Neuroplastin 65 modulates anxiety- and depression-like behavior likely through adult hippocampal neurogenesis and central 5-HT activity.
Neuroplastin 65 (Np65) is a brain-specific cell adhesion molecule that is highly expressed in the hippocampus, amygdala, and cortex, regions of the brain that are associated with memory and emotions. However, the role of Np65 in regulation of emotional behavior is still unclear. In the present study, we show that Np65 knock-out (Np65 KO) mice display enhanced anxiety-like behavior, a reduction in some aspects of depressive-like behaviors, and increased sociability and memory. Biochemical investigations revealed that Np65 KO mice show increased adult-born neurons and proliferation in the hippocampus. In addition, the level of 5-hydroxytryptamine (5-HT) in the hippocampus was reduced. The expression of tryptophan hydroxylase 2 in the brainstem and the expression of the 5-HT3A receptor were also decreased. Electrophysiological recordings confirmed an impaired maintenance of long-term potentiation in the hippocampus of Np65 KO mice. Together, our findings uncover a role for Np65 in regulating anxiety- and depressive-like behaviors and suggest that Np65 may be essential for the maintenance of emotional stability, indicating that it might be an attractive potential target for treatment of psychiatric disorders.


Identification of a polygalacturonase (Cup s 2) as the major CCD-bearing allergen in Cupressus sempervirens pollen.
As IgE glyco-epitopes, also referred to as cross-reactive carbohydrate determinants (CCDs), can share significant structural homologies between different plants, they are prone to extensive cross-reactivity among allergen pollen extracts. Here, cypress pollen allergens, especially a polygalacturonase (PG), were further characterized using double one-dimensional electrophoresis (D1-DE). The presence of specific IgE directed against CCDs was investigated by bromelain IgE inhibition and concanavalin A binding assays using sera of cypress pollen-sensitized patients. Our results showed that IgE reactivity to CCDs in Cupressus sempervirens pollen extracts is mainly related to bromelain-type epitopes of a newly identified cypress PG. This glycoprotein has been further characterized through an immunoproteomic approach and officially indexed as Cup s 2 by the WHO/IUIS allergen nomenclature. Cup s 2 could thus be associated with the increased prevalence of IgE reactivity to cypress pollen extracts because of CCD interference.


Gene Editing in Human Pluripotent Stem Cells: Choosing the Correct Path.
The recent emergence of targeted nucleases has opened up new opportunities for performing genetic modifications with human pluripotent stem cells (hPSCs). These modifications can range from the creation of a routine knock-out to the more challenging single point-mutation. For both the new and established user, deciding on the best approach for the specific modification of interest can be an arduous task, as new and improved technologies are rapidly and continuously being developed. The choices between the reagents and methodologies depends entirely on the end-goal of the experiments and the locus to be modified. Investigators need to decide on the best nuclease to use for each experiment from among Zinc-Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 that would result in the highest likelihood of success with the fewest pitfalls. Furthermore, there have been significant improvements over the first-generation nucleases, such as the development of the dimeric CRISPR RNA-guided Fok1 nucleases (RFNs, marketed as NextGEN™ CRISPR) that reduces the "off-target" mutation rate, providing further options for investigators. Should researchers need to perform a point mutation, then considerations must be made between using single-stranded oligo-deoxynucleotides (ssODN) as the donor for homology-directed repair or utilizing a selection cassette within a donor vector in combination with an excision-only piggyBac™ transposase to leave a seamless edit. In this review, we will provide a general overview of the current technologies, along with methodologies for generating point mutations, while considering both their pros and cons.


Prognostic Value of [18F]FDG PET Radiomics to Detect Peritoneal and Distant Metastases in Locally Advanced Gastric Cancer-A Side Study of the Prospective Multicentre PLASTIC Study.
To improve identification of peritoneal and distant metastases in locally advanced gastric cancer using [18F]FDG-PET radiomics. [18F]FDG-PET scans of 206 patients acquired in 16 different Dutch hospitals in the prospective multicentre PLASTIC-study were analysed. Tumours were delineated and 105 radiomic features were extracted. Three classification models were developed to identify peritoneal and distant metastases (incidence: 21%): a model with clinical variables, a model with radiomic features, and a clinicoradiomic model, combining clinical variables and radiomic features. A least absolute shrinkage and selection operator (LASSO) regression classifier was trained and evaluated in a 100-times repeated random split, stratified for the presence of peritoneal and distant metastases. To exclude features with high mutual correlations, redundancy filtering of the Pearson correlation matrix was performed (r = 0.9). Model performances were expressed by the area under the receiver operating characteristic curve (AUC). In addition, subgroup analyses based on Lauren classification were performed. None of the models could identify metastases with low AUCs of 0.59, 0.51, and 0.56, for the clinical, radiomic, and clinicoradiomic model, respectively. Subgroup analysis of intestinal and mixed-type tumours resulted in low AUCs of 0.67 and 0.60 for the clinical and radiomic models, and a moderate AUC of 0.71 in the clinicoradiomic model. Subgroup analysis of diffuse-type tumours did not improve the classification performance. Overall, [18F]FDG-PET-based radiomics did not contribute to the preoperative identification of peritoneal and distant metastases in patients with locally advanced gastric carcinoma. In intestinal and mixed-type tumours, the classification performance of the clinical model slightly improved with the addition of radiomic features, but this slight improvement does not outweigh the laborious radiomic analysis.


Aggressiveness and brain amine concentration in dominant and subordinate finishing pigs fed the beta-adrenoreceptor agonist ractopamine.
Under farm conditions, aggression related to the formation of social hierarchy and competition for resources can be a major problem because of associated injuries, social stress, and carcass losses. Any factor that may affect the regulation and amount of aggression within a farmed system, for instance, feeding the beta-adrenoreceptor agonist ractopamine (RAC), is therefore worthy of investigation. The objectives of this study were to assess the effects of the widely used swine feed additive RAC, considering also the effects of sex and social rank on aggressiveness and concentrations of brain amines, neurotransmitters essential for controlling aggression, in finishing pigs. Thirty-two barrows and 32 gilts (4 pigs/pen by sex) were fed either a control diet or a diet with RAC (Paylean, Elanco Animal Health, Greenfield, IN) added (5 mg/kg for 2 wk, followed by 10 mg/kg for 2 wk). The top dominant and bottom subordinate pigs (16 pigs/sex) in each pen were determined after mixing by a 36-h period of continuous behavioral observation. These pigs were then subjected to resident-intruder tests (maximum 300 s) during the feeding trial to measure aggressiveness. At the end of wk 4, the amygdala, frontal cortex, hypothalamus, and raphe nuclei were dissected and analyzed for concentrations of dopamine (DA); serotonin (5-HT); their metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively; norepinephrine; and epinephrine using HPLC. Ractopamine-fed gilts performed more attacks during the first 30 s of testing than pigs in all other subgroups (P < 0.05). By the end of the resident-intruder test (300 s), the dominant control gilts and barrows, and both dominant and subordinate RAC-fed gilts performed the greatest percentage of attacks (P < 0.05). Gilts had decreased norepinephrine and DOPAC concentrations in the amygdala and frontal cortex, and when fed RAC, gilts also had the least 5-HIAA concentration and greatest DA turnover rate in the amygdala (P < 0.05). The 5-HT concentration was less in the frontal cortex of gilts compared with barrows and in the raphe nuclei (single site for brain 5-HT synthesis) of dominant gilts (P < 0.05). Ractopamine may be affecting aggressive behavior through indirect action on central regulatory mechanisms such as the DA system. The aggressive pattern observed in the tested pigs, especially in gilts, is likely linked to brain monoamine profiling of a deficient serotonergic system in the raphe nuclei, amygdala, and frontal cortex, and enhanced DA metabolism in the amygdala, brain areas vital for aggression regulation.


[Oxytocin and its role in the control of intracellular level of calcium ions in the myometrium].
The work deals with the study of molecular and membrane mechanisms of uterotonic peptide hormone oxytocin action on Ca ions homeostasis in the uterus myocites and activity of passive and active transport systems of this cation, localized in the myometrium subcellular structures. Biochemical mechanisms of additional Ca2+ influx into the myometrium cells from extracellular environment activated by oxytocin and thapsigargin were determined. Such Ca2+ influx has got the name of capacitative cation entry (CCE), or which is activated by intracellular store depletion (store-operated calcium entry). It was shown that cells from the nonpregnant human myometrium and PHM1-41 cells (immortalized pregnant human myometrial cells) expressed endogenous hTrpC1, 3, 4, 6 and 7 mRNA. The membrane-permeable derivative of diacylglycerol (OAG) stimulated an increase in oscillations of intracellular free Ca2+ concentration in PHM1-41 and myometrium cells. OAG-induced Ca2+ -oscillations were not affected by inhibition of PKC. It was proved that hTrpC channels take part in the regulation of free Ca ions concentration in the myometrium cells. On the basis of results of experiments, conducted on myometrium plasma membrane fraction, the conclusion was made that oxytocin does not influence the passive Ca2+ efflux. It was shown that peptyde hormone partially inhibited Ca2+ accumulation in plasma membrane fraction. Oxytocin also partially inhibited endoplasmic reticulum calcium pump activity of the myometrium cells. The conceptual pattern of myometrial Ca2+ exchange regulation by oxytocin is offered.


Seven-tesla magnetic resonance imaging accurately quantifies intratumoral uptake of therapeutic nanoparticles in the McA rat model of hepatocellular carcinoma: preclinical study in a rodent model.
After inducing McA tumors in Sprague-Dawley rats (McA-SD), the following hypotheses were tested: first, that hypervascular McA tumors grown in Sprague-Dawley rats provide a suitable platform to investigate drug delivery; and second, that high-field MRI can be used to measure intratumoral uptake of DOX-SPIOs. McA cells were implanted into the livers of 18 Sprague-Dawley rats. In successfully inoculated animals, 220-μL DOX-SPIOs were delivered to tumors via the intravenous or intra-arterial route. Pretreatment and posttreatment T2*-weighted images were obtained using 7-T MRI, and change in R2* value (ΔR2*) was obtained from mean signal intensities of tumors in these images. Tumor iron concentration ([Fe]), an indicator of DOX-SPIO uptake, was measured using mass spectroscopy. The primary outcome variable was the Pearson correlation between ΔR2* and [Fe]. Tumors grew successfully in 13 of the 18 animals (72%). Mean (SD) maximum tumor diameter was 0.83 (0.25) cm. The results of phantom studies revealed a strong positive correlation between ΔR2* and [Fe], with r = 0.98 (P < 0.01). The results of in vivo drug uptake studies demonstrated a positive correlation between ΔR2* and [Fe], with r = 0.72 (P = 0.0004). The McA tumors grown in the Sprague-Dawley rats demonstrated uptake of nanoparticle-based therapeutic agents. Magnetic resonance imaging quantification of intratumoral uptake strongly correlated with iron concentrations in pathological specimens, suggesting that MRI may be used to quantify uptake of iron-oxide nanotherapeutics.


[Effect of oxygen baths and massage on hemodynamics in patients with neurocirculatory dystonia].
56 patients with neurocirculatory asthenia (NCA) of a hypertensive and cardial type aged 30 to 55 years took general oxygen baths and collar zone massage, no drugs were used. The baths and the massage improved the disease course in 92.6% patients: improved hemodynamics, relieved high vascular resistance, lowered high diastolic blood pressure, decreased heart rate in tachycardia. More effective was the treatment in hypertensive NCA.


An unusual localization of snakebite treated without antivenin: case report.
Snakebite is one of the commonest causes of morbidity and mortality in tropical regions. This paper focuses on the medical treatment of a patient who had been bitten by a snake on the vertex of his head. It was a severe envenomation with ensuing marked edema associated with coagulation abnormalities. Although the antivenin was extensively sought in various medical centers, it was unavailable. We observed and treated the patient, with special regard to his hematological findings and potential complications. Specifically, tetanus prophylaxis and intravenous fluids were administered, and the wound was cleaned and dressed. Fresh frozen plasma was also administered. The patient responded well, and was discharged on the fourth day of his admission, without any sequelae.


CT doses in cylindrical phantoms.
A single CT scan of thickness T in a cylindrical phantom produces a three-dimensional dose distribution, which depends primarily on the photon energy spectrum, the x-ray beam shaping filter and the size and composition of the irradiated phantom. Monte Carlo simulations employing monoenergetic photons were employed to investigate the effect of each of these factors on phantom dose distributions. The fractional energies scattered, imparted and transmitted through the CT phantom were calculated. A dose index (D(r)), which is a function of phantom radius r, was computed. Phantom materials investigated included lung, fat, water, soft tissue, acrylic and bone with calculations performed for head (160 mm diameter) and body (320 mm diameter) phantoms. All dose and energy imparted data generated for CT phantoms were normalized using an 'in air' dose (Dair), which is defined as the axial dose (in acrylic) at the isocentre in the absence of any phantom. Results obtained show how CT parameters impact on doses in cylindrical phantoms. These dosimetry data are likely to be useful to estimate energy imparted to phantoms (and patients) undergoing CT examinations.


Disruptive mood dysregulation disorder in offspring of parents with depression and bipolar disorder.
BackgroundIt has been suggested that offspring of parents with bipolar disorder are at increased risk for disruptive mood dysregulation disorder (DMDD), but the specificity of this association has not been established.AimsWe examined the specificity of DMDD to family history by comparing offspring of parents with (a) bipolar disorder, (b) major depressive disorder and (c) a control group with no mood disorders.MethodWe established lifetime diagnosis of DMDD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children for DSM-5 in 180 youth aged 6-18 years, including 58 offspring of parents with bipolar disorder, 82 offspring of parents with major depressive disorder and 40 control offspring.ResultsDiagnostic criteria for DMDD were met in none of the offspring of parents with bipolar disorder, 6 of the offspring of parents with major depressive disorder and none of the control offspring. DMDD diagnosis was significantly associated with family history of major depressive disorder.ConclusionsOur results suggest that DMDD is not specifically associated with a family history of bipolar disorder and may be associated with parental depression.


Analysis of infectious spondylodiscitis: 7-years data.
Infectious spondylodiscitis (SD) is an infectious disease that is rare and difficult to diagnose due to its non-specific clinical features. In this study, we aimed to describe the clinical and diagnostic features of infectious spondylodiscitis. All patients who were diagnosed with SD at our hospital during a 7-year period from January 1, 2011 through December 31, 2017 were included in the study. Spondylodiscitis is divided into the following three types: pyogenic, tuberculous, and brucellar. Clinical and laboratory data were collected retrospectively from the medical records of the patients. Of the 118 patients, 66 (55.9%) were female, 81 (68.6%) had pyogenic SD (PSD), 21 (17.8%) had tuberculous SD (TSD), and 16 (13.6%) had brucellar SD (BSD). The mean age was 59.3 ± 14.6 years. Leucocytosis was significantly higher in patients with PSD (p=0.01) than in patients with other types of SD. Thoracic involvement (47.6%) was significantly higher in patients with TSD (p=0.005) than in other patients. Sacral involvement (12.5%) was significantly higher in patients with BSD (p=0.01) than in other patients. Paravertebral abscess formation (42.8%) occurred most frequently in patients with TSD. Microbiologic agents were defined in 50% (18/36) of the surgical specimens and in 12.5% of the fine needle aspiration biopsy (FNAB) specimens. Staphylococcus aureus was the most common microbiological agent in patients with PSD. Spinal surgery was defined as a risk factor for PSD (p = 0.0001). Binary logistic regression analysis revealed that female gender, thoracic involvement and night sweats were the predictive markers for TSD (OR 4.5 [95% CI 1.3-15.3] and OR 5 [95% CI 1.7-14.6]). PSD is the most frequent form of SD. Leucocytosis is most common in patients with PSD. Thoracic involvement and paraspinal abscess were prominent in patients with TSD. Sacral involvement was most common in patients with BSD. Thoracic involvement, female gender and night sweats were the predictive markers for TSD. The microbiological culture positivity rate was higher in surgical specimens compared to FNAB specimens. The need for surgical treatment was most common in patients with TSD.


A prospective stepped wedge cohort evaluation of the new national trauma team activation criteria in Sweden - the TRAUMALERT study.
Trauma triage based on prehospital information facilitates correct allocation of in-hospital resources. The Swedish national two-tier trauma team activation (TTA) criteria were revised in 2016. The current study aimed to evaluate the safety and efficacy of the new criteria. Five centres covering trauma care for 1.2 million inhabitants registered all trauma patients prospectively in the Swedish trauma registry (SweTrau) prior to and after stepwise introduction of new TTA criteria within the cohort (a prospective stepped-wedge cohort study design; period August 2016-November 2017). Evaluation of full- and limited-TTA frequency, under- and overtriage were performed at equal duration before and after this change. The centres registered 1948 patients, 1882 (96.6%) of which were included in the study. With new criteria, frequency of full-TTA was unchanged, while limited-TTA decreased with 46.3% (from 988 to 531). 30-day trauma mortality was unchanged. The overtriage was 107/150 (71.3%) with former criteria, and 104/144 (72.2%) with new criteria, p = 0.866. Undertriage was 50/1037 (4.8%) versus 39/551 (7.1%), p = 0.063. Undertriage was consistently > 20% in patients with fall injury. Among patients with Injury Severity Score (ISS) > 15, 50/93 (53.8%) did not initiate full-TTA with former, vs 39/79 (49.4%) with new criteria, p = 0.565. Age > 60-years was a risk factor for undertriage (OR 2.89, p < 0.001), while low fall injuries indicated a trend (OR 2.70, p = 0.051). The newly implemented Swedish TTA criteria result in a reduction in limited TTA frequency, indicating an increased efficiency in use of resources. The over- and undertriage is unchanged compared to former criteria, thus upholding patient safety.


Nonrandom γ-TuNA-dependent spatial pattern of microtubule nucleation at the Golgi.
Noncentrosomal microtubule (MT) nucleation at the Golgi generates MT network asymmetry in motile vertebrate cells. Investigating the Golgi-derived MT (GDMT) distribution, we find that MT asymmetry arises from nonrandom nucleation sites at the Golgi (hotspots). Using computational simulations, we propose two plausible mechanistic models of GDMT nucleation leading to this phenotype. In the "cooperativity" model, formation of a single GDMT promotes further nucleation at the same site. In the "heterogeneous Golgi" model, MT nucleation is dramatically up-regulated at discrete and sparse locations within the Golgi. While MT clustering in hotspots is equally well described by both models, simulating MT length distributions within the cooperativity model fits the data better. Investigating the molecular mechanism underlying hotspot formation, we have found that hotspots are significantly smaller than a Golgi subdomain positive for scaffolding protein AKAP450, which is thought to recruit GDMT nucleation factors. We have further probed potential roles of known GDMT-promoting molecules, including γ-TuRC-mediated nucleation activator (γ-TuNA) domain-containing proteins and MT stabilizer CLASPs. While both γ-TuNA inhibition and lack of CLASPs resulted in drastically decreased GDMT nucleation, computational modeling revealed that only γ-TuNA inhibition suppressed hotspot formation. We conclude that hotspots require γ-TuNA activity, which facilitates clustered GDMT nucleation at distinct Golgi sites.


Synthesis of envelope polypeptides by Haemophilus influenzae during development of competence for genetic transformation.
Six polypeptides with apparent molecular weights of 95,000, 90,000, 80,000, 67,000, 64,000, and 43,000 were found to be characteristic of the cell envelopes of competent Haemophilus influenzae, and were synthesized entirely during the period of competence development. Two polypeptides with apparent molecular weights of 58,500 and 40,500 were synthesized during growth as well as during competence development, but were only associated with the envelope fraction of cells that had developed competence. The kinetics of synthesis of the competence-related envelope polypeptides showed a lag period of approximately 20 min. The observation of this lag period raises the question as to whether some of these competence-related polypeptides might be involved in the process of deoxyribonucleic acid uptake, since the development of this property also exhibits a sigmoid time course during competence development.


Using historical spy satellite photographs and recent remote sensing data to identify high-conservation-value forests.
High-conservation-value forests (HCVFs) are critically important for biodiversity and ecosystem service provisioning, but they face many threats. Where systematic HCVF inventories are missing, such as in parts of Eastern Europe, these forests remain largely unacknowledged and therefore often unprotected. We devised a novel, transferable approach for detecting HCVFs based on integrating historical spy satellite images, contemporary remote sensing data (Landsat), and information on current potential anthropogenic pressures (e.g., road infrastructure, population density, demand for fire wood, terrain). We applied the method to the Romanian Carpathians, for which we mapped forest continuity (1955-2019), canopy structural complexity, and anthropogenic pressures. We identified 738,000 ha of HCVF. More than half of this area was identified as susceptible to current anthropogenic pressures and lacked formal protection. By providing a framework for broad-scale HCVF monitoring, our approach facilitates integration of HCVF into forest conservation and management. This is urgently needed to achieve the goals of the European Union's Biodiversity Strategy to maintain valuable forest ecosystems.


The trajectory of gait speed preceding mild cognitive impairment.
To compare the trajectory of motor decline, as measured by gait speed and finger-tapping speed, between elderly people who developed mild cognitive impairment (MCI) and those who remained cognitively intact. We also sought to determine the approximate time at which the decline in motor function accelerated in persons who developed MCI. Longitudinal cohort study. Participants were 204 healthy seniors (57.8% women) from the Oregon Brain Aging Study evaluated for up to 20 years using annual neurologic, neuropsychological, and motor examinations. The pattern of motor decline with aging was compared using a mixed-effects model with an interaction term for age and a clinical diagnosis of MCI. The time before diagnosis of MCI, when the change in gait or finger-tapping speed accelerates, was assessed using a mixed-effects model with a change point for men and women, separately and combined, who developed MCI. The rates of change, with aging, in gait speed (P < .001) and finger-tapping speed in the dominant hand (P = .003) and nondominant hand (P < .001) were significantly different between participants who developed MCI (converters) and those who did not (nonconverters). Using a change point analysis for MCI converters, the decrease in gait speed accelerated by 0.023 m/s/y (P < .001), occurring 12.1 years before the onset of MCI. An acceleration in gait speed decline occurred earlier in men than women. For tapping speed, the change point occurred after the onset of MCI for both dominant and nondominant hands when men and women were combined. Motor decline as indexed by gait speed accelerates up to 12 years before MCI. Longitudinal changes in motor function may be useful in the early detection of dementia during preclinical stages, when the utility of disease-modifying therapies would be greatest.


Quantitative analysis of abducens neuron discharge dynamics during saccadic and slow eye movements.
The mechanics of the eyeball and its surrounding tissues, which together form the oculomotor plant, have been shown to be the same for smooth pursuit and saccadic eye movements. Hence it was postulated that similar signals would be carried by motoneurons during slow and rapid eye movements. In the present study, we directly addressed this proposal by determining which eye movement-based models best describe the discharge dynamics of primate abducens neurons during a variety of eye movement behaviors. We first characterized abducens neuron spike trains, as has been classically done, during fixation and sinusoidal smooth pursuit. We then systematically analyzed the discharge dynamics of abducens neurons during and following saccades, during step-ramp pursuit and during high velocity slow-phase vestibular nystagmus. We found that the commonly utilized first-order description of abducens neuron firing rates (FR = b + kE + r, where FR is firing rate, E and are eye position and velocity, respectively, and b, k, and r are constants) provided an adequate model of neuronal activity during saccades, smooth pursuit, and slow phase vestibular nystagmus. However, the use of a second-order model, which included an exponentially decaying term or "slide" (FR = b + kE + r + uE - c), notably improved our ability to describe neuronal activity when the eye was moving and also enabled us to model abducens neuron discharges during the postsaccadic interval. We also found that, for a given model, a single set of parameters could not be used to describe neuronal firing rates during both slow and rapid eye movements. Specifically, the eye velocity and position coefficients (r and k in the above models, respectively) consistently decreased as a function of the mean (and peak) eye velocity that was generated. In contrast, the bias (b, firing rate when looking straight ahead) invariably increased with eye velocity. Although these trends are likely to reflect, in part, nonlinearities that are intrinsic to the extraocular muscles, we propose that these results can also be explained by considering the time-varying resistance to movement that is generated by the antagonist muscle. We conclude that to create realistic and meaningful models of the neural control of horizontal eye movements, it is essential to consider the activation of the antagonist, as well as agonist motoneuron pools.


Wagner's spherical periacetabular osteotomy: long term results.
Residual acetabular dysplasia leads to hip arthritis as a consequence of insufficient femoral head coverage which causes abnormal pressure on the joint cartilage. Spherical periacetabular osteotomy, described by H. Wagner, improves the acetabular coverage of the head. This surgical technique has been performed by the senior author, in Galeazzi Orthopaedic Institute of Milan, Italy since 1979. The purpose of this study is to evaluate the clinical and radiographic results of 14 patients affected by acetabular dysplasia and operated before 1985 by the same surgeon with this technique. The analysis of long term results (follow-up longer than 20 years) has shown that it is possible to achieve good clinical outcomes and to delay the need for total hip arthroplasty if a precise surgical technique is employed and if the correct indications are followed. Obese patients or hips with X-ray signs of osteoarthritis show the worst results in our experience. Our attitude is nowadays: full indication of spherical periacetabular osteotomy in dysplasia of the adolescent, indication in young adult patients only when some symptom is present, very rare indication in arthritis and only in very mild cases in young patients.


Outreach and Inreach Strategies for Colorectal Cancer Screening Among Latinos at a Federally Qualified Health Center: A Randomized Controlled Trial, 2015-2018.
Objectives. To compare usual care, inreach consisting of one-on-one education, mailed outreach offering a fecal immunochemical test (FIT), and a combination of outreach and inreach for promoting colorectal cancer (CRC) screening.Methods. We conducted a 4-arm randomized controlled trial from 2015 to 2018 at a US federally qualified health center near the California-Mexico border primarily serving low-income Hispanics/Latinos. A total of 673 individuals aged 50 to 75 years not up to date with screening were assigned to 1 of the 4 intervention groups. The primary outcome was CRC screening through 6 months follow-up.Results. A total of 671 patients were included in intention-to-screen analyses. Their mean age was 59.9 years, 48.9% were male, and 86.3% were primarily Spanish-speaking. Screening was 27.5% for usual care (95% confidence interval [CI] = 0.21, 0.34), 52.7% for inreach (95% CI = 0.45, 0.60), 77.2% for outreach (95% CI = 0.71, 0.83), and 78.9% for combination of inreach and outreach (95% CI = 0.73, 0.85; P < .001 for all comparisons except P = .793 for outreach vs combination).Conclusions. Among individuals at high risk for noncompletion, inreach with one-on-one education nearly doubled, and outreach offering mailed FIT alone or in combination with inreach nearly tripled screening compared with usual care. Mailed FIT outreach was superior to inreach for promoting screening.


Analysis of the efficiency of hair removal by different optical methods: comparison of Trichoscan, reflectance confocal microscopy, and optical coherence tomography.
Noninvasive diagnostic tools, such as Trichoscan®, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT), are efficient methods of hair shaft and growth evaluation. The aim of this study was to carry out a comparative assessment of these three medical procedures by measuring the hair shaft and hair growth after hair removal for a defined period of five days. The application of these techniques was demonstrated by measuring hair growth on the lower leg of six female volunteers. After removal of the hair shaft with a shaving system, the hair follicle infundibula and the length of the growing hairs were measured with the Trichoscan®, RCM, and OCT method. All three methods are reliable hair measuring tools after hair removal. Trichoscan® is best suited in the implementation of hair growth measurement and RCM in the analysis of hair follicles, whereas the OCT system can be consulted as an additional measurement for the evaluation of the hair follicle and length.


[Rational method for producing sera with high titers of virus-neutralizing antibodies. Part III].
The effect of a number of nonspecific stimulators of immunogenesis (complete-Freund's adjuvant, complete adjuvant prepared from Soviet made components, arlacel with vaseline oil, aluminium hydroxide) on the immune process has been studied. The highest titers of virus-neutralizing antibodies have been obtained with the use of complete Freund's adjuvant land complete adjuvant prepared from Soviet components (X=1 : 54040 and X=1 : 40960, respectively).


Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity.
Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH(2)-terminal lobe helix alphaC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E-binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics.


Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability.
The authors report a retrospective analysis of the use of mycophenolate mofetil (MyM) in 85 patients with autoimmune myasthenia gravis. The Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) was used to characterize the treatment response in each patient. Sixty-two patients (73%) achieved a PIS status indicating improvement. Quantitative strength testing performed on the majority of patients before and after treatment also improved. Side effects to MyM were observed in 27% of patients but required discontinuation in only 6%.


HIV/AIDS challenges the normative model of healthcare delivery in Canada.
With advances in therapeutics, effective therapy for human immunodeficiency virus (HIV) has shifted the focus of HIV care from an acute illness to a chronic disease requiring the services of several disciplines in a primary care setting. This article describes a collaborative model in the delivery of HIV care for HIV-infected individuals who remain fragile, both physically and psychosocially.


[Adaptability of sweet corn ears to a frozen process].
The effects of frozen condition on the quality of three sweet corn ears (2038, 2010, 2004) and the pattern (Bonanza), were evaluated. Biometrics characteristics like ear size, ear diameter, row and kernel deep were measured as well as chemical and physical measurement in fresh and frozen states. The corn ears were frozen at -95 degrees C by 7 minutes. The yield and stability of the frozen ears were evaluated at 45 and 90 days of frozen storage (-18 degrees C). The average commercial yield as frozen corn ear for all the hybrids was 54.2%. The industry has a similar value range of 48% to 54%. The ear size average was 21.57 cm, row number was 15, ear diameter 45.54 mm and the kernel corn deep was 8.57 mm. All these measurements were found not different from commercial values found for the industry. All corn samples evaluated showed good stability despites the frozen processing and storage. Hybrid 2038 ranked higher in quality.


Receptor-mediated increase in cytosolic calcium in LLC-PK1 cells by platelet activating factor and thromboxane A2.
Several studies indicate an important role of platelet activating factor (PAF) and thromboxane A2 (TXA2) in glomerular pathophysiology. However, the potential role of PAF or TXA2 in renal tubular pathophysiology has received little attention, and the presence of functional receptors for these autacoids in renal tubular epithelium has not been previously studied. We examined the effects of PAF and the TXA2 analogue, ONO11113, on the cytosolic free calcium concentration [( Ca2+]i) in cultured LLC-PK1 cell line using a fluorescent probe, fura-2. In these cells, the addition of PAF or ONO11113 caused a significant increment in [Ca2+]i in a dose-dependent manner: both agonists (10(-7) M) increased [Ca2+]i from 148 +/- 16 to 288 +/- 39 nM and from 130 +/- 8 to 240 +/- 18 nM, with the values of EC50 for PAF and ONO11113 being 17 +/- 4 and 17 +/- 2 nM, respectively. These effects were both rapid and transient, returning to baseline in two minutes. The effect of PAF was selectively blocked by PAF receptor antagonist BN50730, but not by TXA2 receptor antagonist L657925. Similarly ONO11113 response was abolished by L657925, but not by BN50730. PAF- or ONO11113-challenged cells did not respond to a second addition of the same agent and showed heterologous desensitization to the other agonist. The initial peaks of [Ca2+]i as well as the sustained elevations in [Ca2+]i induced by PAF or ONO11113 were reduced following the chelation of extracellular Ca2+ by 10 mM ethylene glycol-bis(beta-aminomethyl ether)-N,N,N',N'-tetraacetic acid (EGTA).(ABSTRACT TRUNCATED AT 250 WORDS)


Repair of chest wall defects after irradiation for breast cancer.
A simple technique using a contralateral deltopectoral flap is described for the immediate repair of defects of the chest wall resulting from excision of radionecrosis or persistent tumour after radiotherapy. Successful use in 3 consecutive cases has shown that the deltopectoral flap may be rotated through a full 180 degrees without compromise of blood supply and that primary healing may be obtained.


eCry1Gb.1Ig, A Novel Chimeric Cry Protein with High Efficacy against Multiple Fall Armyworm (Spodoptera frugiperda) Strains Resistant to Different GM Traits.
Spodoptera frugiperda (fall armyworm, FAW) is one of the most devastating insect pests to corn and soybean production in the Americas and is rapidly expanding its range worldwide. It is known to be hard to control either by chemical insecticide applications or by GM. Although the use of GM traits can be an effective way to control this pest, it is very rare to find native insecticidal proteins that provide the necessary level of FAW control in crop fields where FAW pressure and damage are high. Insecticidal Cry proteins sourced from Bacillus thuringiensis have been heavily utilized in the development of crops with GM traits; however, it is increasingly difficult to identify Cry proteins with unique modes of action. Protein engineering via a phylogenetically guided Cry protein domain swapping approach enabled us to discover novel chimeric Cry proteins engineered from inactive parent sequences. Some of these chimeras show excellent efficacy against key biotypes of FAW from Brazil and North America. In this study, we characterized a Cry-based chimera eCry1Gb.1Ig that is a very potent FAW toxin. eCry1Gb.1Ig showed high efficacy against multiple FAW strains that are resistant to various traits, including Cry1Fa, Vip3Aa and Cry1A.105/Cry2Ab. These results clearly indicate that the FAW strains resistant to Cry1Fa, Vip3Aa or Cry1A.105/Cry2Ab demonstrate no cross-resistance to eCry1Gb.1Ig and strongly suggest that eCry1Gb.1Ig acts through a novel mode of action compared to the existing traits. In addition to its FAW activity, eCry1Gb.1Ig has also been shown to control Chrysodeixis includens (soybean looper, SBL) and Anticarsia gemmatalis (velvetbean caterpillar, VBC), which are significant pests of soybean. When eCry1Gb.1Ig was introduced into corn and soybean crops, transgenic events showed strong efficacy against FAW, SBL and VBC, but no adverse plant phenotypes. This suggests that the in planta expression of the eCry1Gb.1Ig protein does not compromise plant growth or reproduction and can protect plants from FAW-related damage. Therefore, this valuable discovery will provide a differentiating FAW control trait that will give growers another tool to help them reduce yield loss due to FAW.


Transcriptional Networks Identify BRPF1 as a Potential Drug Target Based on Inflammatory Signature in Primary Lower-Grade Gliomas.
Gliomas are the most common tumors of the central nervous system and are classified into grades I-IV based on their histological characteristics. Lower-grade gliomas (LGG) can be divided into grade II diffuse low-grade gliomas and grade III moderate gliomas and have a relatively good prognosis. However, LGG often develops into high-grade glioma within a few years. This study aimed to construct and identify the prognostic value of an inflammatory signature and discover potential drug targets for primary LGG. We first screened differentially expressed genes in primary LGG (TCGA) compared with normal brain tissue (GTEx) that overlapped with inflammation-related genes from MSigDB. After survival analysis, nine genes were selected to construct an inflammatory signature. LGG patients with a high inflammatory signature score had a poor prognosis, and the inflammatory signature was a strong independent prognostic factor in both the training cohort (TCGA) and validation cohort (CGGA). Compared with the low-inflammatory signature group, differentially expressed genes in the high-inflammatory signature group were mainly enriched in immune-related signaling pathways, which is consistent with the distribution of immune cells in the high- and low-inflammatory signature groups. Integrating driver genes, upregulated genes and drug targets data, bromodomain and PHD finger-containing protein 1 (BRPF1) was selected as a potential drug target. Inhibition of BRPF1 function or knockdown of BRPF1 expression attenuated glioma cell proliferation and colony formation.


Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media.
A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIF(blk))) at a temperature of 37 °C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D(oct) value was identified as a good predictor of the solubilization ratio (R(2) = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.


Mycophenolate Improves Brain-Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats.
Microbiota is involved in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzed whether MMF improves dysbiosis in mineralocorticoid-induced hypertension. Male Wistar rats were assigned to three groups: untreated (CTR), deoxycorticosterone acetate (DOCA)-salt, and DOCA treated with MMF for 4 weeks. MMF treatment reduced systolic BP, improved endothelial dysfunction, and reduced oxidative stress and inflammation in aorta. A clear separation in the gut bacterial community between CTR and DOCA groups was found, whereas the cluster belonging to DOCA-MMF group was found to be intermixed. No changes were found at the phylum level among all experimental groups. MMF restored the elevation in lactate-producing bacteria found in DOCA-salt joined to an increase in the acetate-producing bacteria. MMF restored the percentage of anaerobic bacteria in the DOCA-salt group to values similar to control rats. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. This study demonstrates for the first time that MMF reduces gut dysbiosis in DOCA-salt hypertension models. This effect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation.


Thrombosis Risk in Cancer Patients Receiving Red Blood Cell Transfusions.
Patients with cancer have increased risk of thrombosis and often need red blood cell (RBC) transfusions. However, RBC transfusions may also promote thrombosis because of raised hematocrit and viscosity, storage-related RBC damage, and exposure to thrombogenic mediators from obsolescent RBCs. The authors conducted a literature survey for studies examining whether RBC transfusions were associated with increased risk of venous thromboembolism (VTE) in cancer patients. In perioperative cancer surgery patients with categorical comparisons of any versus no RBC transfusion, increased risk of VTE with RBC transfusion was found in 11 of 31 studies, 5 by univariate correlation only and 6 in multivariate analysis. All six multivariate-positive studies had intermediate overall rates of thrombosis (1.4-6.0%), and three were in urological surgery series. In the larger studies of > 2,000 patients (range: 2,219-44,656), the maximum odds ratio among the multivariate-positive studies was 1.3. Perioperative RBC transfusion volume was more strongly associated with VTE risk, with a positive association in six of seven studies. One large registry-based study of hospitalized cancer patients, not restricted to the perioperative setting, found an adjusted odds ratio of 1.60 (95% confidence interval: 1.53-1.67) for VTE risk in patients receiving RBCs compared with nontransfused patients.


Endoscopic evaluation of the effect of Ulcerone and placebo on duodenal ulcers.
Fifty courses of tripotassium di-citrato bismuthate (Ulcerone) and placebo were administered to ambulant patients with duodenal ulcers in a double-blind trial for 6 weeks. Duodenoscopy was used for initial assessment and to judge improvement. The ulcers of 20 out of 30 patients (67%) healed completely with Ulcerone treatment for 6 weeks, while another 7 patients showed partial improvement. The ulcers of 4 out of 20 patients (20%) on placebo showed healing. The difference is highly significant (chi2 = 20,0; P less than 0,001). Ulcerone is a collodial bismuth substance which is said to act by coating the ulcer by becoming incorporated into granulating tissue at an acid pH. No side-effects of Ulcerone occurred. It is considered to be a safe and effective oral therapeutic substance for ambulant patients with duodenal ulcers.


Antibody-mediated protection against MERS-CoV in the murine model.
Murine antisera with neutralising activity for the coronavirus causative of Middle East respiratory syndrome (MERS) were induced by immunisation of Balb/c mice with the receptor binding domain (RBD) of the viral Spike protein. The murine antisera induced were fully-neutralising in vitro for two separate clinical strains of the MERS coronavirus (MERS-CoV). To test the neutralising capacity of these antisera in vivo, susceptibility to MERS-CoV was induced in naive recipient Balb/c mice by the administration of an adenovirus vector expressing the human DPP4 receptor (Ad5-hDPP4) for MERS-CoV, prior to the passive transfer of the RBD-specific murine antisera to the transduced mice. Subsequent challenge of the recipient transduced mice by the intra-nasal route with a clinical isolate of the MERS-CoV resulted in a significantly reduced viral load in their lungs, compared with transduced mice receiving a negative control antibody. The murine antisera used were derived from mice which had been primed sub-cutaneously with a recombinant fusion of RBD with a human IgG Fc tag (RBD-Fc), adsorbed to calcium phosphate microcrystals and then boosted by the oral route with the same fusion protein in reverse micelles. The data gained indicate that this dual-route vaccination with novel formulations of the RBD-Fc, induced systemic and mucosal anti-viral immunity with demonstrated in vitro and in vivo neutralisation capacity for clinical strains of MERS-CoV.


Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine.
Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the backbone of in vitro cellular models to date, as well as improved expansion protocols to overcome finite supply of the cellular source. We highlight a range of strategies for establishment of three dimensional (3-D) airway and intestinal organoid models and evaluate the limitations and potential improvements in each system, focusing on their application in CF. The in vitro CFTR functional assays in patient-derived organoids allow for preclinical pharmacotherapy screening to identify responsive patients. It is likely that organoids will be an invaluable preclinical tool to unravel disease mechanisms, design novel treatments, and enable clinicians to provide personalized management for patients with CF.


Osteoporosis in Korea.
The increasing occurrence and high cost of osteoporosis pose an enormous public health problem. With continued aging of the populations, osteoporotic fractures may reach one of the major problem in Korea as well as in Asian countries. Although the prevalence of osteoporosis in Korea is somewhat not consistent because of different areas and machines measured bone mass, occurrence of hip fractures have increased about 4 folds during past 10 years. There is no satisfactory way to build up lost bone, thus, prevention is the best way which includes adequate intake of calcium, vitamin D, and protein, exercise, and stop smoking. As a second approach, pharmacologic therapy may be emphasized. Since most of pharmacologic agents for osteoporosis are available in Korea though their reimbursements are limited, preventive measures and pharmacologic therapies should be encouraged to attempt to reduce fragility fractures. Many doctors who work in the field of bone metabolism are establishing the new guidelines for osteoporosis and also attempt to revise the criteria for reimbursement nowadays. New paradigm for osteoporosis will be come and be utilized for clinical applications in the near future.


Association of Depression With Selenium Deficiency and Nutritional Markers in the Patients With End-Stage Renal Disease on Hemodialysis.
Depression is considered as the most common psychological problem in hemodialysis (HD) patients. As there is little evidence regarding the association of depression with serum selenium level as an antioxidant in these patients, the current survey investigates the possible relationship between depression and nutritional status including serum selenium levels. Cross-sectional study. A total of 110 HD patients and 40 healthy controls were enrolled in the study. The patients were in the age range of 18 to 85 years, who had been on hemodialysis for at least 3 months without any acute illness. Beck Depression Inventory was used for assessing the severity of depression. Malnutrition was evaluated through subjective global assessment (SGA) and malnutrition inflammation score (MIS). Serum selenium levels and routine laboratory markers were measured from fasting samples. Sixty-two percent of the patients had some degree of depression based on Beck Depression Inventory score. HD patients were considered to be selenium deficient after comparing the mean value of serum selenium between the patients and controls (P < .001). No significant difference was found in serum selenium levels between depressed HD patients and the rest of patients without depression. The mean level of SGA and MIS in the depressed patients was significantly higher than the rest of patients (P = .03 and P = .04, respectively). Also lower levels of hemoglobin and serum albumin were significantly seen in depressed patients compared with nondepressed ones (P = .004 and P = .04, respectively). Although the HD patients in this study were selenium deficient, no significant association was found between depression and selenium. In addition, depression was more prevalent in malnourished HD patients with higher SGA and MIS scores and lower serum albumin and hemoglobin levels.


Use of the Internet to search for information in type 1 diabetes children and adolescents: a cross-sectional study.
We have studied use of the Internet in search for diabetes-related information in a geographic population of type 1 diabetes children and adolescents. Using a randomised cross-sectional design, 90 out of 110 patients aged 5-20 years responded to a postal questionnaire. Thirty-eight subjects (42%) had searched for diabetes information on the Internet, at a median of 3 occasions, range 1-50. Out of the searching families, 32% had also shown diabetes information from the Internet to others, such as relatives, friends and school staff. Eighty-six percent had found information in Swedish, 32% in English and 68% indicated a need for more information in Swedish. 97% percent anticipated future use. Specific web-sites were suggested by 24%. Searchers as compared to non-searchers had a shorter diabetes duration (p = 0.0255) and more recent extra contacts with their caregivers (p = 0.0018). We conclude that Internet-based information and support may be requested at a high extent by patients, as a complement to regular visits to the diabetes team and other types of traditional care and education. The results suggest a great need for development of systems combining technical and human support, which is discussed. The findings may also have implications for other topics within diabetes education, other ages, and for other diagnosis groups.


Investigating the relationships between chemical element concentrations and discharge to improve our understanding of their transport patterns in rural catchments under subtropical climate conditions.
Solute and particulate elemental concentrations (C) exhibit different responses to changes in discharge (Q), and those relationships are not well understood in subtropical agricultural environments. The objective is to describe the transport processes of different chemical elements during a set of contrasted rainfall events (2011-2015) that occurred in a small rural catchment under subtropical climate. The study was carried out in the Lajeado Ferreira Creek catchment (1.23 km2), southern Brazil. To this end, the concentrations in dissolved organic carbon (DOC), Cl-, NO3-, SO4-, ten chemical elements (in either dissolved or particulate forms) and suspended sediment concentrations (SSC) were determined. Metric indices were then calculated to characterize their transport patterns: (i) the best fit slope between log-C and log-Q (β), (ii) the coefficient of variation of C and Q, (iii) shape of the hysteresis loop and hysteresis index, and (iv) the flushing index. All particulate elements along with the dissolved inorganic phosphorus (PO4-3) were shown to be controlled by the sediment dynamics. Geogenic elements (Fe2+, Zn2+, Cu2+, Mn2+, Si4+) showed a dilution effect with increasing Q values, likely because they were mainly transported with subsurface and base flow. Dissolved elements that are mainly supplied with fertilizers (Na+ and Cl-) as well as DOC showed a dilution effect, although they were mainly transported by surface runoff. Finally, a chemostatic behavior was found for those chemical elements (Mg2+, K+, Ca2+, NO3- and SO42-) that are supplied by more than one flow pathways. The results demonstrate that under subtropical climate conditions, the transport of essential nutrients including PO4-3 and metals (in particulate form), are mainly transported with surface runoff. Accordingly, runoff control on cultivated hillslopes should be improved to reduce the potential contaminant supply to the river and to reduce the potentially deleterious impacts that they may cause in downstream regions.


Effects of acute administration of melatonin on attentional, executive, and working memory processes in rats.
Melatonin is a potential candidate for additive therapy in cancer, neurodegenerative, and mental disorders requiring administration during the activity phase. Nevertheless, because melatonin has mostly been used as a hypnotic, less is known about its cognitive effects. In this study, we investigated the effects of acute administration of melatonin on executive, attentional, and working memory processes in rats during the activity phase. Three doses of melatonin (6, 18, or 36 mg/kg) were tested and compared to a saline control group in two behavioral tests: the Attentional Set Shifting task (for attentional and executive processes assessment) and the Spontaneous Alternation test in a Y-maze (for working memory assessment). Our results revealed that, up to 36 mg/kg, the acute administration dose of melatonin did not alter the attentional or executive processes, nor the working memory in rats. Consequently, this result may be encouraging for the use of melatonin in additive therapy during the activity phase.


Gene expression changes in the MAPK pathway in both Fragile X and Down syndrome human neural progenitor cells.
The two most common genetic developmental disorders that cause intellectual disability are Down syndrome (DS) and Fragile X syndrome (FXS). Although the genetics and behavioral hallmarks of these two disorders are distinct, common underlying defects in neural development may lead to the cognitive impairment characteristic of both. Human neural progenitor cells (hNPCs) enable the study of prenatal human brain development in these developmental disorders. We therefore tested whether there are common affected molecular pathways in FXS and DS hNPCs that may be indicators of the fundamental developmental causes of intellectual disability. Comparison of gene expression data from FXS and DS (disorder group) hNPCs to unaffected hNPCs indicated genes in specific signal transduction cascades are dysregulated. Importantly, altered expression of genes in these signaling pathways did not emerge when the two disorder hNPCs were analyzed separately. Specifically, genes in the mitogen-activated protein kinases (MAPK/ERK) and calcium signaling pathways are mis-expressed in disorder hNPCs. These results suggest that DS and FXS hNPCs do not communicate or respond appropriately to extracellular cues during neural development. These results validate the use of hNPCs as a tool to assess complex cell functions during neural development and suggest that defects in the pathways identified could have profound effects on how neural progenitor cells survive, proliferate and differentiate, thereby leading to intellectual disability.


Multipurpose plant species and circular economy: Corylus avellana L. as a study case.
Corylus avellana L. is one of the most cultivated species in the world. Mainly utilized with the purpose of obtaining food material, hazel trees cannot guarantee constant kernels productions given the threats related to pathogens and to adverse conditions, especially in a globalisation and global changes scenarios. This matter led us to consider the opportunity of using hazel tree in all its parts and for several purposes, due to its multifunctional characteristics. As a pioneer species, it is a precious plant useful for forest restoration purposes and for forest successions/wildlife facilitation. Its roots enter into symbiosis with truffles making this species exploitable for hazelnuts and truffles production. The precious elements contained in what is considered "waste" deriving from hazel crops (i.e., leaves, skins, shells, husks and pruning material), could be reused and valorised in the perspective of a circular economy that is opposed to a linear one. In particular, a list of several phenolic compounds detected in hazelnut shells has been reported in literature to prevent and delay many human diseases due to their antioxidant properties and to free radical scavenging activities, with implications potentially useful even in the fight against COVID-19. All this makes hazel crop by-products interesting to be valorised as a chemical compound source for human health, even more than a biomass fuel or for bio-char applications. The multiple possible uses of the hazel tree would lead to alternative productions than the only nut productions, avoiding significant economic losses, would decrease the cost of disposal of crops residues and would increase the sustainability of agro-ecosystems by reducing, among other things, the production of wastes and of greenhouse gases deriving from the usual burning of residues which often happens directly in fields.


Hyperpolarized 13C-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma.
Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized 13C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized 13C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted "Warburg effect". However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.


Lack of desensitization of muscarinic receptor-mediated second messenger signals in rat brain upon acute and chronic inhibition of acetylcholinesterase.
We studied the effects of acute and chronic in vivo inhibition of acetylcholinesterase on both the density and function of brain muscarinic cholinergic receptors. Adult male rats were treated either once or multiple times over a period of 10 days with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP). The concentration and affinity of muscarinic receptors in various brain regions were determined using radioligand binding techniques. Acute DFP treatment resulted in a significant reduction in receptor number only in the brain stem, while chronic treatment caused receptor down-regulation in the brain stem, cerebral cortex, and striatum. There was no change in ligand affinity in any of the brain regions. In sharp contrast, muscarinic receptor function was fully preserved, in terms of coupling of the receptors to increased phosphoinositide hydrolysis in the cerebral cortex, hippocampus, and striatum, or inhibition of cyclic AMP formation in the cerebral cortex or striatum. Therefore, there is a marked lack or correlation between DFP-induced muscarinic receptor down-regulation and receptor desensitization.


Expression of the respiratory syncytial virus 22K protein on the surface of infected HeLa cells.
Immunofluorescent staining of unfixed respiratory syncytial virus-infected HeLa cells with monoclonal antibodies (MAbs) demonstrated that the 22K protein is expressed on the cell membrane along with the fusion (F) protein and large glycoprotein (G). All three proteins were detected in the cytoplasm at 17 h post-infection and in the case of the F and G proteins this coincided with their appearance on the cell surface. However, the 22K protein could not be detected on the surface until approximately 16 h after its detection in the cytoplasm, when cytopathic effect was extensive. No evidence for the surface expression of the phosphoprotein (P), matrix (M) or nucleocapsid (N) proteins was found. Trypsin treatment of infected cells prior to unfixed immunofluorescent staining and Western blot analysis indicated that, unlike the G protein, the quantity of 22K protein detected on the cell surface constituted only a small proportion of the total present in the cell. A comparison of the patterns of immunofluorescent staining produced by MAbs on acetone-fixed infected cells suggested that the N, P and 22K proteins, but not the M protein, may be associated with the same intracellular structures.


Elevated blood flow velocity in the anterior cerebral artery and stroke risk in sickle cell disease: extended analysis from the STOP trial.
Elevated velocity in the internal carotid artery (ICA) or middle cerebral artery (MCA), detected by transcranial Doppler (TCD) ultrasonography, predicts an increased risk of stroke in children with sickle cell disease (SCD). Although strokes also occur in an anterior cerebral artery (ACA) distribution, the significance of elevated velocity in this vessel has not been determined previously. We assessed the effect of elevated ACA velocity on stroke risk using the results of the first adequate TCD study performed on 1975 children as part of The Stroke Prevention Trial in Sickle Cell Anemia (STOP). Elevated ACA velocity (> or =170 cm/s) was associated with an increased risk of stroke (P = 0.0013) after adjusting for the ICA/MCA classification. Among subjects with normal ICA/MCA velocity, the risk of stroke was more than 10-fold greater in those with elevated compared with normal ACA velocity (2.13 and 0.20 per 100 patient-years, respectively, P < 0.001); risk more than doubled with elevated compared with normal ACA velocity in those already at high risk due to abnormal ICA/MCA findings (7.56 vs. 3.22 per 100 patient-years, P = 0.042). Few of the strokes in those with elevated ACA velocity occurred in an ACA distribution, suggesting changes in blood flow velocity in anterior vessels may be associated with diffuse arterial disease or, alternatively, manifest collateral flow from compromised middle cerebral vessels.


Cellular mechanisms of hyperalgesia and spontaneous pain in a spinalized rat model of peripheral neuropathy: changes in myelinated afferent inputs implicated.
Various hypotheses have been proposed to account for the mechanical hyperalgesia and spontaneous pain seen in animal models of peripheral neuropathy. The purpose of the present study was to determine whether there exists a spinal neuronal correlate to these properties. An experimental neuropathy was induced in male Sprague-Dawley rats by placing a 2-mm PE-90 polyethylene cuff around the sciatic nerve. All rats were subsequently confirmed to exhibit mechanical allodynia in the von Frey test. After induction of anaesthesia with pentobarbital and acute spinalization at T9, electrophysiological experiments were performed, recording extracellular single unit activity from ipsi- and contralateral wide dynamic range dorsal horn neurons in spinal segments L1-4. On-going activity was greater in short-term (11-22 days after cuff implantation) and long-term (42-52 days) cuff-implanted rats; 38 spikes/s in short-term versus 19 spikes/s in controls; 29 spikes/s in long-term ipsi- and contralateral neurons. Receptive fields in controls were always restricted, but in almost all cuff-implanted rats extended over the whole hind paw. Responses to noxious mechanical (pinch) and noxious heat stimulation of the cutaneous receptive field in controls consisted of the typical fast initial discharge followed by an afterdischarge. In all neurons from cuff-implanted rats the initial discharge resembled that in controls. However, the afterdischarge, particularly that in response to noxious pinch, was markedly greater in both magnitude and duration. It is suggested that the greater on-going discharge is the cellular correlate of spontaneous pain, and the potentiation of the afterdischarge in response to noxious stimulation is the correlate of hyperalgesia. Given that acutely spinalized rats were tested, only peripheral and/or spinal mechanisms can be considered to explain these data. Considering all the data, it can be concluded that there is a greater change in fibres mediating noxious mechanical than noxious thermal inputs. Among different hypotheses, the one with which the present data are most compatible is that which proposes that chronic nerve injury or inflammation induces phenotypic changes predominantly in myelinated afferents. There may be a redistribution of membrane-bound ion channels, predominantly sodium channels, which leads to ectopic activity and thus spontaneous discharge of dorsal horn neurons. With regard to mechanical stimulation-evoked synaptic input, the central terminals of myelinated afferents expand into regions of the spinal cord which normally receive their predominant input from unmyelinated nociceptive afferents. This may be coupled with a change in these myelinated afferents so that they now synthesize and release peptides, primarily substance P, from their central terminals with the result that the effects of their chemical mediators of synaptic transmission add to the effects of nociceptive inputs leading to exaggerated responses to painful stimuli, thus the basis of clinical hyperalgesia.


Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): A cluster randomized trial of a computerized clinical decision support tool.
Clinical decision support (CDS) tools designed to digest, filter, organize, and present health data are becoming essential in providing clinical and cost-effective care. Many are not rigorously evaluated for benefit before implementation. We assessed whether computerized CDS for primary care providers would improve atrial fibrillation (AF) management and outcomes as compared to usual care. Overall, 203 primary care providers were recruited, randomized, and then cluster stratified by location (urban, rural) to usual care (n = 99) or CDS (n = 104). Providers recruited 1,145 adult patients with AF to participate. The intervention was access to an evidenced-based, point-of-care computerized CDS designed to support guideline-based AF management. The primary efficacy outcome was a composite of unplanned cardiovascular hospitalizations and AF-related emergency department visits; the primary safety outcome was major bleeding, both over 1 year. Patients were the units of intention-to-treat analysis. No significant effects on the primary efficacy (130 control, 118 CDS, hazard ratio: 0.98 [95% CI 0.71-1.37], P = .926) or safety (n = 7 usual care, n = 8 CDS, 1.3% total, P = .939) outcomes were observed at 12-months. IMPACT-AF rigorously assessed a CDS tool in a highly representative sample of primary care providers and their patients; however, no impact on outcomes was observed. Considering the proliferating use of CDS applications, this study highlights the need for efficacy assessments prior to adoption and clinical implementation.


Deformable gas-filled microbubbles targeted to P-selectin.
Ultrasound contrast microbubbles have been successfully targeted to a number of intravascular disease markers. We hypothesized that targeted delivery could be improved further, by making the microbubbles deformable, leading to increased microbubble-endothelium adhesion contact area and stabilized adhesion. Activated leukocytes utilize such strategy; they deform after binding to inflamed endothelium in the vasculature. Lipid-shell microbubbles were targeted to the endothelial inflammatory protein P-selectin with a monoclonal anti-P-selectin antibody attached to the microbubble shell. Deformable microbubbles were created by controlled pressurization with partial gas loss, which generated an average excess shell surface area of approximately 30% and the formation of outward-projected wrinkles and folds. Targeted microbubble adhesion and deformability were assessed in the parallel plate flow chamber under shear flow. Sustained adhesion of deformable microbubbles at wall shear stresses between 0.4 and 1.35 dyn/cm(2) was consistently better than adhesion of wrinkle-free microbubbles. Over this shear range, targeted wrinkled microbubbles were deformed by shear flow, unlike wrinkle-free microbubbles. In a murine cremaster inflammation model, a significant improvement of deformable microbubble targeting was observed by intravital microscopy. Overall, the mechanical aspects of adhesion, such as particle shape, deformability and surface microstructure, are important in engineering efficient site-targeted particle-based agents for medical imaging and therapy.


Indium (zinc)-copper-mediated Barbier-type alkylation reaction of nitrones in water: synthesis of amines and hydroxylamines.
An efficient method for the Barbier-type alkylation reaction of various nitrones (including chiral version) and alkyl halides in water is described. The amines and hydroxylamines can be obtained in good yields, depending on the judicious choice of the metal complexes used.


Urinary oestradiol and testosterone levels from novel male mice approach values sufficient to disrupt early pregnancy in nearby inseminated females.
Previous research has established that exposure to novel male mice can disrupt intrauterine implantation of fertilised ova in inseminated females and that much of this effect is mediated by factors in the male urine. The present studies were designed to examine whether the steroid content of male urine is sufficient to account for this effect. Pregnancy was terminated by exogenous 17beta-oestradiol administered intranasally on days 2-4 after insemination in doses as low as 0.14 microg/day. Enzyme immunoassay indicated that male mouse urine reliably contains unconjugated 17beta-oestradiol and testosterone. A small but significant increase in the amount of urinary oestradiol was observed in males housed nearby previously inseminated females as opposed to those housed in isolation. This influence was absent in the sire and absent in novel males when the sire was also present. The quantity of active steroids in novel male urine approaches the level sufficient to account for the disruption of implantation in nearby inseminated females.


Surgical outcome of patients with vesicoureteral reflux from a single institution in reference to the ESPU guidelines: a retrospective analysis.
Vesicoureteral reflux (VUR) is an anatomic or functional disorder, and it is a condition associated with renal scarring, hypertension, and end-stage renal disease. Renal damage can be prevented by appropriate medical and surgical intervention for selected patients. The objective of this study was to retrospectively analyze the surgically treated patient group of this study in reference to the risk analysis criteria used in European Association of Urology (EAU), European Society for Paediatric Urology (ESPU) guidelines to see the outcome of the study management protocol within the last 15 years in respect to this risk analysis. A total of 686 patients who were operated upon in a single institution for VUR between 1997 and 2016 were retrospectively analyzed. According to the criteria in EAU/ESPU guidelines, the patients were classified into three groups: low, medium, and high risk. Risk factors were compared between the groups. The patient numbers for low, medium, and high risk were 92 (13.4%), 485 (70.7%), and 109 (15.9%), respectively. In the high-risk group, surgeons tended to do more ureteroneocystostomy (UNC) (82.6%), whereas in the low-risk group, surgeons tended to do more subureteric injection (STING) (76.1%). The success rates for STING and UNC were found to be 75% and 93%, respectively. Although there was a difference in success rates among patients treated with STING or UNC, this difference was not statistically significant in success rates regarding risk groups for patients treated with STING or UNC. The most recent guideline was that which was published by the EAU/ESPU organization in 2012. This guideline is established based on the risk analysis. The analysis revealed that patients in the low-risk group tended to undergo endoscopic surgery treatment method, whereas patients in the high-risk group tended to undergo open surgery. Therefore, the study management over the last 10 years has been mainly in line with the current recommendations. The analysis shows that when the patients are classified according to the EAU/ESPU risk classification, surgeons tended to perform more endoscopic and more open surgery for the low- and high-risk groups, respectively. Although each surgical modality had similar success rates in each group, open surgical results were overall much higher than those of endoscopic surgery in each group. This was a specifically important finding in high-risk group where the endoscopically treated group of patients was small in number, and the need for a definitive correction is essential in this group because of increased risk of renal injury.


Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study.
A prospective study of a series of 77 patients on adjuvant radiochemotherapy following surgery for high-grade gliomas was conducted to evaluate the risk of deep vein thrombosis and identify risk factors. We found a 20.8% risk of deep vein thrombosis at 12 months (standard error = 4.8%) and a 31.7% risk (standard error = 7.4%) at 24 months (Kaplan-Meier method). Twenty patients (26%) developed deep vein thrombosis with a maximum incidence within the first 7 months after surgery when chemotherapy was still being administered, often with corticosteroids. The risk factors identified were histology (glioblastoma versus anaplastic astrocytoma, P = 0.032, log rank test; 0.0485 L-ratio) and the presence of paresis (P = 0.010, log rank test; 0.0161 L-ratio). A borderline tendency was found for an association between the deep vein thrombosis site and the side of paresis (P = 0.103, Fisher's exact test). Four patients (5%) had massive pulmonary embolism, which was fatal in 3 (4%).


A Survey of the Course: 'How to Successfully Write a Scientific Article'.
The aim of the present survey was to analyze the knowledge and skills in medical paper writing of physicians who attended the course "how to write successfully a scientific paper." A blind survey was used to analyze participants' knowledge on the topic of the course "how to write successfully a scientific paper." Before starting the workshop, participants anonymously filled out the input questionnaire containing 12 preliminary data questions. The three-hour course included a lecture on the steps of creating and writing a scientific article with examples. At the end, all participants anonymously completed the exit questionnaire consisting of 18 questions. Differences and associations between the collected data were analyzed using appropriate statistical tests. The survey included 22 participants, most of whom were women (16, 72.7%). The participants' educational level was proportional to their age. 12 of the participants had an intermediate level, while the others reported higher English proficiency. Half of the participants had never published an article. A significant difference was observed between English level and being the first author of an article published in a scientific journal (p = 0.044). Before class, only 13.6% of participants knew that guidelines are mandatory for making clinical decisions according to evidence- based medicine. There was a significant positive correlation between sex and current affiliation (p = 0.038). A negative correlation was observed between sex and article publication (p = 0.037). A positive correlation was observed between English level and current affiliation (p = 0.020). There was a negative correlation observed between previous sources of learning scientific article writing and having already published an article (p = 0.025). A positive correlation was found between reading an article and publishing it (p = 0.046). Statistical analysis showed a significant difference between reading frequency, number of published articles, being the first author, and knowing the title of a scientific article (p = 0.036, p = 0.027, and p = 0.030, respectively). The results of the questionnaires revealed discrepancies in prior research engagement and understanding of scientific concepts and rules. This survey highlights the importance of the course "how to successfully write a scientific article" in improving participants' knowledge of scientific work and the process of creating an article for submission to medical journals.


Dynamic phosphorus-31 magnetic resonance spectroscopy in arterial occlusive disease. Correlation with clinical and angiographic findings and comparison with healthy volunteers.
The aim of this prospective study was to explore muscular metabolism in arterial occlusive disease (AOD) by dynamic phosphorus-31 (31P) magnetic resonance spectroscopy (MRS). The authors examined 56 patients with AOD. Acquisition of up to 60 consecutive phosphorus spectra of the quadriceps muscle was done by "time series" in 36 seconds each. In this way, the authors achieved uninterrupted monitoring of muscle metabolism during rest, exhaustion, and recovery. During 31P MRS, the volunteers performed an isometric and an isotonic exercise until exhaustion of the quadriceps muscle. Spectroscopic results of 56 patients with AOD were correlated with clinical and angiographic findings and were compared with spectroscopic results of 10 age-matched healthy volunteers. There were no significantly differing spectroscopic results between patients and volunteers at rest, except for an elevated ratio phosphomonoester (PME)/beta-adenosine triphosphate (ATP) in patients with AOD (0.66 +/- 0.19 versus 0.48 +/- 0.09). Despite a sixfold duration of both of the exercises until exhaustion in healthy volunteers, exercise-induced changes of inorganic phosphate (P1)/phosphocreatine (PCr), PME/beta-ATP, and pH were similar in healthy volunteers and patients with AOD. Compared with maximal exercise-induced values of Pi/PCr, acidosis was relatively increased in AOD, resulting in a steeper slope of linear regression line (-0.33 +/- 0.06 versus -0.14 +/- 0.06) between these parameters. Recovery rate of Pi/PCr was markedly prolonged in AOD (time of half recovery: 80 seconds versus 25 seconds [isometric exercise] and 70 seconds versus 37 seconds [isotonic exercise]), whereas recovery rate of pH was not significantly slowed down in our patients (192 seconds versus 166 seconds [isometric exercise] and 234 seconds versus 220 seconds [isotonic exercise]). Dynamic 31P MRS provides a direct judgment of muscular metabolism, which is not only influenced by macro-, but also by microangiopathia. Results of 31P MRS suggest a reduced mitochondrial oxidative phosphorylation in AOD.


Lessons learnt from a series of hemodynamic and interventional complications during pulmonary valvotomy and device closure of ventricular septal defect.
In an adolescent girl with coexistent valvar pulmonary stenosis (PS) and muscular ventricular septal defect (VSD) causing right to left shunt and severe cyanosis, a series of complications were encountered during transcatheter intervention. After balloon pulmonary valvotomy (BPV) and device closure of the VSD, dynamic infundibular hypercontractility elevated the right ventricular (RV) systolic pressures leading to embolization of the device into the left ventricle. During retrieval of the device from the left ventricular outflow tract (LVOT), there was injury to the atrioventricular nodal tissue resulting in transient complete heart block. Even though the device was successfully retrieved out from the right femoral arterial access, there was a retroperitoneal hematoma causing severe anemia. A combination of dynamic infundibular obstruction, intravascular volume depletion caused by hemorrhage, low oxygen carrying capacity due to anemia, and inotropes resulted in a life-threatening hypercyanotic spell. Once this combination of suicidal hypercontractile right ventricle, anemia, and dehydration was recognized; management of the pathophysiology resulted in recovery of the patient. On a subsequent day, device closure of the VSD was complicated by unstable device position, but was finally achieved by an innovative device stabilization technique. We propose to explain the basis of hemodynamic and procedural complications, their recognition, and management. During preparatory stage before interventions in patients with multiple defects, which are linked by strong hemodynamic interdependence, meticulous planning should be done and multiple untoward events should be foreseen. While a few complications were completely unanticipated, some others could have been predicted.


Wind in November, Q fever in December.
Q fever, a worldwide zoonosis caused by Coxiella burnetii, can be transmitted from animal reservoirs to humans by the inhalation of infected aerosols. We investigated the epidemiology of Q fever in the Bouches-du-Rhone district of southern France, particularly the role of wind and rainfall in C. burnetii transmission. During the winter of 1998 to 1999, an unexpected number of cases were diagnosed in the area. This statistically higher incidence was associated with an increased frequency of the mistral 1 month before onset of disease, i.e., shortly after the main lambing season. These data confirm that wind plays a role in C. burnetii transmission, a factor that can be monitored but not prevented. Further studies are needed to identify and confirm preventable individual behavioral risk factors for Q fever.


Pediatric Gastrostomy Tube Placement: Lessons Learned from High-performing Institutions through Structured Interviews.
Gastrostomy tube (GT) placement is one of the most common operations performed in children, and it is plagued by high complication rates. Previous studies have shown variation in readmission and emergency room visit rates across different children's hospitals, with both low and high outliers. There is an opportunity to learn how to optimize outcomes by identifying practices at high-performing institutions. Surgeons and nurses routinely involved in GT care at 8 high-performing pediatric centers were identified. We conducted structured interviews focusing on the approach to GT education, technical aspects of GT placement, and postoperative management. Summary statistics were performed on quantitative data, and the open-ended responses were analyzed by 2 independent reviewers using content analysis. Several common practices among high-performing centers were identified (standardized approach to education, availability by phone and in clinic to manage GT-related issues, and empowering families to feel confident with troubleshooting and dealing with GT problems). There was substantial variation in operative technique and postoperative care. The participants expressed that technical aspects of operative placement and postoperative management of feedings and common complications are not as important as education, availability, and empowerment in optimizing outcomes. We have identified common themes among pediatric centers with favorable outcomes after GT placement. Identifying which components of GT care are associated with optimal outcomes is critical to our understanding of current practice and may help identify opportunities to improve care quality.


The Gram-negative permeability barrier: tipping the balance of the in and the out.
Gram-negative bacteria are intrinsically resistant to many antibiotics, due in large part to the permeability barrier formed by their cell envelope. The complex and synergistic interplay of the two Gram-negative membranes and active efflux prevents the accumulation of a diverse range of compounds that are effective against Gram-positive bacteria. A lack of detailed information on how components of the cell envelope contribute to this has been identified as a key barrier to the rational development of new antibiotics with efficacy against Gram-negative species. This review describes the current understanding of the role of the different components of the Gram-negative cell envelope in preventing compound accumulation and the state of efforts to describe properties that allow compounds to overcome this barrier and apply them to the development of new broad-spectrum antibiotics.


Transcriptional activation of the membrane-bound progesterone receptor (mPR) by dioxin, in endocrine-responsive tissues.
We originally identified the membrane-bound progesterone receptor (mPR) using a screening for genes differentially expressed in liver of rats exposed to dioxin. Recent findings have suggested a role for the mPR in sperm cells, ovary, and brain; however, its mechanisms of action are largely unknown. In this study, we examined the expression pattern of the mPR in liver of rats exposed to dioxin and identified possible mechanisms of its regulation. We observed that mPR expression was induced by dioxin, but was also dependent on the hormonal responsiveness of the tissue. In particular, in male, but not female liver, dioxin induced the expression of the mPR. However, in control, untreated female liver the level of mPR transcript was higher than in control males. Moreover, in breast cancer cells MCF-7 dioxin induced mPR expression. Promoter studies using the luciferase assay indicated that a fragment of approximately 350 bp of the mPR promoter was able to induce luciferase activity in the presence of dioxin, suggesting that the presumptive XREs sites contained in this mPR promoter region are responsive to dioxin. Analysis of mPR protein level confirmed the results observed at the RNA level, both in rat liver and MCF-7 cells. Taken together, these observations suggest the existence of a novel cross-talk between steroid and aromatic hydrocarbon receptors (AhR), and underline the importance of the mPR as a mediator of physiologic effects of the sex hormones.


Low 5-HT1B receptor binding in the migraine brain: A PET study.
Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT1B receptor is considered a key player due to the efficacy of 5-HT1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT1B receptor binding in interictal migraine patients without aura compared to controls. Methods Eighteen migraine patients, who had been migraine free for >48 hours, and 16 controls were scanned after injection of the 5-HT1B receptor specific radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1B receptor binding. Patients who reported migraine <48 hours after the PET examination were excluded from the final analysis. We defined seven brain regions involved in pain modulation as regions of interest and applied a latent variable model (LVM) to assess the group effect on binding across these regions. Results Our data support a model wherein group status predicts the latent variable ( p = 0.038), with migraine patients having lower 5-HT1B receptor binding across regions compared to controls. Further, in a whole-brain voxel-based analysis, time since last migraine attack correlated positively with 5-HT1B receptor binding in the dorsal raphe and in the midbrain. Conclusion We report here for the first time that migraine patients have low 5-HT1B receptor binding in pain modulating regions, reflecting decreased receptor density. This is either a primary constitutive trait of the migraine brain or secondary to repeated exposure to migraine attacks. We also provide indirect support for the dorsal raphe 5-HT1B receptors being temporarily downregulated during the migraine attack, presumably in response to higher cerebral serotonin levels in the ictal phase.


[Daily rhythms of cortisol and serotonin concentrations in children with chronic viral hepatitis].
The daily rhythms of cortisol (C) and serotonin (S) concentrations were investigated in saliva of children with chronic viral hepatitis HBV and HCV. The changes in chronostructure of C and S rhythms were revealed to depend on the viral type and an intensity of the liver inflammatory process. The circadian rhythms of C and S were found to be desynchronized which was manifested as quantitative (period) and qualitative (mesor value, amplitude of oscillations, daily acro- and miniphase) changes in the rhythm. The daily rhythm of S in children with an active and inactive HBV, as well as in those with an active HCV had the circadian character with a high mesor and an amplitude of oscillations, as compared to the control group. The transformation of the S rhythm was similar to the inactive HCV. Shifts in daily acrophase of the S rhythm were established for each clinic group. Daily C rhythm was not determined in the active HBV and HCV, either. The circadian C rhythm with daily acrophase was revealed for inactive HBV; the tendency to circadian rhythm of such type was marked for inactive HCV. The mesor of the above-mentioned groups didn't differ from the control.


Inverse planning for IMRT with nonuniform beam profiles using total-variation regularization (TVR).
Radiation therapy with high dose rate and flattening filter-free (FFF) beams has the potential advantage of greatly reduced treatment time and out-of-field dose. Current inverse planning algorithms are, however, not customized for beams with nonuniform incident profiles and the resultant IMRT plans are often inefficient in delivery. The authors propose a total-variation regularization (TVR)-based formalism by taking the inherent shapes of incident beam profiles into account. A novel TVR-based inverse planning formalism is established for IMRT with nonuniform beam profiles. The authors introduce a TVR term into the objective function, which encourages piecewise constant fluence in the nonuniform FFF fluence domain. The proposed algorithm is applied to lung and prostate and head and neck cases and its performance is evaluated by comparing the resulting plans to those obtained using a conventional beamlet-based optimization (BBO). For the prostate case, the authors' algorithm produces acceptable dose distributions with only 21 segments, while the conventional BBO requires 114 segments. For the lung case and the head and neck case, the proposed method generates similar coverage of target volume and sparing of the organs-at-risk as compared to BBO, but with a markedly reduced segment number. TVR-based optimization in nonflat beam domain provides an effective way to maximally leverage the technical capacity of radiation therapy with FFF fields. The technique can generate effective IMRT plans with improved dose delivery efficiency without significant deterioration of the dose distribution.


Pseudomonas aeruginosa pyocyanin and 1-hydroxyphenazine inhibit fungal growth.
To examine strains of Pseudomonas aeruginosa for specific antifungal factors. Two clinical strains of P aeruginosa with strong in vitro inhibition (by cross streak assay) of Candida albicans and Aspergillus fumigatus were examined. Both strains were isolated from sputum--one from a patient with cystic fibrosis and one from a patient with bronchiectasis. Bacterial extracts were fractionated by high performance liquid chromatography and examined by ultraviolet absorbance and mass spectroscopy. Antifungal activity against C albicans and A fumigatus was determined in a well plate assay. Pyocyanin was the major antifungal agent of P aeruginosa; 1-hydroxy-phenazine also possessed activity. Pyocyanin MICs for C albicans and A fumigatus were > 64 micrograms/ml. These phenazines were active against nine other yeast species pathogenic for man. Preliminary experiments also suggested possible inhibition of yeast mycelial transformation in C albicans by pyocyanin. There may be a role for pyocyanin and 1-hydroxyphenazine in the prevention of pulmonary candidiasis in patients colonised by P aeruginosa.