A comparison of antiarrhythmic drugs for the suppression of ventricular ectopic depolarizations: a meta-analysis.
This article reports the results of a meta-analysis of the effectiveness of antiarrhythmic drugs for the suppression of ventricular ectopic depolarizations. We analyzed 97 published articles that referred to a total of 27 drugs and contained data from 2989 patient-treatment trials; our goal was to determine the number of patients responding to therapy, defined as greater than or equal to 80% suppression of ventricular ectopic depolarizations. By means of logistic regression we tested the effect of 10 clinical and experimental variables on the likelihood of response to therapy. The likelihood of a drug response was significantly affected by the following six variables: increased by the use of dose titration (t = 3.59, p less than 0.0001), increased by the use of a higher daily dose (t = 3.21, p less than 0.0001), decreased by older age (t-2.67, p = 0.004), decreased by the use of blinding (t = -2.28, p = 0.011), increased by treating more male patients (t = 1.72, p = 0.043), and decreased by the presence of cardiovascular disease (t = -1.52, p = 0.064). Incorporating these six variables into our logistic regression model, we adjusted the response rate in each published study and calculated the mean response and standard error for each drug. Of the drugs tested in at least 100 patients, the most effective were amiodarone (estimated response rate 90%), encainide (80%), flecainide (79%), and propafenone (74%). Class IC drugs were significantly more effective than class IB and II drugs (p less than 0.05). With the exception of lorcainide and moricizine, class IC drugs were also more effective than class IA drugs (p less than 0.05). Amiodarone was significantly more effective than all drugs except encainide and flecainide (p less than 0.05). We found no significant differences among the response rates to class IA, IB, and II drugs. Whereas several patient and study characteristics affect the likelihood of response to antiarrhythmic drugs, class IC drugs and amiodarone are significantly more effective than other drugs in suppressing ventricular ectopic depolarizations.


A New Experimental Model for Neuronal and Glial Differentiation Using Stem Cells Derived from Human Exfoliated Deciduous Teeth.
Stem cells isolated from human adult tissues represent a promising source for neural differentiation studies in vitro. We have isolated and characterized stem cells from human exfoliated deciduous teeth (SHEDs). These originate from the neural crest and therefore particularly suitable for induction of neural differentiation. We here established a novel three-stage protocol for neural differentiation of SHEDs cells. After adaptation to a serum-free and neurogenic environment, SHEDs were induced to differentiate. This resulted in the formation of stellate or bipolar round-shaped neuron-like cells with subpopulations expressing markers of sensory neurons (Brn3a, peripherin) and glia (myelin basic protein). Commercial PCR array analyses addressed the expression profiles of genes related to neurogenesis and cAMP/calcium signalling. We found distinct evidence for the upregulation of genes regulating the specification of sensory (MAF), sympathetic (midkine, pleitrophin) and dopaminergic (tyrosine hydroxylase, Nurr1) neurons and the differentiation and support of myelinating and non-myelinating Schwann cells (Krox24, Krox20, apolipoprotein E). Moreover, for genes controlling major developmental signalling pathways, there was upregulation of BMP (TGF β-3, BMP2) and Notch (Notch 2, DLL1, HES1, HEY1, HEY2) in the differentiating SHEDs. SHEDs treated according to our new differentiation protocol gave rise to mixed neuronal/glial cell cultures, which opens new possibilities for in vitro studies of neuronal and glial specification and broadens the potential for the employment of such cells in experimental models and future treatment strategies.


Cost functions and model combination for VaR-based asset allocation using neural networks.
We introduce an asset-allocation framework based on the active control of the value-at-risk of the portfolio. Within this framework, we compare two paradigms for making the allocation using neural networks. The first one uses the network to make a forecast of asset behavior, in conjunction with a traditional mean-variance allocator for constructing the portfolio. The second paradigm uses the network to directly make the portfolio allocation decisions. We consider a method for performing soft input variable selection, and show its considerable utility. We use model combination (committee) methods to systematize the choice of hyperparameters during training. We show that committees using both paradigms are significantly outperforming the benchmark market performance.


Poor mental health, depression, and associations with alcohol consumption, harm, and abuse in a national sample of young adults in college.
The purpose of this article was to describe patterns of poor mental health/depression (PMHD) in a national sample of college students and the relationships among PMHD, alcohol consumption, harm, and abuse. Responses to mailed questionnaires completed by a random sample of 27,409 students at 119 colleges were analyzed using logistic regression. Nationally, 4.8% of students reported PMHD. The average college prevalence was 5.01% (range, 0.68% to 13.23%). Students with PMHD were more likely than their peers to be female, nonwhite, and from low socioeconomic status families; less likely to report never drinking; as likely to report frequent, heavy, and heavy episodic drinking; and more likely to report drinking to get drunk. Students with PMHD-especially females-were more likely to report drinking-related harms and alcohol abuse. College is a critical context for studying youth mental health. The interrelationship of mental health problems and their clustering by group and college are important considerations for prevention and treatment.


Expression and regulation of voltage-gated sodium channel beta1 subunit protein in human gliosis-associated pathologies.
Auxiliary beta1 subunits of voltage-gated sodium channels (NaChs) critically regulate channel activity and may also act as cell adhesion molecules (CAMs). In a recent study we have shown that the expression of beta1 NaCh protein is increased in reactive astrocytes in a rat epilepsy model of mesial temporal lobe epilepsy. The present study was undertaken to examine whether changes of NaCh beta1 subunit protein expression are also associated with structural changes occurring in human reactive astrocytes under different pathological conditions in vivo, as well as in response to changing environmental conditions in vitro. Strong beta1 astroglial immunoreactivity was present in human brain tissue from patients with astrogliosis. The over-expression of beta1 protein in reactive glia was observed in both epilepsy-associated brain pathologies (temporal lobe epilepsy, cortical dysplasia), as well as non-epileptic (cerebral infarction, multiple sclerosis, amyotrophic lateral sclerosis, meningo-encephalitis) disorders. The up-regulation of beta1 subunit protein in astrocytes can be reproduced in vitro. beta1 protein is highly expressed in human astrocytes cultured in the presence of trophic factors, under conditions in which they show morphology similar to the morphology of cells undergoing reactive gliosis. The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway. These findings demonstrate that the expression of NaCh beta1 subunit protein in astrocytes is plastic, and indicate a novel mechanism for modulation of glial function in gliosis-associated pathologies.


Metabolic engineering of the astaxanthin-biosynthetic pathway of Xanthophyllomyces dendrorhous.
This review describes the different approaches that have been used to manipulate and improve carotenoid production in Xanthophyllomyces dendrorhous. The red yeast X. dendrorhous (formerly known as Phaffia rhodozyma) is one of the microbiological production systems for natural astaxanthin. Astaxanthin is applied in food and feed industry and can be used as a nutraceutical because of its strong antioxidant properties. However, the production levels of astaxanthin in wild-type isolates are rather low. To increase the astaxanthin content in X. dendrorhous, cultivation protocols have been optimized and astaxanthin-hyperproducing mutants have been obtained by screening of classically mutagenized X. dendrorhous strains. The knowledge about the regulation of carotenogenesis in X. dendrorhous is still limited in comparison to that in other carotenogenic fungi. The X. dendrorhous carotenogenic genes have been cloned and a X. dendrorhous transformation system has been developed. These tools allowed the directed genetic modification of the astaxanthin pathway in X. dendrorhous. The crtYB gene, encoding the bifunctional enzyme phytoene synthase/lycopene cyclase, was inactivated by insertion of a vector by single and double cross-over events, indicating that it is possible to generate specific carotenoid-biosynthetic mutants. Additionally, overexpression of crtYB resulted in the accumulation of beta-carotene and echinone, which indicates that the oxygenation reactions are rate-limiting in these recombinant strains. Furthermore, overexpression of the phytoene desaturase-encoding gene (crtI) showed an increase in monocyclic carotenoids such as torulene and HDCO (3-hydroxy-3',4'-didehydro-beta,-psi-carotene-4-one) and a decrease in bicyclic carotenoids such as echinone, beta-carotene and astaxanthin.


[Clinical curative effect of Shenxiong Bushen Capsule and its effect on the quality of life of patients with Vascular dementia].
To observe clinical curative effect of Shenxiong Bushen Capsule for the treatment of mild vascular dementia (VaD), and probe the partial mechanism. With a block random, double-blinded and controled clinical research method adopted, seventy patients with VaD were randomly assigned to two groups in a ratio of 5:2, including 50 cases in the trial group and 20 cases in the control group. The patients in the trial group were given the Shenxiong Bushen Capsule (5 tablets, thrice a day), while those in the control group were given Piracetam (5 tablets, twice a day). All patients of the two groups were treated for 2 months, and one third cases were follow-up surveyed for 1 month. The cognitive ability, the activities of daily living, Chinese medicine syndrome of VaD, and the quality of life were measured respectively before and after the treatment. According to the Mini-Mental State Examination, the clinical effects of patients showed that there was insignificant difference between the trial group (total effective rate was 74.46% and 80.85%, respectively) and the control group (total effective rate was 68.42% and 78.95%, respectively) on the cognitive ability and the activities of daily living (P > 0.05), while the curative effect of the trial group (total effective rate was 85.11%) was superior to that of the control group (total effective rate was 63.16%) on Chinese medicine syndrome of VaD, and had significant difference between the two groups (P < 0.05). The results measured by WHOQOL-SF36 indicated that the total scores and the scores of each field in both the trial group and the control group after treatment increased more than those of before treatment (P < 0.01, P < 0.05), except physical function (PF) field and role physical (RP) field of the control group (P > 0.05). The scores of the trial group about total body, PF field, RP field and vitality (VT) field increased more than those of the control group (P < 0.05); while no difference was shown between the trial group and control group in the scores of bodily pain field, role emotional field, general health field, social function field and mental health field (P > 0.05). Shenxiong Bushen Capsule has a definite curative effect on mild VaD, and it can improve the quality of life of patients. Adopting the SF36 Scale to evalute the quality of life of patients with VaD has significance and avaibility to some extent.


Potentially serious Lamotrigine-related skin rash.
To report our experience with lamotrigine (LTG)-related skin rash in children with epilepsy. We identified a series of consecutive children with epilepsy treated with LTG prospectively over a 5-year period ending 1st October 2005 at King Abdul-Aziz University Hospital and King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia. Of 207 children on LTG, 15 (7.2%) developed a skin rash with ages ranging between 3-12 years (mean 7.5). We used LTG as monotherapy in 3/15 and as add on in 12/15, mostly (10/15) in addition to valproic acid (VPA). The rash was mild with complete recovery in 7 children (47%). The remaining 8 (3.9% of the total) had severe rash that necessitated admission to hospital. Seven out of these 8 children were also receiving VPA. One child had superimposed secondary bacterial infection and admitted for intravenous antibiotics. Two children recovered slowly with extensive post-inflammatory hyperpigmentation. We diagnosed Stevens-Johnson syndrome in 5 children (2.4% of the total). One of these 5 children had progressive symptoms that evolved to toxic epidermal necrolysis. He required prolonged intensive care admission and developed sepsis with disseminated intravascular coagulopathy. He deteriorated despite supportive therapy, and died 5 weeks after the initiation of LTG therapy. Lamotrigine is a novel antiepileptic drug with a favorable therapeutic profile and good tolerability. However, LTG-related skin rash is a potentially serious adverse event that should be carefully monitored. Although the risk is small, one should weigh this against the potential benefits, particularly in children on VPA.


Dietary Quantity and Diversity among Anemic Pregnant Women in Madura Island, Indonesia.
Dietary diversity and quantity are important for pregnant women, particularly anemic pregnant women. This study aimed to analyze the association between dietary quantity and diversity among anemic pregnant women. This cross-sectional study was conducted in 2017 at Madura Island, Indonesia, and involved 152 anemic pregnant women. Hemoglobin concentration was analyzed by the cyanmethemoglobin method. Dietary quantity was measured by the 2 × 24 h recall. Dietary diversity was determined by Minimum Dietary Diversity for Women of Reproductive Age (MDD-W). Spearman's rank association was performed to analyze the association between dietary diversity and quantity. The median of hemoglobin concentration was 10.1 g/dL, and 57.2% pregnant women had mild anemia. Most of the pregnant women had low adequacy levels of energy and macro- and micronutrients (except for iron). More than half (57.9%) of anemic pregnant women had reached minimum dietary diversity. Family size (p=0.048) and gestational age (p=0.004) had negative associations with dietary diversity. Dietary diversity had positive associations with energy (p=0.029), protein (p=0.003), vitamin A (p=0.001), vitamin C (p=0.004), and zinc (p=0.015) adequacy levels. Dietary diversity had no significant association with calcium (p=0.078) and iron adequacy level (p=0.206). High prevalence of mild and moderate anemia was found among pregnant women in their third trimester. Anemic pregnant women already consumed food with minimum dietary diversity but did not meet dietary quantity. Increasing dietary quantity is a priority for anemic pregnant women.


Alloying and oxidation of in situ produced core-shell Al@Yb nanoalloy particles--an "on-the-fly" study.
Core-shell-structured nanoalloy particles with an Al-dominated interior covered by few Yb monolayers have been fabricated using a vapor-aggregation method involving magnetron sputtering. The radially segregated structure of the Yb-Al nanoparticles has been disclosed by "on-the-fly" photoelectron spectroscopy monitoring of the nanoparticle beam in Yb 4f and Al 2p electron binding energy regions. Both, the binding energy values and the electron microscopy images taken on the deposited nanoparticles, allow estimating their dimensions to be in the 5-10 nm range. The photoelectron spectroscopy results suggest that in these nanoparticles no trivalent Yb--the typical case for the macroscopic Yb-Al alloy--is present. The oxidation of preformed Yb-Al nanoparticles was successfully attempted, leading to the appearance of divalent Yb surface oxide--in contrast to the bulk macroscopic Yb which is trivalent in the oxide. Our results suggest that at intermediate oxygen exposures "sandwich-like" nanoparticles of YbO/Yb/Al were synthesized. At higher O2 exposures, the oxygen seems to penetrate all the way to the Yb-Al interface. The results of the present study have to be considered when photonic applications of Yb-doped garnet nanoparticles are planned.


2018 n2c2 shared task on adverse drug events and medication extraction in electronic health records.
This article summarizes the preparation, organization, evaluation, and results of Track 2 of the 2018 National NLP Clinical Challenges shared task. Track 2 focused on extraction of adverse drug events (ADEs) from clinical records and evaluated 3 tasks: concept extraction, relation classification, and end-to-end systems. We perform an analysis of the results to identify the state of the art in these tasks, learn from it, and build on it. For all tasks, teams were given raw text of narrative discharge summaries, and in all the tasks, participants proposed deep learning-based methods with hand-designed features. In the concept extraction task, participants used sequence labelling models (bidirectional long short-term memory being the most popular), whereas in the relation classification task, they also experimented with instance-based classifiers (namely support vector machines and rules). Ensemble methods were also popular. A total of 28 teams participated in task 1, with 21 teams in tasks 2 and 3. The best performing systems set a high performance bar with F1 scores of 0.9418 for concept extraction, 0.9630 for relation classification, and 0.8905 for end-to-end. However, the results were much lower for concepts and relations of Reasons and ADEs. These were often missed because local context is insufficient to identify them. This challenge shows that clinical concept extraction and relation classification systems have a high performance for many concept types, but significant improvement is still required for ADEs and Reasons. Incorporating the larger context or outside knowledge will likely improve the performance of future systems.


Does risk-adjusted readmission rate provide valid information on hospital quality?
The purpose of this study was to determine whether readmission rates, adjusted to account for differences in clinical characteristics of patients treated, provide valid information on hospital quality of care. Twelve clinical conditions were selected. Condition-specific models to predict readmission risk were estimated using Medicare UB-82 claims data. These models then were used to calculate readmission risk probabilities for patients whose medical records had been reviewed for quality of care by a Medicare peer review organization. I hypothesized that patients who received poor quality care during a hospitalization episode would be more likely to be readmitted after discharge than those who received acceptable quality care. My analysis found no support for this hypothesis. In each of the 12 clinical conditions studied, readmission rates of cases that received poor quality care were essentially the same as those whose care was judged acceptable. This was true both for readmission rates that were adjusted for patients' demographic and clinical characteristics, and for unadjusted rates, such as those typically displayed in hospital report cards.


[Effects of daunorubicin and its nitroxyl analog on the synthesis of nucleic acids].
The impact of daunorubicin, emoksil in sublethal doses and daunorubicin mixtures with a nitroxyl radical of 2,2,6,6-tetramethyl-4-oxopiperidine-1-oxyl (NR) on synthesis of DNA and RNA in some organs of rats was studied. Daunorubicin and emoksil induced marked (by 80 to 90%) inhibition of DNA synthesis in all the examined organs even within the first hours of administration. In the heart, DNA synthesis remained lower by the end of the experiment. In the spleen its partial recovery up to 40 to 60% of the control level was observed. In the liver the synthesis was stimulated in 24 hours. Its highest stimulation was recorded with the use of emoksil and daunorubicin in combination with NR. After administration of daunorubicin the maximum synthesis of DNA exceeded the control level 2.5 times. Addition of NR lowered 2-fold inhibition of DNA synthesis by daunorubicin within the first hours. It was of interest that the anthracyclines appeared to markedly stimulate RNA synthesis in the spleen, the fact not described in the literature. The stimulation of DNA synthesis in the liver was supposed to be one of the components of the compensatory mechanisms engaged by the cell in response to the drug's damaging effect.


In vitro response of chondrocytes to mechanical loading. The effect of short term mechanical tension.
Chick epiphyseal chondrocytes were grown in high density cultures for 14 days, after which the cell layers were placed in a cyclical stretching apparatus and subjected to a strain of 5.5% at a frequency of 0.2 Hz. There was a 1.4- and 1.7-fold increase in the incorporation of 35SO4 and 14C-glucosamine, respectively, into glycosaminoglycans in cultures subjected to mechanical loading for 24 h. No significant change was observed in the hydrodynamic size of the proteoglycans synthesized by chondrocytes subjected to mechanical loading. In this time period there was no increase in 3H-glycine incorporation into acid-insoluble protein, but there was a 2.4-fold increase of 3H-thymidine into DNA in cultures subjected to tensional strain. Concomitant with these changes, the cellular levels of cyclic AMP increased 2.2 times in the mechanically loaded cultures. This is discussed as a possible mechanism whereby chondrocytes respond to mechanical stimuli.


The plasminogen system and cell surfaces: evidence for plasminogen and urokinase receptors on the same cell type.
The capacity of cells to interact with the plasminogen activator, urokinase, and the zymogen, plasminogen, was assessed using the promyeloid leukemic U937 cell line and the diploid fetal lung GM1380 fibroblast cell line. Urokinase bound to both cell lines in a time-dependent, specific, and saturable manner (Kd = 0.8-2.0 nM). An active catalytic site was not required for urokinase binding to the cells, and 55,000-mol-wt urokinase was selectively recognized. Plasminogen also bound to the two cell lines in a specific and saturable manner. This interaction occurred with a Kd of 0.8-0.9 microM and was of very high capacity (1.6-3.1 X 10(7) molecules bound/cell). The interaction of plasminogen with both cell types was partially sensitive to trypsinization of the cells and required an unoccupied high affinity lysine-binding site in the ligand. When plasminogen was added to the GM1380 cells, a line with high intrinsic plasminogen activator activity, the bound ligand was comprised of both plasminogen and plasmin. Urokinase, in catalytically active or inactive form, enhanced plasminogen binding to the two cell lines by 1.4-3.3-fold. Plasmin was the predominant form of the bound ligand when active urokinase was added, and preformed plasmin can also bind directly to the cells. Plasmin on the cell surface was also protected from its primary inhibitor, alpha 2-antiplasmin. These results indicate that the two cell lines possess specific binding sites for plasminogen and urokinase, and a family of widely distributed cellular receptors for these components may be considered. Endogenous or exogenous plasminogen activators can generate plasmin on cell surfaces, and such activation may provide a mechanism for arming cell surfaces with the broad proteolytic activity of this enzyme.


Antiproliferative properties of Padma Lax and its components ginger and elecampane.
Padma Lax (PL) is a multi-component herbal laxative, derived from traditional Tibetan medicine. It has been used in the treatment of constipation dominant irritable bowel syndrome. Beyond its purgative and bowel-regulating properties we found it to exhibit antiproliferative properties. C6 tumor cells were incubated with either an ethanolic or aqueous extract of PL. Cell proliferation, cell cycle, percentage of apoptotic cells, caspase-3/-7 activity as well as mitochondrial membrane potential were determined. Ethanolic extracts of PL inhibited cell proliferation in a dose- and time-dependent manner (half max concentration: 384.4 mug/ml after 48 h of incubation). Aqueous extracts were less effective. Ginger and elecampane were the active components of PL in respect to its antiproliferative action and were found to act synergistically. Supplementing the culture medium with polyamines could not override the cytostatic action of PL. Incubation of C6 cells with PL in the presence of catalase proved that the PL effect was specific and not due to oxidative stress. PL had no effects on the cell cycle at a low dose but arrested cells in G1 at high concentrations. Reduction of cell numbers was found to be due to apoptosis. The caspase- 3/-7 pathway was not involved in the PL-induced cell death. However, mitochondrial membrane potential was lost during the course of incubation with PL indicating a mitochondrial- but not caspase-mediated induction of apoptosis. PL exhibits antiproliferative properties which may be beneficial to prevent constipation-related cancer. This study may also contribute to a future development of a new herbal-based antiproliferative treatment.


Seeking health information online among U.S. pregnant women: findings from the 2009-2018 National Health Interview Surveys.
Seeking health information online has gained in popularity. However, few studies have investigated seeking health information online among U.S. pregnant women. The aim of this study was to investigate the patterns, trends, and characteristics of pregnant women in the U.S. who seek health information online. We obtained data from the National Health Interview Survey from 2009 to 2018. The study population consisted of women aged 18 to 49 years who self-reported being pregnant. Complex survey weighting and Chi-squared tests were used to evaluate trends and compare characteristics of online users and nonusers. Multivariable logistic regression analyses were used to evaluate characteristics associated with seeking health information online. Significantly more pregnant women sought health information online in 2018 compared to 2009 (72.9 percent, standard error [SE]: 3.3, 95 percent confidence interval [CI]: 66.3 percent-79.5 percent, vs. 60.7 percent, SE: 3.3, 95 percent CI: 54.0 percent-67.4 percent, p < .01). Pregnant women who were identified as white or Black, who had more education, and who had higher incomes were significantly more likely to report seeking health information online. Healthcare providers should actively initiate conversations to address the safety, accuracy, and reliability of online health information for their pregnant patients.


Plasmacytomas of the head and neck.
Plasmacytomas are rare tumors that often appear in the head and neck region and are characterized by a monoclonal proliferation of plasma cells. On both clinical presentation and pathologic examination these tumors may be confused with more common tumors of the head and neck. The purpose of this article is to review our experience with these rare neoplasms, with emphasis on clinical, pathologic, and therapeutic features. On retrospective chart review, we identified 20 patients with the diagnosis of plasmacytoma of the head and neck region at the Cleveland Clinic Foundation between 1976 and 1993. Records were reviewed with regard to initial symptoms, location of the neoplasm, diagnostic evaluation, treatment modalities, and survival. Of the 20 cases we identified, the tumor arose in the sinonasal/nasopharyngeal region in 11 (55%). Two cases (10%) represented medullary plasmacytomas, arising in the clavicle and presenting as supraclavicular masses. The mean follow-up was 60.2 months (range 6 to 131 months). In 15 of the 20 cases, immunohistochemistry staining for immunoglobulin light chain production was conducted. One of the two cases (50%) classified as medullary plasmacytoma demonstrated conversion to multiple myeloma, whereas only 2 of 18 cases of extramedullary plasmacytoma (11%) converted to multiple myeloma. The primary modality of treatment was radiation therapy with typical doses of 4500 to 6000 cGy. Kaplan-Meier survival estimates demonstrated 95% survival at 1 year, 82% survival at 5 years, and 10-year estimated survival of 72%. Plasmacytomas of the head and neck region are rare and on initial evaluation must be distinguished from multiple myeloma. The diagnostic evaluation includes appropriate radiologic and pathologic studies including immunohistochemistry. Despite the typical presentation as a locally destructive tumor, plasmacytomas are highly radiosensitive, and 70% to 80% survival may be obtained with the use of radiotherapy. Patients with plasmacytomas require long-term follow-up to detect conversion to multiple myeloma.


Tetrameric and homodimeric camelid IgGs originate from the same IgH locus.
In addition to producing conventional tetrameric IgGs, camelids have the particularity of producing a functional homodimeric IgG type lacking L (light) chains and only made up of two H (heavy) chains. This nonconventional IgG type is characterized by variable and constant regions referred to as V(H)H and C(H)H, respectively, and which differ from conventional V(H) and C(H) counterparts. Although the structural properties of homodimeric IgGs have been well investigated, the genetic bases involved in their generation are still largely unknown. In this study, we characterized the organization of genes coding for the H chains of tetrameric and homodimeric IgGs by constructing an alpaca (Lama pacos) genomic cosmid library. We showed that a single IgH locus in alpaca chromosome 4 contains all of the genetic elements required for the generation of the two types of Igs. The alpaca IgH locus is composed of a V region that contains both V(H)H and V(H) genes followed by a unique D(H)-J(H) cluster and C region genes, which include both C(H)H and C(H) genes. Although this general gene organization greatly resembles that of other typical mammalian V(n)-D(n)-J(n)-C(n) translocon IgH loci, the intermixed gene organization within the alpaca V and C regions reveals a new type of translocon IgH locus. Furthermore, analyses of cDNA coding for the membrane forms of IgG and IgM present in alpaca peripheral blood B cells are most consistent with the notion that the development of a B cell bearing homodimeric IgG passes through an IgM(+) stage, similar to the case for conventional IgG.


Altered pupil responses to social and non-social stimuli in Shank3 mutant dogs.
Pupillary response, an important process in visual perception and social and emotional cognition, has been widely studied for understanding the neural mechanisms of neuropsychiatric disorders. However, there have been few studies on pupil response to social and non-social stimuli in animal models of neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we developed a pupilometer using a robust eye feature-detection algorithm for real-time pupillometry in dogs. In a pilot study, we found that a brief light flash induced a less-pronounced and slower pupil dilation response in gene-edited dogs carrying mutations in Shank3; mutations of its ortholog in humans were repeatedly identified in ASD patients. We further found that obnoxious, loud firecracker sound of 120 dB induced a stronger and longer pupil dilation response in Shank3 mutant dogs, whereas a high reward food induced a weaker pupillary response in Shank3 mutants than in wild-type control dogs. In addition, we found that Shank3 mutants showed compromised pupillary synchrony during dog-human interaction. These findings of altered pupil response in Shank3 mutant dogs recapitulate the altered sensory responses in ASD patients. Thus, this study demonstrates the validity and value of the pupilometer for dogs, and provides an effective paradigm for studying the underlying neural mechanisms of ASD and potentially other psychiatric disorders.


Periosteal reaction-like lesions at the cranial aspect of the humeral diaphysis have a high prevalence in older, large breed dogs and may represent entheses of the superficial pectoral muscles.
Authors have commonly observed lamellar periosteal new bone formation at the cranial aspect of the humeral diaphysis in mediolateral radiographs of the humerus for large breed dogs with no evidence of pain or lameness. The aim of this retrospective, analytical study was to investigate the appearance and prevalence of "humeral periosteal reaction-like lesions" (HPRLL) in dogs and identify any predispositions. Mediolateral radiographs of humeri were evaluated and the presence and extent of "humeral periosteal reaction-like lesions" at the cranial aspect of the humerus were recorded. Macroscopic and histological examination of the humeri were performed for one dog with HPRLL. A total of 2877 mediolateral radiographs of 1727 dogs were included and focal or extended periosteal reaction-like lesions were found in 643 humeri of 387 dogs. Body weight ≥ 30 kg and age ≥ 7 years had a statistically significant, positive effect (P < 0.001) on the presence of HPRLL. German Shepherd dogs and Rottweilers were overrepresented in the group with HPRLL (P < 0.01). At the level of the HPRLL, the enthesis of the superficial pectoral muscles (M. pectoralis descendens and M. pectoralis transversus) to the Crista tuberculi majoris and Crista humeri were macroscopically and histologically identified. The authors propose that higher mechanical loads to the enthesis in large breed dogs may lead to physiological, age-related remodeling processes of the muscular attachment. The finding should not be confused with a pathological condition such as bone neoplasia.


[Neuronal migration disorders].
Neuronal migration disorders represent a group of congenital nervous system malformations that affect the process whereby millions of neuroectodermic cells move from germinal matrix to the loci, where they will reside for life. They produce important changes in cytoarchitecture, lamination and normal neuronal physiology, particularly in cerebral cortex. These disorders appear as sporadic cases, genetically determined or caused by external agents as infections, intoxications and radiations, etc. The better identified nosological entities include: schizencephaly, lissencephaly, pachygyria, polymicrogyria, neuronal heterotopias and agenesis of corpus callosum. Patients usually present early symptoms and signs of disease and epilepsy is a dominant manifestation. By means of studies of craneal computed tomography (CCT), magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and immunohistochemical and Golgi studies (IHG), it has been recently shown that nervous system dysgenesis can be a frequent cause of many refractory epilepsies and epileptic syndromes considered as cryptogenic. When these disorders are associated with dismorphic stigmas, genetics syndromes such as Miller-Dieker, Zellweger and Aicardi should be suspected.


Biological learning curves outperform existing ones in artificial intelligence algorithms.
Recently, deep learning algorithms have outperformed human experts in various tasks across several domains; however, their characteristics are distant from current knowledge of neuroscience. The simulation results of biological learning algorithms presented herein outperform state-of-the-art optimal learning curves in supervised learning of feedforward networks. The biological learning algorithms comprise asynchronous input signals with decaying input summation, weights adaptation, and multiple outputs for an input signal. In particular, the generalization error for such biological perceptrons decreases rapidly with increasing number of examples, and it is independent of the size of the input. This is achieved using either synaptic learning, or solely through dendritic adaptation with a mechanism of swinging between reflecting boundaries, without learning steps. The proposed biological learning algorithms outperform the optimal scaling of the learning curve in a traditional perceptron. It also results in a considerable robustness to disparity between weights of two networks with very similar outputs in biological supervised learning scenarios. The simulation results indicate the potency of neurobiological mechanisms and open opportunities for developing a superior class of deep learning algorithms.


Microwave plasma surface modification of silicone elastomer with allylamine for improvement of biocompatibility.
The microwave plasma surface modification of silicone elastomer with allylamine was studied to improve the biocompatibility of the material. An effort was made to clarify the relationships among plasma conditions and surface chemical composition, physical surface properties and biocompatibility of material, as well as the stability of plasma deposited layers. ATR-IR, XPS, Ellipsometry measurements, and contact angle measurements were used to investigate the changes of surface. The stability of plasma-treated silicone surfaces were also studied. The results demonstrated that the temperature and pressure had a strong influence on the chemical composition and structure of surface-deposited layer. The layer was nearly completely crosslinking when the modification was carried out at 60 degrees C. The polymerization speed decreased linearly with temperature. The XPS analysis results showed that the nitrogen element content in the surface layer was very high, especially under low pressure. The nitrogen/carbon ratio in the layer even greatly surpassed that of the allylamine monomer. The wettability of the silicone surface was greatly improved after plasma modification, and increased with the quantities of amine groups. The plasma-treated surfaces have good storage stability in air up to 3 months. The wettability of the surfaces decreased incipiently and then it dramatically increased with further time. The human skin fibroblasts were used to evaluate biocompatibility of plasma-treated silicone elastomer. The surface biocompatibility was greatly improved after modification; human skin fibroblasts adhered quickly and grew well on the modified silicone surface.


Development of severe hyponatremia due to cerebrospinal fluid leakage following meningomyelocele surgery in a newborn.
Cerebrospinal fluid leakage following meningomyelocele surgery is a frequent complication in the wound-healing period and is associated with wound dehiscence. CSF loss can cause severe hyponatremia, especially in the newborn and early infancy periods when dietary sodium content is relatively low. Hyponatremia in the newborn period can result in adverse neurodevelopmental outcomes. In addition, hyponatremia's cerebral effects can increase complications in neurosurgery patients. The authors present the case of a newborn in whom CSF leakage from the operative site and severe hyponatremia developed following meningomyelocele surgery. To the best of their knowledge, severe hyponatremia caused by CSF leakage after meningomyelocele surgery has not been previously reported in the literature.


Analyzing reflective narratives to assess the ethical reasoning of pediatric residents.
A limiting factor in ethics education in medical training has been difficulty in assessing competence in ethics. This study was conducted to test the concept that content analysis of pediatric residents' personal reflections about ethics experiences can identify changes in ethical sensitivity and reasoning over time. Analysis of written narratives focused on two of our ethics curriculum's goals: 1) To raise sensitivity to ethical issues in everyday clinical practice and 2) to enhance critical reflection on personal and professional values as they affect patient care. Content analysis of written reflections was guided by a tool developed to identify and assess the level of ethical reasoning in eight domains determined to be important aspects of ethical competence. Based on the assessment of narratives written at two times (12 to 16 months/apart) during their training, residents showed significant progress in two specific domains: use of professional values, and use of personal values. Residents did not show decline in ethical reasoning in any domain. This study demonstrates that content analysis of personal narratives may provide a useful method for assessment of developing ethical sensitivity and reasoning.


Making expert knowledge through the image: connections between antiquarian and early modern scientific illustration.
This essay examines drawings of antiquities in the context of the history of early modern scientific illustration. The role of illustrations in the establishment of archaeology as a discipline is assessed, and the emergence of a graphic style for representing artifacts is shown to be closely connected to the development of scientific illustration in the seventeenth and early eighteenth centuries. The essay argues that the production of conventionalized drawings of antiquities during this period represents a fundamental shift in the approach to ancient material culture, signifying the recognition of objects as evidence. As has been demonstrated in other scientific fields, the creation of a visual system for recording objects was central to the acceptance of artifacts as "data" that could be organized into groups, classified as types, and analyzed to gain knowledge of the past.


Associations between CD70 methylation of T cell DNA and age in adults with systemic lupus erythematosus and population controls: The Michigan Lupus Epidemiology & Surveillance (MILES) Program.
Environmental factors can influence epigenetic regulation, including DNA methylation, potentially contributing to systemic lupus erythematosus (SLE) development and progression. We compared methylation of the B cell costimulatory CD70 gene, in persons with lupus and controls, and characterized associations with age. In 297 adults with SLE and 92 controls from the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, average CD70 methylation of CD4+ T cell DNA across 10 CpG sites based on pyrosequencing of the promoter region was higher for persons with SLE compared to controls, accounting for covariates [β = 2.3, p = 0.011]. Using Infinium MethylationEPIC array data at 18 CD70-annoted loci (CD4+ and CD8+ T cell DNA), sites within the promoter region tended to be hypomethylated in SLE, while those within the gene region were hypermethylated. In SLE but not controls, age was significantly associated with pyrosequencing-based CD70 methylation: for every year increase in age, methylation increased by 0.14 percentage points in SLE, accounting for covariates. Also within SLE, CD70 methylation approached a significantly higher level in Black persons compared to White persons (β = 1.8, p = 0.051). We describe altered CD70 methylation patterns in T lymphocyte subsets in adults with SLE relative to controls, and report associations particular to SLE between methylation of this immune-relevant gene and both age and race, possibly a consequence of "weathering" or accelerated aging which may have implications for SLE pathogenesis and potential intervention strategies.


Predicting the fatty acid composition of milk: a comparison of two Fourier transform infrared sampling techniques.
In the present study a novel approach for Fourier transform infrared (FT-IR) characterization of the fatty acid composition of milk based on dried film measurements has been presented and compared to a standard FT-IR approach based on liquid milk measurements. Two hundred and sixty-two (262) milk samples were obtained from a feeding experiment, and the samples were measured with FT-IR as dried films as well as liquid samples. Calibrations against the most abundant fatty acids, CLA (i.e., 18:2cis-9, trans-11), 18:3cis-9, cis-12, cis-15, and summed fatty acid parameters were obtained for both approaches. The estimation errors obtained in the dried film calibrations were overall lower than the corresponding liquid sample calibrations. Similar and good calibrations (i.e., R(2) ranges from 0.82 to 0.94 (liquid samples) and from 0.88 to 0.97 (dried films)) for short-chain fatty acids (6:0-14:0), 18:1cis-9, SAT, MUFA, and iodine value were obtained by both approaches. However, the dried film approach was the only approach for which feasible calibrations (i.e., R(2) ranges from 0.78 to 0.93) were obtained for the major saturated fatty acids 16:0 and 18:0, the minor fatty acid features 4:0, CLA (i.e., 18:2cis-9, trans-11), PUFA, and the summed 18:1 trans isomers. For the dried film approach, logical spectral features were found to dominate the respective fatty acid calibration models. The preconcentration step of the dried film approach could be expected to account for a major part of the prediction improvements going from predictions in liquid milk to predictions in dried films. The dried film approach has a significant potential for use in high-throughput applications in industrial environments and might also serve as a valuable supplement for determination of genetic and breeding factors within research communities.


The development of the Xenopus retinofugal pathway: optic fibers join a pre-existing tract.
The developing optic nerve and tract have received considerable attention in recent years, but the cellular and subcellular microenvironment of the growing axons has not been described. In the belief that such a description is essential (though certainly not sufficient) for an understanding of pathway formation, we have examined the normal development of the retinofugal projection of Xenopus laevis. Optic fibers were labeled anterogradely at the retina with horseradish peroxidase (HRP) or the carbocyanine dye, DiI, at stages 32 to postmetamorphosis. The brains were examined both as whole mounts and in sections, light- and electron-microscopically, with the emphasis on tracts associated with the route of the optic fibers. At stage 32, two ventral commissures were present, the anterior and postoptic. They were immediately subjacent to the pia. All tracts and even isolated axons were in similarly superficial locations. The first deep pathway (separated from the pia by cell nuclei) was seen at stage 46; it was a dorsal commissure, probably the posterior. The first retinal axons passed from the optic stalk into the ventral part of the diencephalon, where they coursed along the rostral edge of the postoptic commissure, and maintained this position, relative to the other fibers in the tract of the commissure, throughout the remainder of their contralateral trajectory. They reached the presumptive thalamic and tectal termination sites and arborized. Subsequent optic axons followed this same route, thus enlarging the optic pathway relative to the more slowly growing nonoptic part of the commissure and its tract. Electron microscopy revealed, as early as stage 35, specialized contacts between cellular processes in the neuropil. These contacts had the form of symmetric membranous thickenings; some were associated with vesicles and were presumed to be synapses. We conclude that the early forebrain and midbrain have only two ventral commissural pathways, and most axons that grow out after these pathways have formed add to them rather than establish new tracts. The optic axons travel a stereotyped pathway alongside a pre-existing tract associated with the postoptic commissure. The possibility that optic fiber outgrowth is normally influenced by pre-existing tracts is discussed in relation to recent experimental investigations of fiber growth from ectopic eyes.


Transient expression of A-type K channel alpha subunits Kv4.2 and Kv4.3 in rat spinal neurons during development.
A-type K(+) currents (I(A)s) have been detected from the ventral horn neurons in rat spinal cord during embryonic day (E) 14 to postnatal day (P) 8 but not in adulthood. It is not known which types of neurons and which A-type K(+) channel alpha subunits express the I(A)s and what the possible function might be. Here, we examined the expression of two A-type K(+) channel alpha subunits, Kv4.2 and Kv4.3, in rat spinal cord at various developmental stages by immunohistochemistry. We found a transient expression of Kv4.2 in somatic motoneurons during E13.5-P8 with a peak around E17.5, which coincides temporally with the natural selection of motoneurons. Transient expression of Kv4.2 and Kv4.3 was also observed in the intermediate gray (IG) interneurons. During E19.5-P14, some IG interneurons express Kv4.2, some express Kv4.3 and a subset co-express Kv4.2 and Kv4.3. Peak expression of Kv4.2 and Kv4.3 in the IG interneurons was detected around P1, which coincides temporally with the developmental selection of IG interneurons. In contrast to the I(A)-expressing subunits Kv4.2 and Kv4.3, a delayed-rectifier K(+) channel alpha subunit Kv1.6 is persistently expressed in somatic motoneurons and IG interneurons. Together, these data support the hypothesis that expression of I(A)s may protect I(A)-expressing somatic motoneurons, and possibly also IG interneurons, from naturally occurring cell death during developmental selection.


Mental disorders and violence in a total birth cohort: results from the Dunedin Study.
We report on mental disorders and violence for a birth cohort of young adults, regardless of their contact with the health or justice systems. We studied 961 young adults who constituted 94% of a total-city birth cohort in New Zealand, April 1, 1972, through March 31, 1973. Past-year prevalence of mental disorders was measured using standardized DSM-III-R interviews. Past-year violence was measured using self-reports of criminal offending and a search of official conviction records. We also tested whether substance use before the violent offense, adolescent excessive perceptions of threat, and a juvenile history of conduct disorder accounted for the link between mental disorders and violence. Individuals meeting diagnostic criteria for alcohol dependence, marijuana dependence, and schizophrenia-spectrum disorder were 1.9 (95% confidence interval [CI], 1.0-3.5), 3.8 (95% CI, 2.2-6.8), and 2.5 (95% CI, 1.1-5.7) times, respectively, more likely than control subjects to be violent. Persons with at least 1 of these 3 disorders constituted one fifth of the sample, but they accounted for half of the sample's violent crimes (10% of violence risk was uniquely attributable to schizophrenia-spectrum disorder). Among alcohol-dependent individuals, violence was best explained by substance use before the offense; among marijuana-dependent individuals, by a juvenile history of conduct disorder; and among individuals with schizophrenia-spectrum disorder, by excessive perceptions of threat and a history of conduct disorder. In the age group committing most violent incidents, individuals with mental disorders account for a considerable amount of violence in the community. Different mental disorders are linked to violence via different core explanations, suggesting multiple-targeted prevention strategies.


Mechanical interlocking of engineered cartilage to an underlying polymeric substrate: towards a biohybrid tissue equivalent.
This study investigates the feasibility of engineering a biohybrid cartilage equivalent (BCE) with the long-term goal of restoring the mechanical integrity and interfacial characteristics of severely damaged cartilage. The BCE depends on the successful adhesion, via mechanical interlocking, of a cartilage layer to a nondegradable composite scaffold or prosthesis. The model scaffold, consisting of a nonwoven mesh bonded to a solid core, was seeded with bovine articular chondrocytes. High molecular weight poly(L-lactic acid), which has a slow degradation time, was used to model the nondegradable polymer. Biochemical and histological analysis demonstrate that the BCE can support the growth of a cartilaginous matrix for at least 6 weeks in culture. Mechanical testing of the BCE showed cartilage adhesion strength increased from 19.27+/-1.62 to 43.79+/-3.88 kPa between 35 and 50 days in culture. Nonmechanically interlocked cartilage achieved less than 5% of this adhesion strength. For the first time, atomic force microscopy (AFM) was used to characterize surface topography of tissue-engineered cartilage. Surface roughness of constructs after 8 and 10 weeks ranged from 153 to 171 nm, falling within the range of native cartilage (100-600 nm). This study demonstrates the feasibility of creating a biohybrid cartilage equivalent by mechanically interlocking a cartilaginous layer to an underlying polymeric matrix.


Application of stem cells for articular cartilage regeneration.
Articular cartilage is a highly organized tissue lacking self-regeneration capacity upon lesion. Current surgical intervention by application of in vitro-expanded autologous chondrocytes transplantation procedure is associated with several disadvantages, including donor-site morbidity and inferior fibrocartilage formation at the defect site. However, recent advancements in tissue engineering have provided notable strategies for stem cell-based therapies and articular cartilage tissue engineering. In this review, we discuss the current strategies to engineer cartilage tissues from adult stem cells and human embryonic stem cell-derived cells. The characteristics of adult stem cells, the microenvironmental control of cell fate determination, and the limitation imposed by the intrinsic nature of stem cells are discussed. The strategy to commit the stem cells for functional cartilage tissues in vivo is also discussed.


Phase 1b dose-finding study of rituximab, lenalidomide, and ibrutinib (R2I) in patients with relapsed/refractory mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n = 25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1-21) and ibrutinib 560 mg (days 1-28) of 28-day cycles. The MTD for lenalidomide was 20 mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92 months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67 > 30%). R2I was safe and tolerable in patients with R/R MCL.


Relation of motility of subgingival microflora as a clinical parameter to periodontal disease status in human subjects.
The purpose of this study was to evaluate the possible relationship between the motility of subgingival microflora and 5 clinical parameters commonly used in dental clinics. The clinical parameters were pocket depth, gingival inflammation, plaque accumulation, bleeding on probing and pus discharge. The motility of human subgingival microflora was estimated as the number of pixels remaining after subtraction of serial video frames using a high speed shutter camera and image analysis system, and was defined as the sum of pixels of 10 successive subtractions per sample over a 10-s time period. The bacterial motility showed significant positive, moderate or low associations with the five clinical parameters. The highest correlation was observed between the bacterial motility and pocket depth (r=0.36, p=0.0001). Furthermore, clinically defined periodontal healthy and diseased sites were significantly different with respect to the bacterial motility (p<0.0001). To determine whether the bacterial motility was dependent or independent of the other clinical variables, the data were analyzed based on common factor analysis. Three factors were extracted and explained about 75% of the variance of the original 6 clinical parameters. Only the bacterial motility had a positive coefficient for all these three factors. The plot of bacterial motility was placed separately from those of other variables in the scatterplot of the loadings of factor 2 versus factor 1 and factor 2 versus factor 3. This suggests that bacterial motility may be an independent variable among the clinical parameters. Taken together, these data indicate that bacterial motility provides unique information about the clinical periodontal condition and may be a useful tool for the monitoring of subgingival plaque in relation to periodontal disease.


Association of Statin Therapy and Risks of Cholelithiasis, Biliary Tract Diseases, and Gallbladder Procedures: Retrospective Cohort Analysis of a US Population.
Gallstone disease is a leading cause of morbidity in Western countries and carries a high economic burden. Statin medications decrease hepatic cholesterol biosynthesis and may, therefore, lower the risk of cholesterol cholelithiasis by reducing the cholesterol concentration in the bile. Population-based evidence, however, is sparse. To assess the risk of gallbladder diseases among statin users compared with nonusers in an American patient cohort. We performed a retrospective cohort study of patients enrolled in the San Antonio Tricare health system using data between October 2003 and March 2012. We defined 2 groups: statin users (use for 90 days or greater) and nonusers (no prior statin). A propensity score based on 82 variables was generated to match statin users and nonusers 1:1. Outcomes included incidence of cholelithiasis, biliary tract diseases, and gallbladder procedures. A total of 43 438 patients were identified; 13 626 (31.4%) were statin users, and 29 812 (68.6%) were nonusers. We matched 6342 pairs of statin users and nonusers based on propensity score. The odds ratios (ORs) in statin users in comparison to nonusers were similar for cholelithiasis (OR = 0.86; 95% CI = 0.73, 1.02), biliary tract disease (OR = 0.85; 95% CI = 0.67-1.08), and gall bladder procedures (OR = 0.85; 95% CI = 0.69, 1.04). Statin use was not significantly associated with either an increased or decreased risk of cholelithiasis or gallbladder disease.


[Influence of frequency of splanchnic nerve stimulation on development of habituation in the cat cerebral cortex].
Changes of amplitude of evoked potentials in the areas SI and SII of the cortex on repeated stimulation of the splanchnic nerve were studied in anesthetized and immobilized cats. The rate of decrement amplitude responses is increased with increasing of the frequency of stimulation from 0.5 to 5 stimuli per 1 sec. in the focus of maximal activity and in peripheral areas SI and SII. The decrement responses are more obvious in the peripheral sites of these areas. The data obtained seem to indicate a development of habituation in the cortex.


Hardy-Weinberg quality control.
An efficient test of deviation from Hardy-Weinberg frequencies with one degree of freedom was applied to 44 marker loci in a genome scan, and 7 loci had a significant excess of apparent homozygotes (chi2 (1) > 6) suggestive of typing error. In this example evidence for linkage did not increase when outliers were censored. Statistical quality control is an essential part of genotyping, and the effect of mistyping and map error should be considered in evaluating any genome scan.


Disparate Contributions of Human Retrovirus Capsid Subdomains to Gag-Gag Oligomerization, Virus Morphology, and Particle Biogenesis.
The capsid domain (CA) of the retroviral Gag protein is a primary determinant of Gag oligomerization, which is a critical step for immature Gag lattice formation and virus particle budding. Although the human immunodeficiency virus type 1 (HIV-1) CA carboxy-terminal domain (CTD) is essential for CA-CA interactions, the CA CTD has been suggested to be largely dispensable for human T-cell leukemia virus type 1 (HTLV-1) particle biogenesis. To more clearly define the roles of the HTLV-1 CA amino-terminal domain (NTD) and CA CTD in particle biogenesis, we generated and analyzed a panel of Gag proteins with chimeric HIV-1/HTLV-1 CA domains. Subcellular distribution and protein expression levels indicated that Gag proteins with a chimeric HIV-1 CA NTD/HTLV-1 CA CTD did not result in Gag oligomerization regardless of the parent Gag background. Furthermore, chimeric Gag proteins with the HTLV-1 CA NTD produced particles phenotypically similar to HTLV-1 immature particles, highlighting the importance of the HTLV-1 CA NTD in HTLV-1 immature particle morphology. Taken together, these observations support the conclusion that the HTLV-1 CA NTD can functionally replace the HIV-1 CA CTD, but the HIV-1 CA NTD cannot replace the HTLV-1 CA CTD, indicating that the HTLV-1 CA subdomains provide distinct contributions to Gag-Gag oligomerization, particle morphology, and biogenesis. Furthermore, we have shown for the first time that HIV-1 and HTLV-1 Gag domains outside the CA (e.g., matrix and nucleocapsid) impact Gag oligomerization as well as immature particle size and morphology.IMPORTANCE A key aspect in virus replication is virus particle assembly, which is a poorly understood process for most viruses. For retroviruses, the Gag structural protein is the primary driver of virus particle biogenesis, and the CA CTD is the primary determinant of Gag-Gag interactions for HIV-1. In this study, the HTLV-1 capsid amino-terminal domain was found to provide distinct contributions to Gag-Gag oligomerization, particle morphology, and biogenesis. This study provides information that will aid efforts for discovery of therapeutic targets for intervention.


Cytokinin-responsive MdTCP17 interacts with MdWOX11 to repress adventitious root primordium formation in apple rootstocks.
Adventitious root (AR) formation plays an important role in vegetatively propagated plants. Cytokinin (CK) inhibits AR formation, but the molecular mechanisms driving this process remain unknown. In this study, we confirmed that CK content is related to AR formation and further revealed that a high auxin/CK ratio was beneficial to AR formation in apple (Malus domestica). A correlation between expression of CK-responsive TEOSINTE BRANCHED1, CYCLOIDEA, and PCF17 (MdTCP17) and AR formation in response to CK was identified, and overexpression of MdTCP17 in transgenic apple inhibited AR formation. Yeast two-hybrid, bimolecular fluorescence complementation, and co-immunoprecipitation assays revealed an interaction between MdTCP17 and WUSCHEL-RELATED HOMEOBOX11 (MdWOX11), and a significant correlation between the expression of MdWOX11 and AR ability. Overexpression of MdWOX11 promoted AR primordium formation in apple, while interference of MdWOX11 inhibited AR primordium production. Moreover, a positive correlation was found between MdWOX11 and LATERAL ORGAN BOUNDARIES DOMAIN29 (MdLBD29) expression, and yeast one-hybrid, dual luciferase reporter, and ChIP-qPCR assays verified the binding of MdWOX11 to the MdLBD29 promoter with a WOX-box element in the binding sequence. Furthermore, MdTCP17 reduced the binding of MdWOX11 and MdLBD29 promoters, and coexpression of MdTCP17 and MdWOX11 reduced MdLBD29 expression. Together, these results explain the function and molecular mechanism of MdTCP17-mediated CK inhibition of AR primordium formation, which could be used to improve apple rootstocks genetically.


Are you listening? Have you heard?
Remember there is a cost associated with failure to listen. The development of active listening skills can produce the following outcomes: fewer misunderstandings less wasted time more accurate information stronger relationships As an advanced practice nurse these outcomes can result in a substantial payoff. Congratulate yourself on your positive listening skills, and identify opportunities for future gains. You deserve it.


M-F interatomic distances and effective volumes of second and third transition series MF6- and MF6(2-) anions.
Synchrotron X-ray powder diffraction data (SPDD) for representative LiMF6 and Li2MF6 salts of the second and third transition series have provided unit-cell parameters and, from Rietveld analysis, M-F interatomic distances. M-F distances have also been obtained from X-ray single-crystal structural analyses of LiOsF6, Li2PtF6, and KRhF6. The LiMF6 all have the LiSbF6 structure type (space group R3). For M = Ta to Au the primitive unit cell volume decreases with increasing nuclear charge (Z), the volumes (sigma = 0.01 A3) being as follows: Ta, 111.26; Os, 102.42; Ir, 100.77; Pt, 99.62; and Au, 99.12 A3. A similar contraction, with increase in Z, occurs from Nb to Rh, the primitive cell volume (sigma = 0.01 A3) being: Nb, 110.92; Ru, 100.51; and Rh, 98.64 A3. For the TaF6- to AuF6- the M-F distances are not significantly different across the series, at approximately 1.87(1) A; also, Nb-F, Ru-F, and Rh-F = 1.86(1) A. In each series, the a and c values of the hexagonal-cell representation for the LiMF6 structure (separate layers of MF6- and Li+ stacked along c) change smoothly. As Z increases, a decreases and c increases. The variation in a, like the volume change, indicates that the size of MF6- is decreasing with Z. The variation in c suggests that the charge on the F-ligand is decreasing with Z. In the trirutile Li2MF6 series, M = Mo to Pd, the formula-unit volume decreases with Z(Mo, 100.92(6); Ru, 98.21(1); Rh, 97.43(1); Pd, 96.83(1) A3) and a shortening in M-F occurs (Mo-F = 1.936(4); Ru-F = 1.921(7); Rh-F = 1.910(7); Pd-F = 1.899(4) A). The less abundant data for MF6(2-) salts of the third transition series indicate similar trends. For both series, M-F distances of MF6(2-) are longer by 0.03-0.09 A than in MF6-.


Development and Validation of the Modified Patient-Reported Outcome Scale for Chronic Obstructive Pulmonary Disease (mCOPD-PRO).
The present study aimed to develop and validate the modified patient-reported outcome scale for chronic obstructive pulmonary disease (mCOPD-PRO) for measuring the health status in COPD using both classical test theory and item response theory. A working group was initially established. The conceptual framework of COPD-PRO was modified. Subsequently, items related to COPD were gathered and selected through expert consultation, patient cognitive interviewing, classical test theory methods, as well as the item response theory method. Finally, the formed mCOPD-PRO was evaluated in terms of reliability, content validity, construct validity, criterion validity, known groups validity, and feasibility. A total of 155 items were gathered in the item bank, and two rounds of expert consultation, interviews with patients and field survey were conducted. The mCOPD-PRO included 27 items in the physiological, psychological, and environmental domains. The Cronbach's alpha of the instrument was 0.954. The correlation coefficients between the scores of each item and its domain scores ranged from 0.429 to 0.902. Confirmatory factor analysis showed that the comparative fit index, incremental fit index, non-normed fit index, standardized root-mean-square residual, and root-mean-square error of approximate were 0.91, 0.91, 0.90, 0.11, and 0.16, respectively. The correlation coefficient between mCOPD-PRO total scores and COPD assessment test scores and the modified Medical Research Council dyspnea scale scores was 0.771 and 0.651, respectively. The differences in mCOPD-PRO total scores and domain scores between the mild/moderate group and severe/extremely severe group of patients with COPD were both statistically significant (P<0.01). The acceptance and completion rates of mCOPD-PRO were both 99.5%, and the median completion time was 5 min (IQR, 4-11 min). The 27-item mCOPD-PRO is well developed and has good reliability, validity, and feasibility. It may provide a scientific and effective instrument for the clinical evaluation of COPD.


[Investigations into synchronisation of heart rate and musical rhythm in a relaxation therapy in patients with cancer pain].
Registration of the influence of musical rhythm on synchronisation and coordination of heart rate. Randomized pilot study. 28 patients with chronic cancer pain in a stable phase of the disease. 14-day training of a relaxation therapy designed for improving the falling asleep, including a 30-minute lullaby-like, rhythmically dominated music with gradually decreasing tempi. No training in the control group. Continuous registration of heart rate and comparison with musical beat on day 1 and 15. Analysis of the degree of synchronisation, i.e. the coordination of systole and musical central time point (1st beat of the 6/8 time alla breve). Recording of the time of falling asleep and registration of the patient's subjective evaluation of the relaxation therapy and the pain intensity using verbal rating scales. Documentation of the use of analgetics. Under the relaxation therapy trained patients showed an increasing synchronisation and coordination of heart rate and musical beat. At a musical tempo between 48 and 42 beats per min a very stable 2 : 3 synchronisation occurred. Trained patients who reported the best relaxing and analgetic effects showed the highest degree of synchronisation. Relaxation therapy led to an improvement of falling asleep and to a decrease in consumption of analgetics. Lullaby-like music within a special range of tempi can induce a trainable synchronisation of heart rate, functionally associated with the formation and intensity of a relaxation reaction. Further investigations are promising, however, substantial improvements in the measurement and documentation methods are needed.


Value of Contrast Transesophageal Echocardiography in the Detection of Intrapulmonary Vascular Dilatations in Hepatosplenic Schistosomiasis.
Hepatopulmonary syndrome (HPS), found in cirrhotic patients, has been little studied in hepatosplenic schistosomiasis (HSS) and includes the occurrence of intrapulmonary vascular dilatations (IPVD). Contrast transesophageal echocardiography (cTEE) with microbubbles is more sensitive than contrast transthoracic echocardiography (cTTE) with microbubbles in the detection of IPVD in cirrhosis. To assess the performance of the cTEE, compared with that of cTTE, in detecting IPVD for the diagnosis of HPS in patients with HSS. cTEE and cTTE for investigation of IPVD and laboratory tests were performed in 22 patients with HSS. Agitated saline solution was injected in peripheral vein during the cTEE and cTTE procedures. Late appearance of the microbubbles in the left chambers indicated the presence of IPVD. Results of the two methods were compared by the Student's t-test and the chi-square test (p < 0.05). cTEE was performed in all patients without complications. Three patients were excluded due to the presence of patent foramen ovale (PFO). The presence of IPVD was confirmed in 13 (68%) of 19 patients according to the cTEE and in only six (32%, p < 0.01) according to the cTTE. No significant differences in clinical or laboratory data were found between the groups with and without IPVD, including the alveolar-arterial gradient. The diagnosis of HPS (presence of IPVD with changes in the arterial blood gas analysis) was made in five patients by the cTEE and in only one by the cTTE (p = 0.09). In HSS patients, cTEE was safe and superior to cTTE in detecting IPVD and allowed the exclusion of PFO.


The impact of menu energy labelling across socioeconomic groups: A systematic review.
Menu energy labelling at point of purchase is gaining traction worldwide, yet the potential impact for different socioeconomic groups is unclear. We aimed to summarise evidence on the effectiveness of menu energy labelling by socioeconomic position (SEP). A systematic search for papers published to September 2015 was conducted using terms for labelling, food outlets, and SEP. Quality of studies was assessed. Results were summarised across stages of an intervention logic pathway. Eighteen papers were identified. Of twelve studies reporting the effect of menu energy labelling in low SEP populations, six reported on purchase outcomes. All but one of these reported no positive effect of the policy for this population. Two of the five studies that compared purchase outcomes of menu labelling across SEP groups reported that the policy was effective overall. These two studies reported either a significant decline in fast food calories purchased from consumers in high (but not low) SEP neighbourhoods or a significantly greater decline in calories purchased among consumers visiting stores in higher SEP neighbourhoods post policy implementation. None of the included papers reached the highest quality score. The current evidence describing the impact of menu energy labelling within or across SEP is limited in quantity and quality. Of the two studies that reported a positive benefit of menu energy labelling overall, both identified a greater effect on fast food purchases among consumers visiting stores in high compared to low SEP neighbourhoods. It is difficult to know whether the absence of effectiveness reported in low SEP populations represents a true lack of effectiveness or is a result of a more general lack of policy effectiveness or the limited quality of the reviewed studies.


Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.
The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.


Initial Exposure of Wax Foundation to Agrochemicals Causes Negligible Effects on the Growth and Winter Survival of Incipient Honey Bee (Apis mellifera) Colonies.
Widespread use of agrochemicals in the U.S. has led to nearly universal contamination of beeswax in honey bee hives. The most commonly found agrochemicals in wax include beekeeper-applied miticides containing tau-fluvalinate, coumaphos, or amitraz, and field-applied pesticides containing chlorothalonil or chlorpyrifos. Wax contaminated with these pesticides negatively affects the reproductive quality of queens and drones. However, the synergistic effects of these pesticides on the growth and survival of incipient colonies remain understudied. We established new colonies using frames with wax foundation that was pesticide free or contaminated with field-relevant concentrations of amitraz alone, a combination of tau-fluvalinate and coumaphos, or a combination of chlorothalonil and chlorpyrifos. Colony growth was assessed by estimating comb and brood production, food storage, and adult bee population during a colony's first season. We also measured colony overwintering survival. We found no significant differences in colony growth or survivorship between colonies established on pesticide-free vs. pesticide-laden wax foundation. However, colonies that had Varroa destructor levels above 3% in the fall were more likely to die over winter than those with levels below this threshold, indicating that high Varroa infestation in the fall played a more important role than initial pesticide exposure of wax foundation in the winter survival of newly established colonies.


Establishment of the relationship between tumor size and range of histological involvement to evaluate the rationality of current retinoblastoma management.
To determine whether tumor size correlates with histopathological involvement and hence evaluate the rationality of conservative treatment for retinoblastoma. We retrospectively studied 221 patients (221 eyes) treated for retinoblastoma with enucleation in the Zhongshan Ophthalmic Center of Sun Yat-sen University, China, from October 1995 to December 2004. Histopathological data included involvement of the anterior chamber, sclera, choroids, and optic nerve. Tumor size was measured by B-ultrasound examination. Tumor invasion of the optic nerve correlated with the Reese-Ellsworth (R-E) staging system and the International Classification for Retinoblastoma (ICRB): optic nerve involvement was significantly more frequent in R-E stage V (P = 0.009) and ICRB Group E (P = 0.002) cases. However, 19.1% of patients with R-E stage I, II and III, and 16.7% of patients with ICRB Group B and C disease showed histopathological involvement of the postlaminar optic nerve. Extraocular involvement was observed in 17.7% of tumors ≤ 15 mm in diameter. Tumors >15 mm in diameter showed greater extraocular involvement, including the optic nerve (P = 0.000) and sclera (P = 0.032), than tumors ≤ 15 mm in diameter. Postlaminar optic nerve invasion was observed in 19.6% of tumors ≤ 10 mm in thickness. Tumors >10 mm in thickness had sclera involvement more frequently than tumors ≤ 10 mm in thickness (P = 0.029). Postlaminar optic nerve invasion was noted in 17.1% of patients with tumors ≤ 15 mm in diameter and ≤ 10 mm in thickness. Medium-sized retinoblastomas frequently invade outside the globe. Thus, indications for conservative treatment need improvement.


A Triblock Copolymer Design Leads to Robust Hybrid Hydrogels for High-Performance Flexible Supercapacitors.
We report here an intriguing hybrid conductive hydrogel as electrode for high-performance flexible supercapacitor. The key is using a rationally designed water-soluble ABA triblock copolymer (termed as IAOAI) containing a central poly(ethylene oxide) block (A) and terminal poly(acrylamide) (PAAm) block with aniline moieties randomly incorporated (B), which was synthesized by reversible additional fragment transfer polymerization. The subsequent copolymerization of aniline monomers with the terminated aniline moieties on the IAOAI polymer generates a three-dimensional cross-linking hybrid network. The hybrid hydrogel electrode demonstrates robust mechanical flexibility, remarkable electrochemical capacitance (919 F/g), and cyclic stability (90% capacitance retention after 1000 cycles). Moreover, the flexible supercapacitor based on this hybrid hydrogel electrode presents a large specific capacitance (187 F/g), superior to most reported conductive hydrogel-based supercapacitors. With the demonstrated additional favorable cyclic stability and excellent capacitive and rate performance, this hybrid hydrogel-based supercapacitor holds great promise for flexible energy-storage device.


Associations between Traumatic Brain Injury, Drug Abuse, Alcohol Use, Adverse Childhood Events, and Aggression Levels in Individuals with Foster Care History.
Nearly 50,000 Canadian children live in foster care. Compared with their peers, foster children experience greater independence and decreased guidance, predisposing them to harmful exposures such as traumatic brain injury (TBI), illicit drugs, and alcohol. Foster children also report a higher level of childhood abuse compared with the general population. This study aimed to: 1) investigate substance/alcohol use disorder, adverse childhood events (ACE), TBI, aggression levels, and the difference between normalized percentages of brain regions of interest (ROIs) in a sample of Canadian youths with and without foster care history; 2) determine the prevalence of substance/alcohol use disorder, ACE, and aggression levels within individuals with foster care history when stratified by likelihood of TBI; and 3) determine the significant correlates of elevated aggression levels within this population. Participants completed standardized questionnaires that measured the prevalence of TBI, substance and alcohol use disorder, ACE, and aggression. Magnetic resonance imaging (MRI) was used to measure differences in brain ROI. Regression and network analysis were used to study interactions between variables. Seventy-four participants (51 individuals with foster care history and 23 age-matched controls from the general population) completed standardized questionnaires. Fifty-five of these individuals (39 foster participants and 16 controls) underwent brain MRI. Foster participants had higher prevalence of substance use disorder (p < 0.001), alcohol use disorder (p = 0.003), ACE (p < 0.001), and elevated aggression levels (p < 0.001) than healthy controls. No significant difference was found among brain ROI. The prevalence of TBI in foster participants was 65%. Foster participants with moderate or high likelihood of TBI exposure had higher levels of drug use and aggression than those with no or low likelihood of exposure. Brain volumes were not associated with substance/alcohol use disorder or ACE. No significant associations were found between aggression levels and the studied variables.


The moderating effects of cluster B personality traits on violence reduction training: a mixed-model analysis.
Cognitive behavioral therapies have positive effects on anger and aggression; however, individuals differ in their response to treatment. The authors previously found that dynamic factors, such as increases in readiness to change, are associated with enhanced outcomes for violence reduction training. This study investigated how less dynamic factors, specifically Cluster B personality traits, moderate the effects of violence reduction training. The authors used mixed modeling to fit growth curves to 14 weeks of anger strategies data and evaluated whether the presence of Cluster B traits affected pretreatment anger levels and rates of change. As expected, overall levels of negative anger strategies decreased across the 14-week treatment. Participants with antisocial, borderline, and histrionic personality features reported higher rates of negative anger strategies, whereas those with narcissistic personality features reported fewer negative anger strategies. Those with antisocial personality features improved at a rate similar to the overall trend of those without Cluster B traits. Those with borderline and histrionic features improved at an accelerated rate.


Value, time and outcomes of elevated lactate levels in adult patients on extracorporeal membrane oxygenation.
Lactate levels have been recognized as a reliable tool for monitoring critically ill patients requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) or venovenous extracorporeal membrane oxygenation (VV ECMO) but the reasons behind the overproduction of lactate are different and the influance for survival remains controversial. We analyzed the lactate values and lactate clearance in adult patients in these two forms of extracorporeal support. Patient demographics, ECMO duration, 30-day mortality, lactate values and lactate clearance at 24, 48 and 72 h from ECMO initiation of patients supported with VV and VA ECMO at Silesian Centre for Heart Deasese, between January 2011 and April 2020 were retrospectively analyzed. The changes in lactate levels were analyzed using the non-parametric U Mann-Whitney tests and Chi-square test. The ROC curves were draw and the area under the curve was calculated. The study comprised 91 adult patients, Mortality in the first 30 days from initiation of VV and VA ECMO was 39% and 66%, respectively. Lactate levels were significantly higher in non-survivors that received VV and VA ECMO (p < .001), while lactate clearance was similar (p = .256 and p = 1.000, respectively). Survival curves for patients with elevated (>2.0 mmol/L) vs normal (≤2.0 mmol/L) lactate levels at 72 h were significantly different for VV ECMO (p = .007) and VA ECMO (p = .037) but in both groups of ECMO, lactate levels above 2.0 mmol/L at 72 h from ECMO initiation predicted 30 day-mortality. This results emphasized the importance of lactate levels below 2.0 mmol/L at 72 h from both VV and VA ECMO initiation.


Endovascular Devices and Revascularization Techniques for Limb-Threatening Ischemia in Individuals With Diabetes.
Diabetes mellitus (DM) is a rapidly worsening global epidemic over the last thirty-five years. The increased prevalence of DM has changed the phenotypic expression of atherosclerotic limb threatening ischemia (LTI), resulting in an increase in lesions in the tibial vessels. These patients are also afflicted with peripheral neuropathy, foot deformities, and medial calcification of the vasculature. In response to the evolving phenotype of atherosclerosis, newer minimally invasive tools and techniques have been developed to improve the blood supply in LTI. Arterial access, traditionally obtained from the contralateral common femoral artery (CFA) in a retrograde fashion, is now also frequently being obtained in the ipsilateral limb in an antegrade fashion. Retrograde access of the tibial, pedal, tarsal, or calf collateral vessels is also being utilized to provide a route through which wires, catheters, balloons and stents may be placed. Wires have evolved to have a variety of diameters, materials and coatings providing interventionalists with a wide variety of choices when attempting to traverse blockages in the arteries. When catheters and wires fail to traverse the lesion, newer chronic total occlusion (CTO) devices have been developed to aid in the placement of a wire across the offending lesions. Due to medial calcification associated with DM, atherectomy devices have been developed to debulk the atherosclerotic plaque within the vessel. High pressure balloon angioplasty with or without stents remain the mainstay of intervention, with drug-coated balloons (DCBs) and drug-eluting stents (DESs) now being frequently used to prevent reocclusions of atherosclerotic lesions.


Boron Nitride Nanostructures: Fabrication, Functionalization and Applications.
Boron nitride (BN) structures are featured by their excellent thermal and chemical stability and unique electronic and optical properties. However, the lack of controlled synthesis of quality samples and the electrically insulating property largely prevent realizing the full potential of BN nanostructures. A comprehensive overview of the current status of the synthesis of two-dimensional hexagonal BN sheets, three dimensional porous hexagonal BN materials and BN-involved heterostructures is provided, highlighting the advantages of different synthetic methods. In addition, structural characterization, functionalizations and prospective applications of hexagonal BN sheets are intensively discussed. One-dimensional BN nanoribbons and nanotubes are then discussed in terms of structure, fabrication and functionality. In particular, the existing routes in pursuit of tunable electronic and magnetic properties in various BN structures are surveyed, calling upon synergetic experimental and theoretical efforts to address the challenges for pioneering the applications of BN into functional devices. Finally, the progress in BN superstructures and novel B/N nanostructures is also briefly introduced.


Stem cells with neurogenic potential and steroid hormones.
Pluripotent and multipotent stem cells with differentiation potential to neural phenotypes have been described and characterized in the last decades. Embryonic stem cells, as well as neural stem cells from developing and adult nervous system, can differentiate into different types of neurons, astrocytes or oligodendrocytes. Although the initially identified actions of estradiol, progesterone and testosterone are related to sexual reproductive functions, recent evidence shows that these steroid hormones modulate development, physiology and survival of nerve cells. Furthermore, neurosteroids can be synthesized in the developing and adult nervous system. A description of the molecular modulatory actions of sex steroid hormones on the Central Nervous System is presented. The main focus of this review is to summarize the described effects of steroid hormones (progesterone, allopregnanolone, dehydroepiandrosterone, estradiol and androgens) on cell parameters relevant to stem cells, both in vitro and in vivo. The overall conclusion is that steroid hormones influence stem cell behavior by several mechanisms, namely regulation of gene expression by binding to their cognate receptors, activation of intracellular pathways involving kinases or intracellular calcium signaling, and modulation of receptors for neurotransmitters; in some instances, these hormones can substitute or modulate the action of growth factors, and also directly influence self-renewal, proliferation, differentiation or cell death of neurogenic stem cells.


Activation of a muscarinic receptor selectively inhibits a rapidly inactivated Ca2+ current in rat sympathetic neurons.
Sympathetic neurons dissociated from the superior cervical ganglion of 2-day-old rats were studied by whole-cell patch clamp and by fura-2 measurements of the cytosolic free Ca2+ concentration, [Ca2+]i. Step depolarizations in the presence of tetrodotoxin and hexamethonium triggered two Ca2+ currents that differed in the voltage dependence of activation and kinetics of inactivation. These currents resemble the L and N currents previously described in chicken sensory neurons [Nowycky, M. C., Fox, A. P. & Tsien, R. W. (1985) Nature (London) 316, 440-442]. Treatment with acetylcholine resulted in the rapid (within seconds), selective, and reversible inhibition of the rapidly inactivated, N-type current, whereas the long-lasting L-type current remained unaffected. The high sensitivity to blocker drugs (atropine, pirenzepine) indicated that this effect of acetylcholine was due to a muscarinic M1 receptor. Intracellular perfusion with nonhydrolyzable guanine nucleotide analogs or pretreatment of the neurons with pertussis toxin had profound effects on the Ca2+ current modulation. Guanosine 5'-[gamma-thio]triphosphate caused the disappearance of the N-type current (an effect akin to that of acetylcholine, but irreversible), whereas guanosine 5'-[beta-thio]diphosphate and pertussis toxin pretreatment prevented the acetylcholine-induced inhibition. In contrast, cAMP, applied intracellularly together with 3-isobutyl-1-methylxanthine, as well as activators and inhibitors of protein kinase C, were without effect. Acetylcholine caused shortening of action potentials in neurons treated with tetraethylammonium to partially block K+ channels. Moreover, when applied to neurons loaded with the fluorescent indicator fura-2, acetylcholine failed to appreciably modify [Ca2+]i at rest but caused a partial blunting of the initial [Ca2+]i peak induced by depolarization with high K+. This effect was blocked by muscarinic antagonists and pertussis toxin and was unaffected by protein kinase activators. Thus, muscarinic modulation of the N-type Ca2+ channels appears to be mediated by a pertussis toxin-sensitive guanine nucleotide-binding protein and independent of both cAMP-dependent protein kinase and protein kinase C.


A regular meal and insulin infusion regimen: its use in the treatment of acute-onset ketotic diabetes and in stabilization of poorly controlled established diabetic subjects.
A simple regimen, consisting of a constant intravenous insulin infusion at either a basal, nocturnal rate or at a daytime rate matched by seven small, isocaloric meals taken every 2 h, has been applied to two clinical situations requiring optimal blood glucose control. In eight poorly controlled established diabetic subjects, quantitative estimates of daily insulin requirements were possible, with consequent improved control upon reinstitution of twice-daily subcutaneous insulin. In five acute-onset, ketotic diabetic subjects first treated by intravenous saline and low-dose intramuscular insulin, the regimen was used to achieve and maintain basal and postprandial normoglycemia. Ketonuria was abolished quickly in these patients, and falling insulin requirements and large doses of insulin were handled easily. In both clinical situations, subsequent subcutaneous insulin doses required little adjustment. The regimen is cheap, convenient to use, and widely applicable.


Evaluation of bifenthrin barrier spray on foliage in a suburban eastern North Carolina neighborhood.
Mosquitoes can transmit pathogens through blood feeding. Mosquito control programs conduct surveillance and source reduction, treat mosquito oviposition sites and spray adulticides to protect public health. In some areas, homeowners may contract with private mosquito control companies to address mosquito-related issues. We evaluated the efficacy of barrier sprays by comparing weekly host-seeking mosquito abundance at treatment and control properties in a residential neighborhood. The chemical concentration of bifenthrin residue on foliage was quantified, and field-collected mosquitoes, primarily Aedes albopictus, were tested for bifenthrin resistance using bottle bioassays. Mosquito abundance at treatment properties was significantly (P < 0.05) lower than at control properties. Quantities of bifenthrin detected on foliage from treatment properties was not correlated with mosquito abundance. No bifenthrin resistance was detected in captured mosquitoes. Based on the rate of application, we expected that chemical analysis of bifenthrin residue would show similar concentrations of bifenthrin on foliage in treatment areas. Although mosquitoes were not bifenthrin resistant, further studies are needed to evaluate the extent to which resistance changes over time with repeated applications. Findings from this study provide insight into control methods commonly used by mosquito control companies and could potentially be used to guide future mosquito management strategies.


Recurrent respiratory papillomatosis with lung involvement.
The case of a 27-year-old male with recurrent respiratory papillomatosis including lung involvement is presented. Laryngotracheal papillomatosis with lung involvement is a rare entity associated with human papillomavirus infection. Computed tomography (CT) was essential in guiding diagnostic and therapeutic approaches. Knowledge about the findings of this disease is needed for correct diagnosis, since findings are nonspecific. Lesions may show malignant transformation; regular follow-up with CT is essential.


Spatio-temporal spread and evolution of influenza A (H7N9) viruses.
The influenza A (H7N9) virus has been seriously concerned for its potential to cause an influenza pandemic. To understand the spread and evolution process of the virus, a spatial and temporal Bayesian evolutionary analysis was conducted on 2,052 H7N9 viruses isolated during 2013 and 2018. It revealed that the H7N9 virus was probably emerged in a border area of Anhui Province in August 2012, approximately 6 months earlier than the first human case reported. Two major epicenters had been developed in the Yangtze River Delta and Peral River Delta regions by the end of 2013, and from where the viruses have also spread to other regions at an average speed of 6.57 km/d. At least 24 genotypes showing have been developed and each of them showed a distinct spatio-temporal distribution pattern. Furthermore, A random forest algorithm-based model has been developed to predict the occurrence risk of H7N9 virus. The model has a high overall forecasting precision (> 97%) and the monthly H7N9 occurrence risk for each county of China was predicted. These findings provide new insights for a comprehensive understanding of the origin, evolution, and occurrence risk of H7N9 virus. Moreover, our study also lays a theoretical basis for conducting risk-based surveillance and prevention of the disease.


MYCOPLASMA PNEUMONIA-ASSOCIATED CHOROIDAL NEOVASCULARIZATION-BEVACIZUMAB INTRAVITREAL INJECTION AND LASER TREATMENT.
To report a rare case of bilateral subretinal granulomas with choroidal neovascularization after Mycoplasma pneumoniae atypical pneumonia. Presentation of a 7-year-old girl, who showed bilateral atypical subretinal granulomas with choroidal neovascularization. Visual acuity was 20/20 oculus dexter and 20/200 oculus sinister. Evaluation revealed a systemic Mycoplasma pneumoniae infection with pulmonary involvement. Successful ocular treatment was performed by intravitreal injection of Bevacizumab and laser photocoagulation. Visual acuity was unchanged 36 months after treatment. No further subretinal lesions were seen oculus uterque. To the best of their knowledge and according to literature this patient report is the first one of subretinal granuloma formation after pneumonia due to mycoplasma infection. Since Mycoplasma pneumoniae is a common pathogen, especially in children and young adults, it should be considered in the differential diagnosis of any febrile illness accompanied by ocular signs.