOD, 10(-4)μg/mL) is 3-fold lower than that of some conventional immunoassay techniques for blood serum (e.g., LOD of 0.2 μg/mL for high-sensitivity enzyme-linked immunosorbent assay), and the dynamic range (10(-4)-10(2)μg/mL) is about 6-fold higher. Furthermore, this simple and low-cost methodology allows the use of sample volumes as low as 1 μL for the label-free detection of CRP.


A human expression system based on HEK293 for the stable production of recombinant erythropoietin.
Mammalian host cell lines are the preferred expression systems for the manufacture of complex therapeutics and recombinant proteins. However, the most utilized mammalian host systems, namely Chinese hamster ovary (CHO), Sp2/0 and NS0 mouse myeloma cells, can produce glycoproteins with non-human glycans that may potentially illicit immunogenic responses. Hence, we developed a fully human expression system based on HEK293 cells for the stable and high titer production of recombinant proteins by first knocking out GLUL (encoding glutamine synthetase) using CRISPR-Cas9 system. Expression vectors using human GLUL as selection marker were then generated, with recombinant human erythropoietin (EPO) as our model protein. Selection was performed using methionine sulfoximine (MSX) to select for high EPO expression cells. EPO production of up to 92700 U/mL of EPO as analyzed by ELISA or 696 mg/L by densitometry was demonstrated in a 2 L stirred-tank fed batch bioreactor. Mass spectrometry analysis revealed that N-glycosylation of the produced EPO was similar to endogenous human proteins and non-human glycan epitopes were not detected. Collectively, our results highlight the use of a human cellular expression system for the high titer and xenogeneic-free production of EPO and possibly other complex recombinant proteins.


Oral sensation of ethanol in a primate model III: responses in the lingual branch of the trigeminal nerve of Macaca mulatta.
Ethanol administered orally has been shown to elicit a powerful response in rhesus monkey taste nerves. In this study we focused on the effects of ethanol on lingual non-gustatory receptors by recording from 70 single lingual nerve fibers. Of these 70 fibers, 54 (78%) responded to one or more concentrations of 0.7-12 M ethanol; 16 fibers (22%) were not affected. In 48 (69%) fibers, ethanol increased nerve activity, whereas 6 fibers (9%) exhibited suppression, which was displayed as a diminished response to mechanical stimulation. The excitatory response was characterized by regular impulse activity after a latency of 3-40 sec. With higher concentrations of ethanol, the latency became shorter, and the impulse activity evoked became higher. In many fibers the response peaked and ceased before the end of the 52-sec long-stimulation period. Most of the fibers affected by ethanol responded to light touch and cooling. During repeated touch, ethanol initially potentiated and then abolished the response to mechanical stimulation. Methanol and propanol gave similar results. Butanol only inhibited nerve activity.


Simultaneous biosynthesis of (R)-acetoin and ethylene glycol from D-xylose through in vitro metabolic engineering.
(R)-acetoin is a four-carbon platform compound used as the precursor for synthesizing novel optically active materials. Ethylene glycol (EG) is a large-volume two-carbon commodity chemical used as the anti-freezing agent and building-block molecule for various polymers. Currently established microbial fermentation processes for converting monosaccharides to either (R)-acetoin or EG are plagued by the formation of undesirable by-products. We show here that a cell-free bioreaction scheme can generate enantiomerically pure acetoin and EG as co-products from biomass-derived D-xylose. The seven-step, ATP-free system included in situ cofactor regeneration and recruited enzymes from Escherichia coli W3110, Bacillus subtilis shaijiu 32 and Caulobacter crescentus CB 2. Optimized in vitro biocatalytic conditions generated 3.2 mM (R)-acetoin with stereoisomeric purity of 99.5% from 10 mM D-xylose at 30 °C and pH 7.5 after 24 h, with an initial (R)-acetoin productivity of 1.0 mM/h. Concomitantly, EG was produced at 5.5 mM, with an initial productivity of 1.7 mM/h. This in vitro biocatalytic platform illustrates the potential for production of multiple value-added biomolecules from biomass-based sugars with no ATP requirement.


Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial.
Oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract, where it affects gut function. Clinically, we have noticed an improvement of bowel habits during lactation in constipated women. The aim of this study was to examine whether oxytocin has an effect on bowel symptoms and psychological well being in women with refractory constipation. Fifty-nine women with refractory constipation were included in a double blind, multicentre study. After a 2-week run-in period, they were randomly allocated to nasal inhalation of either placebo or oxytocin treatment twice daily for 13 weeks, followed by a 2 weeks, posttreatment period. The patients completed a questionnaire every day concerning bowel habits, abdominal pain and discomfort, and Gastrointestinal Symptoms Rating Scale (GSRS) and Psychological General Well-being (PGWB) twice during the study; namely, during the baseline period and at the end of the treatment period. Both oxytocin and placebo led to improvement of the constipation according to the GSRS and led to improvement in the sensation of incomplete evacuation and anorectal obstruction, without significant differences between the groups. Abdominal pain and discomfort responded weakly to oxytocin, with no effect of the placebo. In a subgroup of patients with IBS and concomitant depression, a weak improvement in depressed mood was observed after oxytocin administartion. Nasal administration of oxytocin had no significant advantage over placebo concerning an effect on constipation. However, it seems to have a positive effect on abdominal pain and discomfort and depressed mood. These findings should be further explored.


Surface-Enhanced Raman and Surface-Enhanced fluorescence of charged dyes based on alginate silver nanoparticles and its calcium alginate hydrogel beads.
This study shows a new SERS (Surface-enhanced Raman Scattering) and SEF (Surface-enhanced Fluorescence) platform approach, in which substrates were constructed from the silver nanoparticles stabilized by alginate polymer (AgALG) and encapsulated in hydrogel calcium alginate beads (AgALGbead). In this regard, the electrostatic repulsion or attraction concerning the charged dyes and the carboxylate groups of the alginate could define the distances between the probe molecules and metallic nanoparticles to determine the SERS or SEF effect. In this sense, the anionic dye named New Indocyanine Green (IR-820) and the cationic dye Rhodamine 6G (Rh6G) were selected to discuss the alginate's ability to quench or enhance the fluorescence and the Raman dyes signals. Furthermore, the SEF effect using the IR-820 dye can be detected for the near-infrared emission (S1 → S0) using the 532 and 633 nm laser lines as well at the visible region (S2 → S0) applying the excitation at 532 nm in the AgALGbead substrates. Nevertheless, the cationic dye provides the Surface-enhanced Resonance Raman Scattering (SERRS) effect and quenching of the fluorescence for the same AgALGbeads substrate at 532 nm laser line.


Evidence-informed vaccine decision making: The introduction of Human Papilloma Virus (HPV) vaccination in the Netherlands.
Little is known about the role of (economic) information or evidence in the different stages of the decision-making process on vaccine introduction. By conducting a document analysis on the public decision-making process of introducing human Papilloma virus (HPV) vaccine into the national vaccination program (NVP) in the Netherlands, we aim to gain insight into which information plays a role during the introduction of a vaccination programme. A document analysis was performed on the public decision-making process regarding the introduction of HPV vaccine into the NVP in the Netherlands. Information used or asked for by various stakeholders during different stages of the policymaking process was identified. In total, 42 documents were found, analyzed and synthesized, for the period between August 2006 and September 2009. Documents were analyzed using directed content analysis based on eight broad categories of criteria used in decision-making frameworks for introducing a vaccine. Our analysis demonstrates that a wide variety of stakeholders is involved in the process. Financial or economic issues were stipulated in 64.3% of the documents and information on vaccine characteristics were discussed in 59.5%. Economic information from economic evaluations was discussed most (47.6%). Based on our analysis, it can be concluded that economic information, in particular information from economic evaluations, played an important role in the decision-making process regarding the introduction of HPV-vaccination.


Some interesting isolates from a diagnostic laboratory.
Citrobacter koseri, Plesiomonas shigelloides, Edwardsiella tarda, Yersinia enterocolitica, Alkalescens dispar, Vibrio parahaemolyticus, and Vibrio alginolyticus were seven interesting microorganisms isolated recently in our diagnostic laboratory.


Perceived attachment: relations to anxiety sensitivity, worry, and GAD symptoms.
This investigation examined the relation between perceived alienation from parents and peers, anxiety sensitivity (AS), and current worry and generalized anxiety disorder (GAD) symptoms with the goal of expanding the knowledge base on factors that may contribute to the development of AS and its role in worry. The mediating role of AS between perceptions of alienation and current worry and GAD symptoms was also examined. Ninety-four non-clinical worriers completed self-report questionnaires assessing their perceptions of attachment, AS levels, and worry and GAD symptoms. Even after controlling for worry and GAD symptoms, greater perceptions of alienation from mothers and peers were significantly associated with higher AS symptoms. AS as a unitary construct mediated the relation between perceptions of alienation from mothers and peers and worry and GAD symptoms. The facets fear of publicly observable symptoms and fear of cognitive dyscontrol also mediated this relation. The role of alienation in relation to AS, worry, and GAD symptoms is discussed along with directions for future research.


Naloxone reversal of stress-induced reproductive effects in the male rhesus monkey.
Adolescent male rhesus monkeys, stressed by placement in tethering systems, were administered naloxone to discern the involvement of endogenous opioids in the stress-induced reproductive dysfunction. Stressed monkeys exhibited decreased plasma levels of luteinizing hormone (LH), testosterone, and increased levels of prolactin. Administration of naloxone temporarily returned hormone levels to non-stressed values. Stress depressed sexual activity was increased following naloxone treatment. GnRH administration stimulated plasma LH and testosterone levels. These results indicate that stress-induced changes in reproductive function may be mediated by opioids at levels above the pituitary.


Prospective validation of VEGF and eNOS polymorphisms as predictors of first-line bevacizumab efficacy in patients with metastatic colorectal cancer.
Bevacizumab (Bev) plus chemotherapy is a standard first-line treatment in metastatic colorectal cancer (mCRC), however to date no predictive factors of response have been identified. Results of our previous analysis on patients enrolled in a randomized prospective phase III multicenter study (ITACa study) showed a predictive value of Vascular Endothelial Growth Factor (VEGF) polymorphism (VEGF + 936), a 27-nucleotide variable number tandem repeat (VNTR) of the endothelial nitric oxide synthase (eNOS) gene and eNOS + 894 polymorphism. mCRC patients, treated with Bev plus chemotherapy, were included in this prospective validation trial. eNOS + 894G > T was analyzed by Real time PCR, while the eNOS VNTR and VEGF + 936C > T were determined by standard PCR and direct sequencing analysis. These polymorphisms were assessed in relation to progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). These three polymorphisms were not predictive of PFS (p 0.91, 0.59 and 0.09, respectively), and OS (p 0.95, 0.32 and 0.46, respectively). Moreover, the haplotype analyses did not confirm what was found in our previous study; patients bearing a specific haplotype of eNOS had not significantly improved outcomes. This prospective study failed to validate the predictive impact of eNOS and VEGF polymorphisms for response to Bev plus first-line chemotherapy in mCRC patients.


Processing deficits and the mediation of positive affect in persuasion.
Motivational and cognitive mediators of the reduced processing of persuasive messages shown by recipients in a positive mood were tested. Ss in positive or neutral moods read strong or weak counterattitudinal advocadies for either a limited time or for as long as they wanted. Under limited exposure conditions, neutral mood Ss showed attitude change indicative of systemic processing, whereas positive mood Ss showed no differentiation of strong and weak versions of the message. When message exposure was unlimited, positive mood Ss viewed the message longer than did neutral mood Ss and systematically processed it rather than relying on persuasion heuristics. These findings replicated with 2 manipulations of mood and 2 different attitude issues. We interpret the results as providing evidence that reduced cognitive capacity to process the message contributes to the decrements shown by positive mood Ss.


Occurrence, mortality and cost of brain disorders in Denmark: a population-based cohort study.
To examine the occurrence of brain disorders (ie, neurological and mental disorders) in Denmark and mortality and cost of illness among affected persons. Matched cohort study. We obtained routinely collected registry data on all Danish residents during 1995-2015. We identified all persons alive on 1 January 2015 with a diagnosis of 25 specific brain disorders (prevalent cohort) and all persons with an incident diagnosis during 2011-2015 (incident cohort). Each person was matched on age and sex with 10 persons from the general population without the brain disorder of interest. Prevalence and incidence of hospital-diagnosed brain disorders, 1-year absolute and relative mortality, and attributable direct and indirect costs of illness compared with the corresponding matched cohorts. We identified 1 075 081 persons with at least one prevalent brain disorder (any brain disorder) on 1 January 2015, corresponding to 18.9% of the Danish population. The incidence rate of any brain disorder during 2011-2015 was 1349 per 100 000 person-years (95% CI 1345 to 1353). One-year mortality after diagnosis was increased in persons with any brain disorder (HR 4.7, 95% CI 4.7 to 4.8) and in persons in every group of specific brain disorders compared with the matched cohort from the general population. The total attributable direct costs of brain disorders in 2015 were €5.2 billion and total attributable indirect costs were €11.2 billion. Traumatic brain injury, stress-related disorders, depression and stroke were the most common brain disorders. Attributable costs were highest for depression, dementia, stress-related disorders and stroke. One in five Danish residents alive on 1 January 2015 had been diagnosed with at least one brain disorder, and mortality was five times higher in persons with any diagnosed brain disorder than in the general population. We found high attributable direct and indirect costs of brain disorders.


A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations.
There is much interest in early T-cell development, particularly in relation to the diversification of the T-cell receptor repertoire and the elucidation of the lineage relationships between T-cell populations in the thymus and peripheral lymphoid organs. However, the requirements for the growth of the earliest thymic T-cell precursor in 13-14-day mouse embryo thymus in isolation from the thymic environment are unknown. Proliferation and maturation of such cells are not sustained either in the presence of monolayers of thymic stromal cells or by the addition of interleukin-2 (IL-2), despite the expression of receptors for this growth factor on a proportion of thymocytes displaying the immature Thy 1+ Lyt-2-L3T4- phenotype in the embryonic thymus. In contrast, when maintained within the intact thymic environment in organ cultures, 13-14-day thymic stem cells do show a pattern of surface marker and functional development similar to that seen in vivo, suggesting that short-range growth signals, perhaps necessitating direct contact with organized epithelial cells, are required. We have shown, by exploiting the selective toxicity of deoxyguanosine (dGuo) for early T cells, that this organ culture system can be manipulated to produce alymphoid lobes that can be recolonized from a source of precursors in a transfilter system. We now show that recolonization of alymphoid lobes can also be achieved by association with T-cell precursors in hanging drops, allowing recolonization by exposure to defined numbers of precursors, including a single micromanipulated stem cell. Analysis of T-cell marker expression in these cultures shows that a single thymic stem cell can produce progeny of distinct phenotypes, suggesting that these marker-defined populations are not derived from separate prethymic precursors, but arise within the thymus.


Concomitant common iliac and common femoral artery pseudoaneurysms revealing Behcet's disease.
Vascular involvement is one of the major causes of mortality and morbidity in Behçet's disease (BD). Vasculo-Behçet patients are at risk for multiple vessel-related complications including thromboses, stenoses, occlusions, and aneurysms. In this report, we describe the case of a young woman admitted in our department for management of a concomitant common iliac and common femoral artery pseudoaneurysms revealing Behçet's disease.