School readiness among children insured by Medicaid, South Carolina.
The American Academy of Pediatrics recommends a schedule of age-specific well-child visits through age 21 years. For children insured by Medicaid, these visits are called Early and Periodic Screening, Diagnosis, and Treatment (EPSDT). These visits are designed to promote physical, emotional, and cognitive health. Six visits are recommended for the first year of life, 3 for the second year. We hypothesized that children with the recommended visits in the first 2 years of life would be more likely than others to be ready for school when they finish kindergarten. We studied children insured by Medicaid in South Carolina, born during 2000 through 2002 (n = 21,998). Measures included the number of EPSDT visits in the first 2 years of life and an assessment of school readiness conducted at the end of kindergarten. We used logistic regression to examine the adjusted association between having the recommended visits and school readiness, controlling for characteristics of mothers, infants, prenatal care and delivery, and residence area. Children with the recommended visits had 23% higher adjusted odds of being ready for school than those with fewer visits. EPSDT may contribute to school readiness for children insured by Medicaid. Children having fewer than the recommended EPSDT visits may benefit from school readiness programs.


s-Myc acts as a transcriptional activator and its sequence-specific DNA binding is required for induction of programmed cell death in glioma cells.
We previously reported that s-Myc expression effectively induces programmed cell death (PCD) by apoptosis in glioma cells that express only mutated p53. To determine the molecular mechanism of s-Myc-induced PCD, we examined the correlation between transcriptional activation of s-Myc and its ability to induce PCD. Using a reporter plasmid having an upstream promoter region containing four repeats of the hexanucleotide CACGTG, we found that s-Myc can activate transcription of a reporter gene from this plasmid. Two mutated forms of s-Myc protein, s-MycCKII and s-MycmBR, were created. While s-MycCKII whose casein kinase (CK) II cognate sequence was restored in the internal acidic domain activated transcription as efficiently as wild-type s-Myc and induced PCD in glioma cells, s-MycmBR having a mutated basic region unable to bind the CACGTG motif did not. These findings suggest that transactivation activity of s-Myc through sequence-specific DNA binding may be indispensable for induction of PCD but that lack of a CK-II cognate sequence in the internal acidic domain may have little effect on these functions of s-Myc.


A novel P755L mutation in LRRK2 gene associated with Parkinson's disease.
Parkinson's disease is a common neurodegenerative disorder. The identification of leucine-rich repeat kinase 2 (LRRK2) gene mutations as a cause of Parkinson's disease has greatly expanded our knowledge of the genetic and molecular pathogenesis of this disorder. By denaturing high-performance liquid chromatography and gene sequencing in patients and controls, we identified a novel frequent heterozygous 2264C-->T substitution, which causes a proline-to-leucine mutation (P755L) in LRRK2 gene. In our sample of 598 patients of Chinese Han ancestry, 12 cases carried the same LRRK2 mutation. Our results indicated that this single mutation was implicated in 2% of sporadic patients. We suggest that testing for this mutation will be important in the management and genetic counseling of patients with Parkinson's disease.


Massively parallel CRISPRi assays reveal concealed thermodynamic determinants of dCas12a binding.
The versatility of CRISPR-Cas endonucleases as a tool for biomedical research has led to diverse applications in gene editing, programmable transcriptional control, and nucleic acid detection. Most CRISPR-Cas systems, however, suffer from off-target effects and unpredictable nonspecific binding that negatively impact their reliability and broader applicability. To better evaluate the impact of mismatches on DNA target recognition and binding, we develop a massively parallel CRISPR interference (CRISPRi) assay to measure the binding energy between tens of thousands of CRISPR RNA (crRNA) and target DNA sequences. By developing a general thermodynamic model of CRISPR-Cas binding dynamics, our results unravel a comprehensive map of the energetic landscape of nuclease-dead Cas12a (dCas12a) from Francisella novicida as it inspects and binds to its DNA target. Our results reveal concealed thermodynamic factors affecting dCas12a DNA binding, which should guide the design and optimization of crRNA that limits off-target effects, including the crucial role of an extended protospacer adjacent motif (PAM) sequence and the impact of the specific base composition of crRNA-DNA mismatches. Our generalizable approach should also provide a mechanistic understanding of target recognition and DNA binding when applied to other CRISPR-Cas systems.


A specific kinetic assay for tripeptide aminopeptidase in serum.
This is a method for measuring tripeptide aminopeptidase (EC 18.104.22.168) activity in serum. L- Leucylglycylglycine is used as substrate, and the reaction is followed by monitoring the absorbance increase at 340 nm when NAD+ is reduced to NADH in the presence of an excess of leucine dehydrogenase. This principle allows kinetic determination of the enzyme without interference by carboxypeptidases. Amastatin is added to the reaction mixture to prevent nonspecific hydrolysis of the substrate catalyzed by other aminopeptidases. As final reaction concentrations we recommend (per liter): 100 mmol of Tris buffer (pH 8.2), 4.0 mmol of L- leucylglycylglycine , 10 kU of leucine dehydrogenase, 3.8 mmol of NAD+, and 85 mumol of amastatin . The assay is suited to modern enzyme analyzers and has high precision.


Cardiac function as related to adrenergic activity in hypertensive left ventricular hypertrophy.
Studies in experimental animals and in hypertensive patients have shown that changes in cardiac anatomy and function are not just a simple consequence of the increased pressure load. The activity of the sympathetic nervous system is one of the factors that may influence cardiac performance and also, possibly, the cardiac anatomy of hypertensive patients. Animal studies have strongly suggested a possible role of adrenergic factors in the development of left ventricular hypertrophy. In man, plasma catecholamines are usually higher in hypertensive patients with left ventricular hypertrophy, and a correlation between left ventricular mass and plasma noradrenaline has also been observed. The decrease of cardiac performance after acute beta blockade has been found to be directly related to basal plasma noradrenaline concentration. An impaired response to beta-adrenergic stimulation has been reported in hypertensive animals and has been confirmed in hypertensive patients with left ventricular hypertrophy.


The Metabolic Cytokine Adiponectin Inhibits Inflammatory Lung Pathology in Invasive Aspergillosis.
Systemic immunity and metabolism are coregulated by soluble factors, including the insulin-regulating adipose tissue cytokine adiponectin. How these factors impact detrimental inflammatory responses during fungal infection remains unknown. In this study, we observed that mortality, fungal burden, and tissue histopathology were increased in adiponectin-deficient mice in a neutropenic model of invasive aspergillosis. Lung RNA sequencing, quantitative RT-PCR, and subsequent pathway analysis demonstrated activation of inflammatory cytokine pathways with upstream regulation by IL-1 and TNF in adiponectin-deficient mice with decreased/inhibited anti-inflammatory genes/pathways, suggesting broad cytokine-mediated pathology along with ineffective fungal clearance. Quantitative RT-PCR analysis confirmed increased transcription of IL-1a, IL-6, IL-12b, IL-17A/F, and TNF in adiponectin-deficient mice at early time points postinfection, with a specific increase in intracellular TNF in alveolar macrophages. Although eosinophil recruitment and activation were increased in adiponectin-deficient mice, mortality was delayed, but not decreased, in mice deficient in both adiponectin and eosinophils. Interestingly, neutrophil depletion was required for increased inflammation in adiponectin-deficient mice in response to swollen/fixed conidia, suggesting that immune suppression enhances detrimental inflammation, whereas invasive fungal growth is dispensable. Our results suggest that adiponectin inhibits excessive lung inflammation in invasive aspergillosis. Our study has therefore identified the adiponectin pathway as a potential source for novel therapeutics in immune-compromised patients with detrimental immunity to invasive fungal infection.


Structure Guided Deep Neural Network for Unsupervised Active Learning.
Unsupervised active learning has become an active research topic in the machine learning and computer vision communities, whose goal is to choose a subset of representative samples to be labeled in an unsupervised setting. Most of existing approaches rely on shallow linear models by assuming that each sample can be well approximated by the span (i.e., the set of all linear combinations) of the selected samples, and then take these selected samples as the representative ones for manual labeling. However, the data do not necessarily conform to the linear models in many real-world scenarios, and how to model nonlinearity of data often becomes the key point of unsupervised active learning. Moreover, the existing works often aim to well reconstruct the whole dataset, while ignore the important cluster structure, especially for imbalanced data. In this paper, we present a novel deep unsupervised active learning framework. The proposed method can explicitly learn a nonlinear embedding to map each input into a latent space via a deep neural network, and introduce a selection block to select the representative samples in the learnt latent space through a self-supervised learning strategy. In the selection block, we aim to not only preserve the global structure of the data, but also capture the cluster structure of the data in order to well handle the data imbalance issue during sample selection. Meanwhile, we take advantage of the clustering result to provide self-supervised information to guide the above processes. Finally, we attempt to preserve the local structure of the data, such that the data embedding becomes more precise and the model performance can be further improved. Extensive experimental results on several publicly available datasets clearly demonstrate the effectiveness of our method, compared with the state-of-the-arts.


Comparing Alternative Effect Decomposition Methods: The Role of Literacy in Mediating Educational Effects on Mortality.
Inverse odds ratio weighting, a newly proposed tool to evaluate mediation in exposure-disease associations, may be valuable for a host of research questions, but little is known about its performance in real data. We compare this approach to a more conventional Baron and Kenny type of decomposition on an additive hazards scale to estimate total, direct, and indirect effects using the example of the role of literacy in mediating the effects of education on mortality. Health and Retirement Study participants born in the United States between 1900 and 1947 were interviewed biennially for up to 12 years (N = 17,054). Literacy was measured with a brief vocabulary assessment. Decomposition estimates were derived based on Aalen additive hazards models. A 1 standard deviation difference in educational attainment (3 years) was associated with 6.7 fewer deaths per 1000 person-years (β = -6.7, 95% confidence interval [CI]: -7.9, -5.4). Of this decrease, 1.3 fewer deaths (β = -1.3, 95% CI: -4.0, 1.2) were attributed to the literacy pathway (natural indirect), representing 19% of the total effect. Baron and Kenny estimates were consistent with inverse odds ratio weighting estimates but were less variable (natural indirect effect: -1.2 [95% CI: -1.7, -0.69], representing 18% of total effect). In a cohort of older Americans, literacy partially mediated the effect of education on mortality. See Video Abstract at http://links.lww.com/EDE/B78.


The Cyclooctadepsipeptide Anthelmintic Emodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated Potassium (SLO) Channel Alpha Subunits.
The anthelmintic emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 μM intracellular Ca2+ and were strongly facilitated by emodepside (100 nM; +73.0 ± 17.4%; n = 9; p < 0.001). Drosophila Slo currents on the other hand were activated by emodepside (10 μM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300 nM Ca2+ and emodepside transiently facilitated currents (100 nM; +33.5 ± 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 ± 9.8%; n = 8; p < 0.001). This first cross phyla comparison of the actions of emodepside at nematode, insect and human channels provides new mechanistic insight into the compound's complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of emodepside as an anthelmintic treatment.


Mobile Robot Self-Localization with 2D Push-Broom LIDAR in a 2D Map.
This paper proposes mobile robot self-localization based on an onboard 2D push-broom (or tilted-down) LIDAR using a reference 2D map previously obtained with a 2D horizontal LIDAR. The hypothesis of this paper is that a 2D reference map created with a 2D horizontal LIDAR mounted on a mobile robot or in another mobile device can be used by another mobile robot to locate its location using the same 2D LIDAR tilted-down. The motivation to tilt-down a 2D LIDAR is the direct detection of holes or small objects placed on the ground that remain undetected for a fixed horizontal 2D LIDAR. The experimental evaluation of this hypothesis has demonstrated that self-localization with a 2D push-broom LIDAR is possible by detecting and deleting the ground and ceiling points from the scan data, and projecting the remaining scan points in the horizontal plane of the 2D reference map before applying a 2D self-location algorithm. Therefore, an onboard 2D push-broom LIDAR offers self-location and accurate ground supervision without requiring an additional motorized device to change the tilt of the LIDAR in order to get these two combined characteristics in a mobile robot.


Alzheimer's disease treated patients showed different patterns for oxidative stress and inflammation markers.
Alzheimer's disease (AD) is the most common type of dementia accounting for 60-80% of the reported cases. The aim of this study was to evaluate levels of certain parameters of oxidative stress and markers of endothelial dysfunction in the blood of 21 AD patients under standard treatment compared with 10 controls, in an attempt to elucidate the contribution of AD to the total oxidative stress status of the patients. Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil-Memantine, respectively Donepezil group. Although the study is based on a limited population, the results could constitute the basis for further studies regarding the effect of medication and diet on AD patients.


PD-L1 expression level in different thymoma stages and thymic carcinoma: a meta-analysis.
The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high (I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity (I2 = 55%). PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.


Nonequilibrium Mass Transport in the 1D Fermi-Hubbard Model.
We experimentally and numerically investigate the sudden expansion of fermions in a homogeneous one-dimensional optical lattice. For initial states with an appreciable amount of doublons, we observe a dynamical phase separation between rapidly expanding singlons and slow doublons remaining in the trap center, realizing the key aspect of fermionic quantum distillation in the strongly interacting limit. For initial states without doublons, we find a reduced interaction dependence of the asymptotic expansion speed compared to bosons, which is explained by the interaction energy produced in the quench.


Global trends in indocyanine green fluorescence navigation in the field of gastric cancer: bibliometrics and knowledge atlas analysis.
Indocyanine green (ICG) fluorescence navigation can enhance the visualization of gastric cancer (GC) lesions, increase the lymph node detection rate, and reduce the incidence of anastomotic leakage in the treatment of GC. It thus holds considerable potential for application in GC clinical surgery and has attracted widespread research interest. The purpose of this study was to visualize the current topics and emerging trends in research regarding ICG in GC. We searched the Web of Science Core Collection (WoSCC) for articles relevant to the use of ICG in GC. The resulting information was then analyzed from a bibliometric and knowledge graph analysis perspective using CiteSpace, Scimago Graphica, and R Studio so that the key trends and hot spots in research within this field could be identified and visualized. Ultimately, 1,385 papers from 58 countries or regions published from 1991 to 2022 were included in this study. The largest number of publications were from China, followed by Japan and the United States. High-yield institutions were concentrated in Asian countries, especially China. The top publication contributors were Shanghai Jiao Tong University. Li Y and Bang YJ ranked first among the top 10 most productive authors and top 10 most cocited authors, respectively. World Journal of Gastroenterology was the most productive academic journal on ICG in GC, while Cancer Research was the most commonly cocited journal. The keyword "indocyanine green" was among the top 5 keywords, and will likely remain a popular topic in future research. Furthermore, the emerging themes including surgery, biopsy, lymphadenectomy, dissection, and gastrectomy have attracted increasing attention. Current research hotspots in this area focus on the clinical implementation of ICG in precision surgery for GC. Given the imaging tracer characteristics of ICG and its utility in GC surgery, the optimization and application of ICG-guided precision surgery techniques for GC will be a research hot spot going forward.


PP2A-B56γ is required for an efficient spindle assembly checkpoint.
The Spindle Assembly Checkpoint (SAC) is part of a complex feedback system designed to ensure that cells do not proceed through mitosis unless all chromosomal kinetochores have attached to spindle microtubules. The formation of the kinetochore complex and the implementation of the SAC are regulated by multiple kinases and phosphatases. BubR1 is a phosphoprotein that is part of the Cdc20 containing mitotic checkpoint complex that inhibits the APC/C so that Cyclin B1 and Securin are not degraded, thus preventing cells going into anaphase. In this study, we found that PP2A in association with its B56γ regulatory subunit, are needed for the stability of BubR1 during nocodazole induced cell cycle arrest. In primary cells that lack B56γ, BubR1 is prematurely degraded and the cells proceed through mitosis. The reduced SAC efficiency results in cells with abnormal chromosomal segregation, a hallmark of transformed cells. Previous studies on PP2A's role in the SAC and kinetochore formation were done using siRNAs to all 5 of the B56 family members. In our study we show that inactivation of only the PP2A-B56γ subunit can affect the efficiency of the SAC. We also provide data that show the intracellular locations of the B56 subunits varies between family members, which is consistent with the hypothesis that they are not completely functionally redundant.


Polymorphism in promoter region of growth hormone receptor is associated with potential production capacity of insulin-like growth factor-1 in pre-pubertal Holstein heifers.
Insulin-like growth factor-1 (IGF-1) is one of the important factors for growth, milk production and reproductive functions and mainly released from the liver in response to growth hormone (GH) via GH receptor (GHR) in cattle. Recently, some single nucleotide polymorphisms (SNPs) were identified in the bovine GHR gene. Some GHR-SNPs were shown to be related to plasma IGF-1 concentration in cattle. Hence, the capacity to IGF-1 production in the liver might be affected by GHR-SNP and associated with performance in the future. This study examined whether GHR-SNP is associated with IGF-1 production in the liver of pre-pubertal heifers. In 71 Holstein calves, blood samples for genomic DNA extraction were obtained immediately after birth. To genotype the GHR-SNPs in the promoter region, polymerase chain reaction (PCR) products were digested with restriction enzyme NsiI (cutting sites: AA, AG and GG). All heifers at 4 months of age were intramuscularly injected with 0.4 mg oestradiol benzoate. Blood samples were obtained from the jugular vein just before (0 h) and 24 h after injection. The number of AA, AG and GG at the NsiI site was 0, 17 and 54 respectively. In AG and GG, plasma GH concentrations were higher pre-injection than 24 h post-injection (p < 0.01). Moreover, plasma GH concentrations in AG post-injection were higher than in GG (p < 0.05). In contrast, the GG genotype exhibited higher plasma IGF-1 concentrations in pre-injection than post-injection (p < 0.01), although oestradiol did not change IGF-1 concentration in the AG genotype. We conclude that the GG polymorphism in the promoter region of GHR is associated with a higher potential capacity of IGF-1 production in the liver of cattle.


Experimental Investigation of Self-Assembled Particles on Profile Control in the Fuyu Oilfield.
The particle system is one of the widely used profile control agents in many oilfields, and the matching relationship between the particle and the reservoir pore throat is significant for the profile control effect. In order to enhance oil recovery after water breakthrough in the Fuyu oilfield, a self-assembled particle with some branches on the surface, compounded by inverse emulsion polymerization and added, is introduced as the profile control agent in this paper. Then the permeabilities of the water channel and the oil remaining area in the Fuyu oilfield are achieved after the statistic analysis of 1,022 cores from the practical reservoir. Furthermore, the oil restarting pressure in the oil remaining area and the self-assembled particle plugging strength in the water channel are tested. Finally, the adaption of the self-assembled particle and effect of profile control in the Fuyu oilfield are evaluated by comparing the oil restarting pressure and the plugging strength. The results show that the self-assembled particles can be gathered together easily by the force of the ionic bond, which is good for water channel plugging. The permeability of the water channel in the Fuyu oilfield ranges from 1,000 mD to 1,500 mD. The oil restarting pressure increases with the decreasing of permeability, and the increasing rate grows rapidly when it drops below 50 mD. Comparing the oil restarting pressure with the plugging strength, a self-assembled particle with a diameter of 20-40 μm in the water channel with a permeability of 1,265.7 mD can provide sufficient plugging strength to restart the remaining oil in the oil remaining areas with a permeability over 3.38 mD. The matched window of the self-assembled particle is wider than a normal particle in the Fuyu oilfield.


Lipophilic Fe(III)-Complex with Potent Broad-Spectrum Anticancer Activity and Ability to Overcome Pt Resistance in A2780cis Cancer Cells.
Although iron is essential for all forms of life, it is also potentially toxic to cells as the increased and unregulated iron uptake can catalyze the Fenton reaction to produce reactive oxygen species (ROS), leading to lipid peroxidation of membranes, oxidation of proteins, cleavage of DNA and even activation of apoptotic cell death pathways. We demonstrate that Fe(hinok)3 (hinok = 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a neutral Fe(III) complex with high lipophilicity is capable of bypassing the regulation of iron trafficking to disrupt cellular iron homeostasis; thus, harnessing remarkable anticancer activity against a panel of five different cell lines, including Pt-sensitive ovarian cancer cells (A2780; IC50 = 2.05 ± 0.90 μM or 1.20 μg/mL), Pt-resistant ovarian cancer cells (A2780cis; IC50 = 0.92 ± 0.73 μM or 0.50 μg/mL), ovarian cancer cells (SKOV-3; IC50 = 1.23 ± 0.01 μM or 0.67 μg/mL), breast cancer cells (MDA-MB-231; IC50 = 3.83 ± 0.12 μM or 2.0 μg/mL) and lung cancer cells (A549; IC50 = 1.50 ± 0.32 μM or 0.82 μg/mL). Of great significance is that Fe(hinok)3 exhibits unusual selectivity toward the normal HEK293 cells and the ability to overcome the Pt resistance in the Pt-resistant mutant ovarian cancer cells of A2780cis.


Sexual abuse of children. An epidemiologic study.
An epidemiologic study of sexual abuse of children was made by reviewing Minneapolis Police Department records. Children were involved in 33% of all cases reported. Eighty-five percent of cases involved exposure or indecent liberties. Half of the cases occurred in the summer; half of the cases occurred from 2 to 6 PM. The mean age of victims was 10.7 years, and 88% were girls. All reported offenders were men; their "mean estimated age" was 28 years. The method of study did not allow determination of social relationships between victims and the offenders. Little information regarding the magnitude of the problems of medical, psychological, and social sequelae of sexual abuse of children is available in the literature.


[Adjuvant treatment of head and neck cancers: advances and challenges].
Following the release, in 2004, of the results from 2 multicentric, phase III studies, the adjuvant treatment of locally advanced head-and-neck cancers nowadays belongs to Level I of Evidence-Based Medicine, with the advent of concomitant, high-dose chemoradiation. The concurrent delivery of radiotherapy (60 to 66 Gy using a conventional fractionation) and high-dose, bolus cisplatin (100 mg/m2, days 1, 22 and 43) is considered, in post-operative setting, as the standard approach in patients with locally advanced disease. Future adjuvant treatments should anchor to the development of high-precision irradiation techniques, as well as concomitant delivery of radiotherapy with more efficacious cytotoxic drugs and/or targeted therapies.


Video-assisted thoracoscopic decompression of tubercular spondylitis: clinical evaluation.
A prospective, observational study using a novel procedure of video-assisted thoracoscopy and conventional, long spinal instruments for decompression of dorsal tubercular spondylitis. To assess the efficacy of video-assisted thoracoscopic decompression of dorsal tubercular spondylitis and compare it with the published data of classic thoracotomy procedures. Surgical decompression of dorsal tubercular spine with the transpleural transthoracic method is a standard procedure. It is a major surgery with significant morbidity in terms of blood loss, intensive care unit (ICU) and hospital stay, postoperative incision pain, and chest tube insertion. A procedure that has the potential to achieve comparable recovery in patients with dorsal tubercular spondylitis but with a surgery of lesser magnitude and morbidity has immense potential. There were 16 patients with mid-dorsal tubercular spondylitis with paraplegia/paraparesis requiring surgery who were included in the study. Every patient had a recent paradiscal disease at a single level. A soft tissue shadow was visible on plain radiographs of the spine, and conservative treatment for at least 3 weeks had shown no recovery. Patients with obvious respiratory insufficiency and likely to have significant pleural adhesions were excluded from the study. Single lung anesthesia and ipsilateral lung collapse using a double-lumen tube were administered. A 3-portal thoracoscopy approach was used, and conventional but long spinal instruments were used through an open port to decompress the spine. Patients were assessed for blood loss, duration of surgery, postoperative incision pain, duration of chest tube insertion, ICU and hospital stay, and neurologic recovery. Patients were observed for a minimum of 6 months. Of 16 patients, 14 (88%) had good neurologic recovery. In 1 patient, thoracoscopy was abandoned, and open thoracotomy was performed because of persistent bleeding. Another patient did not recover, and anterolateral decompression was performed 10 weeks after thoracoscopy. She recovered subsequently. Other complications included fracture of the sixth rib in 1 patient and breakage of suction tip in another. Adequate tissue biopsy for histopathologic examination could be obtained in all patients. Duration of surgery was 223 minutes (+/-56), blood loss was 497 ml (+/-302), and blood transfusion was required in 3 patients (3 U in 1 and 1 U in 2). Postoperative analgesic (tramadol) was 243 mg (+/-70) for 2-4 days (median 3), median hospital stay was 5.5 days (range 4-9), chest tube requirement was 3 days (range 2-7), and 2 patients were required to stay in the ICU for 1 day each. Video-assisted thoracoscopic decompression of tubercular dorsal spondylitis is a viable option to achieve significant neurologic recovery with less morbidity, blood requirement, and hospital stay compared to the open thoracotomy procedures.


Structure and properties of the precipitates formed from condensed solutions of the revised simulated body fluid.
Precipitation experiments with aqueous solutions of the Kokubo's revised simulated body fluid (rSBF) equal to 2, 4, 8, and 12 times the ionic concentration of human blood plasma were performed. Instead of Hepes, solution pH was adjusted to the desired value of 7.40 +/- 0.02 by either bubbling of CO2 or addition of HCl. The experiments were performed in tightly closed plastic vessels kept at 37.0 +/- 0.2 degrees C for 72 h under permanent shaking. Afterward, the suspensions were filtrated, and the precipitates were collected and analyzed. The results revealed that increasing the concentration of rSBF resulted in great changes in both the structure and the chemical composition of the precipitates. Phosphate substitution for carbonate (although the amounts of calcium and magnesium remained unchanged) and crystallinity decreasing were the most important modifications found in the precipitates formed from the highly condensed solutions of rSBF.


Recent Developments of Magnetic Nanoparticles for Theranostics of Brain Tumor.
Glioblastoma multiforme, one of the most aggressive brain tumors, has a very poor clinical outcome. Despite the introduction of the alkylating reagent temozolomide (TMZ) to surgery and radiotherapy, the survival of patients could only be modestly increased up to less than 15 months. Therefore, innovative treatment strategies are urgently needed to improve survival of glioma patients. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of attention due to their widespread diagnostic and therapeutic applications in neuro-oncology. In this review article we discuss the possible application of the SPIONs for the diagnostic and theraputic approaches in brain cancer. Additionally we report on recent pre-clinical and clinical developments on the generation of heat in the tumors through the application of SPIONs subjected to an alternating magnetic field (AMF). A comprehensive review of the literature on the current status of using targeted SPIONs in brain tumor detection and therapy and also the potential hurdles to overcome was performed. Functionalized nanoparticles carrying tumor-specific agents, such as antibodies or proteins might further improve their tumor targeting capacity. Furthermore, multifunctional, theranostic SPIONs can be used for simultaneous in vivo tumor imaging and targeted drug deliery. Application of the ultrasound and external magnetic field technologies significantly improves accumulation of nanoparticles in brain tumors. Hyperthermic treatment using AMF has a therapeutic potential in management of brain tumors. Superparamagnetic nanoparticle-based imaging, drug delivery and hyperthermic treatment can potentially be a powerful tool for precise diagnosis and treatment of brain tumors.


Interfacial Reactivity of Silicon Electrodes: Impact of Electrolyte Solvent and Presence of Conductive Carbon.
Silicon (Si) is a promising high-capacity material for lithium-ion batteries; however, its limited reversibility hinders commercial adoption. Approaches such as particle and crystallite size reduction, introduction of conductive carbon, and use of different electrolyte solvents have been explored to overcome these electrochemical limitations. Herein, operando isothermal microcalorimetry (IMC) is used to probe the influence of silicon particle size, electrode composition, and electrolyte additives fluoroethylene carbonate and vinylene carbonate on the heat flow during silicon lithiation. The IMC data are complemented by X-ray photoelectron and Raman spectroscopies to elucidate differences in solid electrolyte interphase (SEI) composition. Nanosized (∼50 nm, n-Si) and micrometer-sized (∼4 μm, μ-Si) silicon electrodes are formulated with and without amorphous carbon and electrochemically lithiated in ethylene carbonate (EC), fluoroethylene carbonate (FEC), or vinylene carbonate (VC) based electrolytes. Notably, n-Si electrodes generate 53-61% more normalized heat relative to their μ-Si counterparts, consistent with increased surface area and electrode/electrolyte reactivity. Introduction of amorphous carbon significantly alters the heat flow profile where multiple exothermic peaks and increased normalized heat dissipation are observed for all electrolyte types. Notably, the VC-containing electrolyte demonstrates the greatest normalized heat dissipation of the electrode compositions tested showing as much as a 50% increase compared to the EC or FEC counterparts. The results are relevant to the understanding of silicon negative electrode function in the presence of electrolyte additives and provide insight relative to silicon containing cell reactivity and safety.


[Genetic epidemiology and psychiatry (I): scope and limitations of familial studies. Case of panic disorder].
Genetics epidemiology shed new light on multifactorial disorders for which genes are partly involved, for example on numerous psychiatric diseases. Nevertheless, each epidemiological technic has it's caracteristics and limitations. This review discuss the impact of aggregation studies, on the bases of an example, namely all aggregation studies on panic disorder. We detected through Medline thirteen studies, comparing 3,700 relatives of 780 probands affected with panic disorder, with 3,400 relatives of 720 unaffected controls. It is computed that relatives of patients with panic disorder have an increased risk (10.7%) for panic disorder than relatives of controls (1.4%), relatives from affected probands having a high relative risk (6.8) for panic disorder according to the meta-analysis. On the basis of these 13 aggregation studies, there is an important attribuable risk (78.3%) of "having a familial history of panic disorder" in the risk for panic disorder. Furthermore, the estimated heritability is 73% (73% of the total variance would be explained by additive genetic effects), if Reich's conditions are fulfilled for a valid estimation of the heritability on the basis of aggregation families. These studies can also be used to highlight the variability of expression according to gender, to show the relevance of quantitative approaches (versus the qualitative approach which is nearly systematically used), to underline the informations raised by experimental technics (such as panic disorder induced by lactate), and to raise the potential existence of phenocopies. Lastly, aggregation studies on panic disorder can help to understand the high comorbidity of this disorder, with other anxiety disorders and mood disorder.


Breaking Transmission with Vaccines: The Case of Tuberculosis.
Members of the Mycobacterium tuberculosis complex (MTBC) have evolved causing tuberculosis (TB) in different mammalian hosts. MTBC ecotypes have adapted to diverse animal species, with M. bovis being the most common cause of TB in livestock. Cattle-to-human transmission of M. bovis through ingestion of raw milk was common before introduction of the pasteurization process. TB in humans is mainly caused by M. tuberculosis. This bacterium is considered a genetically clonal pathogen that has coevolved with humans due to its ability to manipulate and subvert the immune response. TB is a major public health problem due to airborne person-to-person transmission of M. tuberculosis. The essential yet unanswered question on the natural history of TB is when M. tuberculosis decides to establish latent infection in the host (resambling the lysogenic cycle of lambda phage) or to cause pulmonary disease (comparable to the lytic cycle of lambda phage). In this latter case, M. tuberculosis kills the host with the aim of achieving transmission to new hosts. Combating the TB epidemic requires stopping transmission. M. bovis BCG, the present vaccine against TB, is derived from M. bovis and only protects against disseminated forms of TB. Thus, a priority in TB research is development of new effective vaccines to prevent pulmonary disease. Attenuated vaccines based on M. tuberculosis as MTBVAC are potential candidates that could contribute to break the TB transmission cycle.


Withaferin-A Can Be Used to Modulate the Keratin Network of Intermediate Filaments in Human Epidermal Keratinocytes.
The mechanical state of cells is a critical part of their healthy functioning and it is controlled primarily by cytoskeletal networks (actin, microtubules and intermediate filaments). Drug-based strategies targeting the assembly of a given cytoskeletal network are often used to pinpoint their role in cellular function. Unlike actin and microtubules, there has been limited interest in the role of intermediate filaments, and fewer drugs have thus been identified and characterised as modulators of its assembly. Here, we evaluate whether Withaferin-A (WFA), an established disruptor of vimentin filaments, can also be used to modulate keratin filament assembly. Our results show that in keratinocytes, which are keratin-rich but vimentin-absent, Withaferin-A disrupts keratin filaments. Importantly, the dosages required are similar to those previously reported to disrupt vimentin in other cell types. Furthermore, Withaferin-A-induced keratin disassembly is accompanied by changes in cell stiffness and migration. Therefore, we propose that WFA can be repurposed as a useful drug to disrupt the keratin cytoskeleton in epithelial cells.


The N-terminus of the prion protein is a toxic effector regulated by the C-terminus.
PrPC, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrPSc, the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrPC functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrPC, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPC.


More than words: fast acquisition and generalization of orthographic regularities during novel word learning in adults.
In literates, reading is a fundamental channel for acquiring new vocabulary both in the mother tongue and in foreign languages. By using an artificial language learning task, we examined the acquisition of novel written words and their embedded regularities (an orthographic surface feature and a syllabic feature) in three groups of university students with different exposures (Group 1 saw 2 words once, Group 2 saw 20 words once, Group 3 saw 20 words three times). Recognition memory results for Groups 2 and 3 indicated that adults can learn novel written words even with just a single exposure, albeit repeated exposure improved target detection. A generalization task revealed that even the minimal exposure in Group 1 was enough for acquisition of the two embedded regularities. More exemplars and repeated exposure provided more robust effects for the syllable regularity. Finally, post-test interview showed that repeated exposure was needed to become aware of the regularities. The present results show that adults learn novel written words and their inherent regularities in a fast and effective fashion.


Isolation of high-quality RNA from grains of different maize varieties.
The study of gene expression in maize varieties represents a powerful tool aiming to increase vitamin A precursors. However, the isolation of RNA from different maize varieties is challenging because these varieties show different levels of polysaccharides, and most methods available for RNA isolation are inappropriate for grain samples. The polysaccharides co-purify and co-precipitate with RNA during isolation, resulting in low-quality RNA, compromising the use of RNA in subsequent applications. Thus, a cetyltrimethylammonium bromide (CTAB)-based method was adapted in this study and compared with six methods for RNA isolation, including commercial reagents and RNA and DNA isolation kits, in order to identify the most appropriate for maize grains from different varieties. Most of the methods evaluated were considered inadequate due to limitations in terms of purity and/or quantity of the isolated RNA, which affected the efficiency of subsequent RT-qPCR analysis, resulting in nonamplification of β-carotene hydroxylase gene (HYD3) or high deviation among replicates. However, the CTAB modified method allowed the study to obtain intact RNA, with high quality and quantity, from 25 maize varieties. Furthermore, this RNA was successfully used to evaluate the expression of HYD3 gene by real-time qualitative polymerase chain reaction (RT-qPCR), and thus represents a simple, efficient, and low-cost strategy.


Ulnohumeral dislocation despite intact radiocapitellar joint: a rare Monteggia variant.
We treated one patient with a mid-diaphyseal radius fracture and concomitant anteromedial facet fracture of the coronoid. The ulnohumeral joint was severely unstable by complete ligament detachment and interosseous membrane rupture. Despite this gross instability, the radiocapitellar was congruent and stable. The possible mechanism of radiocapitellar stability is discussed and the concept of concavity-compression stability across the radiocapitellar joint is emphasized.


Immobilized enzyme cellulose hollow fibers: II. Kinetic analysis.
Immobilized enzyme hollow fibers may be useful in the purification or treatment of whole blood under clinical conditions. In this study, catalytically pure heparinase was immobilized to cellulose to analyze the feasibility for the removal of heparin's anticoagulant activity from whole blood. The kinetics of catalytically pure heparinase immobilized to regenerated cellulose hollow fibers were quantified with respect to mass transfer coefficient and enzyme loading. The kinetic analysis showed that increases in the mass transfer coefficient of heparin in the fiber lumen decreased the apparent Michaelis constant while increases in enzyme activity immobilized to the fiber lumen increased the apparent Michaelis constant. The apparent Michaelis constant was an order of magnitude greater than the intrinsic K(m) value for the system. The intrinsic K(m) value for heparinase-cellulose is 0.4 +/- 0.3 mg/mL (N = 6) and it is the same order of magnitude as the K(m) value for soluble heparinase.


The CNTN4 c.4256C>T mutation is rare in Japanese with inherited spinocerebellar ataxia.
To confirm the incidence of SCA16 in Japan, we screened DNA samples from a number of patients of ataxia of unknown etiology for the substitution. We examined a total of 323 DNA samples from Japanese patients with inherited spinocerebellar ataxia. We found no 317-base pair band in the patients with ataxia of unknown etiology. It seemed that this mutation (c.4256C>T) is rare in Japanese patients with inherited spinocerebellar ataxia. Mutations in other populations should be analyzed. Pathological examinations and molecular biological examinations are needed to confirm that this mutation is a true cause of SCA16.


Effects of topical ophthalmic application of 0.5% proparacaine hydrochloride on aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs.
OBJECTIVE To evaluate the effects of topical ophthalmic application of 0.5% proparacaine hydrochloride solution (PHCL; containing 0.01% benzalkonium chloride as preservative) on aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs. DESIGN Clinical trial. ANIMALS 25 client-owned dogs with infected corneal ulcers (24 unilaterally affected and 1 bilaterally affected; only 1 eye included/dog) examined between June 2008 and May 2011. PROCEDURES Swab samples for aerobic bacterial culture were collected from the periphery of each corneal ulcer before and approximately 1 minute after topical ophthalmic application of 1 drop of PHCL. Numbers of aerobic bacterial species isolated from affected eyes were compared between sample collection points and between other variables (ie, side [left or right] of affected eye, prior treatments, and patient age, sex, and neuter status). RESULTS There was no significant difference between numbers of aerobic bacterial species isolated per eye or overall aerobic bacterial culture results (positive or negative) before versus after PHCL application. Similarly, prior treatment had no significant effect on aerobic bacterial culture results for samples collected at either point. The most commonly isolated bacteria before and after PHCL application were Staphylococcus spp (40% and 48%, respectively), followed by Streptococcus spp (23% and 22%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE Topical ophthalmic application of PHCL did not significantly affect aerobic bacterial culture results for naturally occurring infected corneal ulcers in dogs as assessed in this study. Therefore, topical ophthalmic PHCL application could be useful in clinical settings prior to sample collection to relieve patient discomfort and to aid in sample acquisition without compromising aerobic bacterial culture results.


Clopidogrel reloading for patients with acute myocardial infarction already on clopidogrel therapy.
We sought to determine the association of clopidogrel reloading with in-hospital bleeding and mortality in contemporary practice. We examined clopidogrel reloading for ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients on pre-admission clopidogrel therapy in the ACTION Registry-GWTG from 2009 to 2014. We used inverse probability weighted propensity adjustment to compare in-hospital mortality and major bleeding risks between patients reloaded in the first 24 h with ≥300 mg of clopidogrel vs. those continued on a maintenance (<300 mg) dose. Among the 12 366 patients on pre-admission clopidogrel therapy who were admitted with STEMI, 9369 (75.8%) received a loading dose. Of 39 158 patients with NSTEMI, 10 144 (25.9%) were reloaded. Reloaded patients were younger, had fewer comorbid conditions, and were more likely to be treated with primary PCI (STEMI) or an early invasive strategy (NSTEMI). Risks of major bleeding were not significantly different between patients with and without reloading, whether presenting with STEMI (OR 0.98, 95% CI 0.85-1.13) or NSTEMI (OR 1.00, 95% CI 0.90-1.11). Among STEMI patients, clopidogrel reloading was associated with lower risks of in-hospital mortality (OR 0.80, 95% CI 0.66-0.96), however no significant mortality difference was observed among NSTEMI patients (OR 1.13, 95% CI 0.93-1.37). Clopidogrel reloading occurs frequently among MI patients who are on pre-admission clopidogrel therapy, particularly among STEMI patients. We did not observe increased bleeding or mortality risk with clopidogrel reloading, and therefore reloading could be safe for most MI patients.


Emicizumab dose up-titration in case of suboptimal bleeding control in people with haemophilia A.
Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors. To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control. Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration. Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0-32.0) weeks. The model-based annualised bleed rate for 'treated bleeds' and 'all bleeds' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4-123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration. The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials.


Matrilin-2 interacts with itself and with other extracellular matrix proteins.
Matrilin-2 is a component of extracellular filamentous networks. To study the interactions by which it can be integrated into such assemblies, full-length and truncated forms of matrilin-2 were recombinantly expressed in HEK-293 cells and purified from conditioned medium. The recombinant proteins, when used in interaction assays, showed affinity to matrilin-2 itself, but also to other collagenous and non-collagenous extracellular matrix proteins. The interaction between matrilin-2 and collagen I was studied in greater detail and could be shown to occur at distinct sites on the collagen I molecule and to have a K (D) of about 3 x 10(-8) M. Interactions with some non-collagenous protein ligands were even stronger, with matrilin-2 binding to fibrillin-2, fibronectin and laminin-1-nidogen-1 complexes, with K (D) values in the range of 10(-8)-10(-11) M. Co-localization of matrilin-2 with these ligands in the dermal-epidermal basement membrane, in the microfibrils extending from the basement membrane into the dermis, and in the dermal extracellular matrix, indicates a physiological relevance of the interactions in the assembly of supramolecular extracellular matrix structures.


Effectiveness of a loudness model for time-varying sounds in equating the loudness of sentences subjected to different forms of signal processing.
A model for the loudness of time-varying sounds [Glasberg and Moore (2012). J. Audio. Eng. Soc. 50, 331-342] was assessed for its ability to predict the loudness of sentences that were processed to either decrease or increase their dynamic fluctuations. In a paired-comparison task, subjects compared the loudness of unprocessed and processed sentences that had been equalized in (1) root-mean square (RMS) level; (2) the peak long-term loudness predicted by the model; (3) the mean long-term loudness predicted by the model. Method 2 was most effective in equating the loudness of the original and processed sentences.


Atypical Melanocytic Matricoma: A Case Report with Molecular Studies.
Melanocytic matricoma is a rare benign pilar tumor characterized by matrical differentiation and interspersed dendritic melanocytes. It may show cellular atypia and brisk mitotic activity. Histological characterization of some lesions may be difficult. In addition, because the reported cases are few and have limited follow-up, there is insufficient experience to define outcome-based criteria for malignancy. Some cases of melanocytic matricoma with more prominent atypia have been reported as malignant, but their clinical behavior is uncertain. We present a melanocytic matricoma with interspersed benign dendritic melanocytes, but moderate basaloid atypia, focally brisk mitotic activity, and atypical mitoses. Despite the apparently good delimitation of this tumor, higher magnification revealed a slightly irregular border. However, overt malignant features such as necrosis, frank asymmetry, deep infiltration, and ulceration were not present. This tumor showed a complex aberrant genomic profile with multiple whole chromosomes or chromosomal arms, losses, and duplications. The tumor mutational burden was high. A loss-of-function alteration in CDKN2A and a loss-of-function mutation in TP53 were also present. This unexpected molecular profile contrasts with the relatively bland histology of the tumor and is in line with the difficulties in microscopic differential diagnosis between melanocytic matricoma and an indolent malignant pilomatrical tumor. We suggest that molecular studies and longer follow-up periods may help to further understand and more precisely categorize borderline pilomatrical tumors with melanocytic hyperplasia.


Antihistamines or decongestants for otitis media with effusion-do they work?: …reducing waste in child health one intervention at a time.
Eco-paediatrics is an occasional feature in Evidence-Based Child Health: A Cochrane Review Journal. Our goal is to contribute to the worldwide discussion on reducing waste in health care. In each instalment, we will select a recent Cochrane review highlighting a practice, still in use, which the available evidence tells us should be discontinued.


Pheochromocytoma an adrenaline addict - a case report.
Pheochromocytomas are rare catecholamine secreting neuroendocrine tumours arising from chromaffin cells of the sympathetic nervous system in the adrenal medulla or extra-adrenal paraganglia. A 20-years-old female presented with paroxysms of abdominal pain, palpitation, sweating and headache since last 2 years. Pheochromocytoma was confirmed by 24 hour urinary catecholamine level and CT of abdomen. After three weeks of preparation, tumour was excised. The following discussion outlines current approaches to preoperative, intraoperative and postoperative anaesthetic management of patients suffering from pheochromocytoma.


Tdap vaccine attitudes and utilization among pregnant women from a high-risk population.
Infants infected with Bordatella pertussis experience high morbidity and significant mortality. Vaccinating pregnant mothers with the tetanus-diphtheria-acellular pertussis (Tdap) vaccine is a recommended strategy for preventing infant pertussis. This is especially important for mothers living in poverty and from racial and ethnic minority populations as these groups are at increased risk of having a pertussis-affected infant. Using the Health Belief Model as a framework, we surveyed a convenience sample of pregnant mothers representing these high-risk populations to understand factors associated with Tdap vaccine uptake during their pregnancy. Among the 316 mothers surveyed, 82% had gotten or planned to get Tdap that same day even though 63% of the sample had concerns about the safety of the vaccine during pregnancy. Perceived benefits and norms were the Health Belief Model constructs most consistently associated with Tdap vaccination. Although 32% of women reported prior Tdap vaccine receipt, this factor was not associated with Tdap vaccination during the current pregnancy, contrasting studies of vaccination done in non-pregnant populations. Important variations in attitudes were apparent, with Spanish-speaking women significantly more likely to have concerns about the vaccine's safety and efficacy than English-speaking women. This study indicates that among this high-risk population acceptance of Tdap vaccine during pregnancy is high. However, our results suggest that it may be important to modify information conveyed about the safety and importance of Tdap during pregnancy based on individual level factors such as language or acculturation.


Long-range effects on the capture and release of a chiral guest by a helical molecular capsule.
Helically folded molecular capsules based on oligoamide sequences of aromatic amino acids which are capable of binding tartaric acid in organic solvents with high affinity and diastereoselectivity have been synthesized, and their structures and binding properties investigated by (1)H NMR, X-ray crystallography, circular dichroism, and molecular modeling. We found that elongating the helices at their extremities by adding monomers remote from the tartaric binding site results in a strong increase of the overall helix stability, but it does not influence the host-guest complex stability. The effect of this elongation on the binding and release rates of the guest molecules follows an unexpected non-monotonous trend. Three independent observations (direct monitoring of exchange over time, 2D-EXSY NMR, and molecular modeling) concur and show that guest exchange rates tend to first increase upon increasing helix length and then decrease when helix length is increased further. This investigation thus reveals the complex effects of adding monomers in a helically folded sequence on a binding event that occurs at a remote site and sheds light on possible binding and release mechanisms.


Heterogeneous proton-bound dimers with a high dipole moment monomer: how could we experimentally observe these anomalous ionic hydrogen bonds?
Electronic structure calculations (CBS-QB3 and G3MP2) have been used to predict a suitable method to experimentally observe the anomalous structure which is predicted to exist in a proton-bound dimer with a high dipole moment monomer. The enthalpy associated with forming the proton-bound dimer from its protonated and neutral monomers is shown to be linearly related to the difference in proton affinities which has been observed experimentally. However, unlike previous experimental studies, the linear correlation is not predicted to depend strongly, if at all, on whether the basic sites are C=O, C=N, or O(H) n-donor bases. Thermochemical measurements, then, are probably not the best method to distinguish between the structures of heterogeneous proton-bound dimers. It has been shown that a suitable method to experimentally observe the anomalous structure of proton-bound dimers containing a high dipole moment monomer (or very polar monomer) is by spectroscopic measurement. The O-H+-O asymmetric stretch is probably not the best infrared band to try to correlate with structure. The best band to observe is one which is in a region of the spectrum not masked by other absorptions and is also sensitive to the proximity of the binding proton. For example, it is shown that the methanol-free O-H stretch is very sensitive to the O-H+ bond distance for a series of heterogeneous proton-bound dimers containing methanol. It is predicted that the free O-H stretch of the methanol/acetonitrile proton-bound dimer is more closely related to the O-H stretch in protonated methanol than the O-H stretch in neutral methanol. Observations of these bands should confirm that the proton is closer to methanol in the methanol/acetonitrile proton-bound dimer despite acetonitrile having a higher proton affinity.


Pathogenesis of Lassa virus infection in guinea pigs.
A rodent model for human Lassa fever was developed which uses inbred (strain 13) and outbred (Hartley) guinea pigs. Strain 13 guinea pigs were uniformly susceptible to lethal infection by 2 or more PFU of Lassa virus strain Josiah. In contrast, no more than 30% of the Hartley guinea pigs died regardless of the virus dose. In lethally infected strain 13 guinea pigs, peak titers of virus (10(7) to 10(8) PFU) occurred in the spleen and lymph nodes at 8 to 9 days, in the salivary glands at 11 days, and in the lung at 14 to 16 days. Virus reached low titers (10(4) PFU) in the plasma and brain and intermediate titers in the liver, adrenal glands, kidney, pancreas, and heart. In moribund animals, the most consistent and severe histological lesion as an interstitial pneumonia. In contrast, the brain was only minimally involved. The immune response of lethally infected strain 13 guinea pigs, as measured by the indirect fluorescent antibody test, was detectable within 10 days of infection and was similar in timing and intensity to the fluorescent antibody test response of both lethally infected and surviving outbred animals. In contrast to the fluorescent antibody response, neutralizing antibody developed late in convalescence and was thus detected only in surviving outbred guinea pigs. The availability of a rodent model for human Lassa fever in uniformly susceptible strain 13 guinea pigs should facilitate detailed pathophysiological studies and efficacy testing of antiviral drugs, candidate vaccines, and immunotherapy regimens to develop control methods for this life-threatening disease in humans.


The influence of high-speed train's transient pressure change on the fetal growth of SD rats.
This research aims to explore the influence of transient pressure fluctuation inside high-speed trains passing throught tunnels on the fetal growth of Sprague - Dawley (SD) rats. A pressure variation simulation system was designed and exposure experiments were performed on SD rats. Forty-eight SD rats are divided into two control groups and two experimental groups, and are then exposed to transient pressure alternation (-1200 Pa ~1200 Pa) from gestation day 0 to gestation day 5 (GD 0-5). Fetal growth and development indicators on GD12 and GD18 between experimental and control groups were compared. Statistical results showed that, compared to the control group, the key indicators in the experimental group, including placental weight, placental diameter, fetal weight, and crown-to-rump length have decreased by 4.77%, 3.38%, 6.20%, and 3.75% respectively on GD18. The findings imply that the pressure fluctuation environment of high-speed trains has potential effects on the fetal growth of SD rats.


Effect of Phacoemulsification on Anterior Chamber Angle in Eyes with Medically Uncontrolled Filtered Primary Angle-Closure Glaucoma.
To evaluate the effect of phacoemulsification and intraocular lens (IOLs) implantation in eyes with medically uncontrolled primary angle-closure glaucoma (PACG) previously treated with trabeculectomy and to quantify the anatomical changes in the anterior chamber angle by ultrasound biomicroscopy (UBM). Forty-four eyes of 37 consecutive patients with medically uncontrolled PACG coexisting cataracts with a surgical history of trabeculectomy were included in this study. Each patient underwent phacoemulsification and IOL implantation. Indentation gonioscopy and UBM were performed preoperatively and then again 3 months after surgery. The main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), number of antiglaucoma medications and anatomical changes in the anterior chamber angle. The mean logarithm of the minimum angle of resolution BCVA significantly improved from 0.52 ± 0.30 preoperatively to 0.26 ± 0.23 postoperatively (p < 0.001). The mean IOP significantly decreased from 24.33 ± 9.65 mmHg preoperatively to 18.04 ± 7.86 mmHg postoperatively (p < 0.05). 001). The median number of antiglaucoma medications decreased from 2 preoperatively to 1 postoperatively (p < 0.001). There was no significant difference in the extent of peripheral anterior synechia after the surgery (p > 0.05). Some parameters, including anterior central chamber depth, angle opening distance at 500 μm, trabecular-iris angle, and scleral ciliary process angle, were significantly higher after than before surgery (p < 0.001). However, the crystalline lens rise was significantly smaller following the surgery (p < 0.001). Phacoemulsification and IOL implantation reduced the IOP and improved vision in eyes with medically uncontrolled filtered PACG. The mechanism underlying the outcomes observed following surgery might be related to the anterior chamber deepening, widened drainage angle, and improved aqueous fluid flow to the trabecular meshwork.


Assessing cell chimerism in an acute graft-versus-host disease model established in TLR4 knockout mice.
Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. To elucidate the role of Toll-like receptor 4 (TLR4), the major receptor for bacterial lipopolysaccharide, in the development of GVHD, we constructed a GVHD model in TLR4 knockout (TLR4-/-) mice and monitored the cell chimerism. In this study, we used polymerase chain reaction to identify whether TLR4 knockout (TLR4-/-) mice were established. Before transplantation, we pretreated mice with irradiation so as to obtain an appropriate irradiation dose. Flow cytometry was applied to measure the chimerism status, the distributions of antigen-presenting cells (APCs), and T-cells in TLR4+/+ and TLR4-/- recipient mice. The general condition of TLR4-/- recipients was better than that of TLR4+/+ recipients, and the TLR4-/- recipient mice showed less severe GVHD manifestations than the TLR4+/+ recipient mice. Most of the APCs and T-cells in the host mouse spleen were derived from donor cells, and CD4+ T-cells, including memory T-cells, were in the majority in host mice. In general, our data show that TLR4 deletion attenuated GVHD development, which suggests that TLR4 could be used as a novel target and therapeutic paradigm in GVHD therapies.


Comparative immunogenicity of four Haemophilus influenzae type b conjugate vaccines in Alaska Native infants.
We compared the immunogenicity of the four available Haemophilus influenzae type b (Hib) conjugate vaccines in Alaska Native infants. Three of the vaccines, Hib oligosaccharide-CRM197 (HbOC), polyribosylribitol phosphate-diphtheria toxoid (PRP-D) and polyribosylribitol phosphate-tetanus toxoid (PRP-T), were given at 2, 4 and 6 months of age, and the PRP Neisseria meningitidis outer membrane protein (PRP-OMP) conjugate vaccine was given at 2 and 4 months of age. Enrollment was largely sequential by vaccine availability beginning with HbOC and ending with PRP-T. A total of 225 infants completed the full vaccination series. Groups of infants receiving the different vaccines did not differ significantly by sex, ethnicity, degree Alaska Native or age at vaccination. The only vaccine that induced a response with the first 2-month dose was PRP-OMP; 91% of infants had > or = 0.15 micrograms/ml and 57% had > or = 1.0 microgram/ml of anti-PRP antibody by 4 months of age. After two doses it also remained the most immunogenic. After the full three vaccine series, trials that requires cough of 21 days is excessively restrictive.


Influence of ambulatory blood pressure-related indicators within 24 h on in-hospital death in sepsis patients.
Background: Sepsis is a serious public health problem worldwide. Blood pressure is one of the indicators that is closely monitored in intensive-care units, and it reflects complex interactions between the internal cardiovascular control mechanism and the external environment. We aimed to determine the impact of indicators related to the ambulatory blood pressure on the prognosis of sepsis patients. Methods: This retrospective study was based on the Medical Information Mart for Intensive Care IV database. Relevant information about sepsis patients was extracted according to specific inclusion and exclusion criteria. Examined parameters included the average blood pressure, blood pressure variability (BPV), and circadian rhythm, and the study outcome was in-hospital death. We investigated the effects of these indicators on the risk of in-hospital death among sepsis patients using Cox proportional-hazards models, restricted cubic splines analysis, and subgroup analysis. Results: This study enrolled 10,316 sepsis patients, among whom 2,117 died during hospitalization. All parameters except the nighttime variation coefficient of the diastolic blood pressure (DBP) were associated with in-hospital death of sepsis patients. All parameters except for fluctuations in DBP exhibited nonlinear correlations with the outcome. The subgroup analysis revealed that some of the examined parameters were associated with in-hospital death only in certain subgroups. Conclusion: Indicators related to the ambulatory blood pressure within 24 h are related to the prognosis of sepsis patients. When treating sepsis, in addition to blood pressure, attention should also be paid to BPV and the circadian rhythm in order to improve the prognosis and the survival rate.


[Expression and significance of Nrf2/ARE pathway ralated factors in the HepG2 cell model of steatosis].
To explore a new method of establishing HepG2 cell model of steatosis and observe the expression and significance of nuclear factor erythroid-2p45-related factor 2(Nrf2)/antioxidative response element (ARE) pathway related factors in HepG2 cells of steatosis. HepG2 cells were induced with DMEM containing 25% fetal bovine serum, 0.1% MCT/LCT Fat Emulsion and 0.1 mmol/L free fatty acid (FFA) at different stages and the control group cells were cultured with normal DMEM medium. After the cell models were successfully established, lipid droplets in cytoplasm were observed with Oil Red 0 staining, and the triglyceride (TG) accumulation in HepG2 cells were tested by biochemical assay. Intracellular reactive oxygen species (ROS) concentration were detected by flow cytometry. Nitric oxide (NO), superoxide dismutase(SOD), malonyldialdehyde(MDA) and glutathione peroxidase(GSH-Px) were tested by biological reagent kit, while the protein expression of nuclear factor erythroid-2p45-related factor 2(Nrf2), heme oxygenase-1 (HO-1) and quinone oxidoreductase-1(NQO1) were analyzed by Western blot. Compared with that in the control group, red cytoplasmic lipid droplets were visible in model group; TG,ROS, NO, MDA concentration (P < 0.05, P < 0.01) and the protein expression of Nrf2, HO-1 and NQO1 (P < 0.05, P < 0.01)were significantly higher in model group, while SOD, GSH-Px concentration reduced significantly (P < 0.01). The in vitro cell model of steatosis and oxidative stress was successfully established. The activation of Nrf2/ARE pathway related factors maybe relevant to the overreaction of oxidative stress in HepG2 cells of steatosis.


Cognitive functioning differentially predicts different dimensions of older drivers' on-road safety.
The extent to which deficits in specific cognitive domains contribute to older drivers' safety risk in complex real-world driving tasks is not well understood. We selected 148 drivers older than 70 years of age both with and without neurodegenerative diseases (Alzheimer disease-AD and Parkinson disease-PD) from an existing driving database of older adults. Participant assessments included on-road driving safety and cognitive functioning in visuospatial construction, speed of processing, memory, and executive functioning. The standardized on-road drive test was designed to examine multiple facets of older driver safety including navigation performance (e.g., following a route, identifying landmarks), safety errors while concurrently performing secondary navigation tasks ("on-task" safety errors), and safety errors in the absence of any secondary navigation tasks ("baseline" safety errors). The inter-correlations of these outcome measures were fair to moderate supporting their distinctiveness. Participants with diseases performed worse than the healthy aging group on all driving measures and differences between those with AD and PD were minimal. In multivariate analyses, different domains of cognitive functioning predicted distinct facets of driver safety on road. Memory and set-shifting predicted performance in navigation-related secondary tasks, speed of processing predicted on-task safety errors, and visuospatial construction predicted baseline safety errors. These findings support broad assessments of cognitive functioning to inform decisions regarding older driver safety on the road and suggest navigation performance may be useful in evaluating older driver fitness and restrictions in licensing.


Phacomatosis pigmentovascularis type IIIb.
Phacomatosis pigmentovascularis (PPV) is a group of syndromes comprising coexistent vascular and pigmentary nevi, which is first classified into five subtypes and then further categorized according to the absence or presence of associated systemic findings as type (a) and (b), respectively. This case report is of an 11-year-old Turkish girl with extensive vascular nevus and nevus spilus. Because of coexistent scoliosis, the patient represents an example of PPV type IIIb. Including the present case, a total of eight cases of PPV type IIIb have been reported to date. The case is discussed in view of the new classification proposed by Happle.


Permeability of the boundary layers of Bdellovibrio bacteriovorus 109J and its bdelloplasts to small hydrophilic molecules.
Measurements of the sucrose-permeable and -impermeable volumes during Bdellovibrio bacteriovorus attack on Escherichia coli or Pseudomonas putida showed that the volume of the bdelloplast increased over that of the substrate cell. Although the pattern of the increase differed with the two organisms, the volumes reached maximum at about 60 min into the bdellovibrio growth cycle. By this time, the cytoplasmic membranes of the attacked cells were completely permeable to sucrose. The kinetics of increase in sucrosepermeable volumes were similar to the kinetics of attachment and penetration (Varon and Shilo, J. Bacteriol. 95:744-753, 1968). These data show that the original cytoplasmic and periplasmic compartmentalization of the substrate cell ceases to exist with respect to small hydrophilic molecules during bdellovibrio attack. In contrast, the effective pore size of the outer membrane of the substrate cell to small oligosaccharides remains unaltered during bdelloplast formation as was shown by direct measurements of its exclusion limits. The major porin protein of E. coli, OmpF, was recoverable from the bdelloplast outer membrane fraction until the onset of lysis. The Braun lipoprotein was removed from the bdelloplast wall early, and OmpA was lost in the terminal part of the bdellovibrio growth cycle.


Transcatheter Valve-in-Valve and Valve-in-Ring Interventions for Failing Bioprostheses and Annuloplasty Rings.
Transcatheter aortic valve implantation has dramatically changed the treatment of valvular heart disease over the past decade. At the same time, the indications for bioprosthesis implantation have been continuously extended toward younger patients, driven by excellent clinical results and improved durability. While the omission of oral anticoagulation reduces the risk of severe bleeding complications, the long-term durability of bioprostheses is still limited. In light of the growing number of elderly transcatheter aortic valve replacement (TAVR) patients, the prevalence of patients with failed bioprostheses and advanced comorbidities is expected to rise. Currently, transcatheter valve-in-valve (ViV) and valve-in-ring (ViR) interventions represent a valuable alternative treatment option for patients with a high risk for surgical reoperation. Several reports have described a high procedural success rate and low postprocedural morbidity and mortality during mid-term follow-up. We are still facing valve-specific and procedure-related challenges in all types of procedures, but especially in transcatheter ViR interventions. Considering the high technical demand of these interventions, a strong and highly specialized heart team in heart valve centers is the cornerstone of successful patient treatment. This review focuses on individualized patient selection, procedure-specific risk factors and technical aspects of transcatheter ViV/R interventions, and explores the currently available literature on postinterventional outcome.


Bioconjugated gold nanoparticles accelerate the growth of new blood vessels through redox signaling.
We have designed and developed novel pro-angiogenic bio-synthesized gold nanoconjugates (b-Au-HP) that make new blood vessels, as observed by several in vitro and in vivo assays, suggesting their future potential applications in alternative treatment strategies for wound healing, cardiovascular diseases (CVD) and ischemic diseases using a nanomedicine approach.


Alveolar-capillary membrane conductance is the best pulmonary function correlate of exercise ventilation efficiency in heart failure patients.
In heart failure (HF), changes in lung mechanics and gas diffusion are limiting factors to exercise. Their contribution to an increased exercise ventilation to CO2 production (VE/VCO2) slope is undefined. A total of 67 stable HF patients underwent cardiopulmonary exercise and pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), maximal voluntary ventilation (MVV), total lung capacity (TLC) and alveolar diffusing capacity with its subcomponents (alveolar-capillary membrane conductance (D(m)) and capillary blood volume (V(c))). Patients showed a mild restrictive pattern (FEV1=85+/-15% and FVC=75+/-13% of normal predicted) and a moderate D(m) reduction (32+/-12 ml min(-1) mm Hg(-1)). Average peak VO(2) was 15.6+/-4.0 ml min(-1) kg(-1) and the VE/VCO2 slope was 39.6+/-11.0. At simple Spearman correlation analysis, all variables, but V(c), correlated with peak VO2; only D(m) correlated with VE/VCO2 slope. At partial Spearman correlation, all variables lost the peak VO2 correlation, and D(m) still inversely correlated with VE/VCO2 slope (r=-0.35; p=0.005). In patients with a high VE/VCO2 slope (cutoff value 34), despite comparable lung volumes, D(m) was significantly more depressed (30+/-13 vs. 35+/-10 ml min(-1) mm Hg(-1); p<0.01). Pulmonary function tests and alveolar gas diffusing capacity poorly correlate with peak VO2. D(m) impairment rather than lung volumes correlates with exercise ventilation efficiency. This finding further adds to the pathophysiological relevance of an abnormal gas exchange in HF patients.


Video as a strategy to evaluate and assist clinical teachers with student assessment.
The assessment of the clinical competence of nursing students requires expertise in nursing as well as skills in student assessment. The development of these student assessment skills is dependent on the preparation of the clinical teacher. The results of this pilot study indicate that video can be one successful tool in evaluating the assessment skills of clinical teachers. Video also may be useful as a staff development tool by providing a nonthreatening way for clinical teachers to familiarize themselves with clinical assessment. In turn, this will have benefits for universities and students by ensuring consistency of clinical assessment by clinical teachers.


Tissue-Resident Macrophages in the Control of Infection and Resolution of Inflammation.
Macrophage, as an integral component of the immune system and the first responder to local damage, is on the front line of defense against infection. Over the past century, the prevailing view of macrophage origin states that all macrophage populations resided in tissues are terminally differentiated and replenished by monocytes from bone-marrow progenitors. Nonetheless, this theory has been reformed by ground-breaking discoveries from the past decades. It is now believed that tissue-resident macrophages (TRMs) are originated from the embryonic precursors and seeded in tissue prenatally. They can replenish via self-renewal throughout the lifespan. Indeed, recent studies have demonstrated that tissue-resident macrophages should not be classified by the over-simplified macrophage polarization (M1/M2) dogma during inflammation. Moreover, multiple lines of evidence have indicated that tissue-resident macrophages play critical roles in maintaining tissue homeostasis and facilitating tissue repair through controlling infection and resolving inflammation. In this review, we summarize the properties of resident macrophages in the lung, spleen, and heart, and further highlight the impact of TRM populations on inflammation control and tissue repair. We also discuss the potential role of local proliferation in maintaining a physiologically stable TRM pool in response to acute inflammation.


Energy loss by keV ions in silicon.
Using silicon photodiodes with an ultrathin passivation layer, the average total energy lost to silicon target electrons (electronic stopping) by incident low energy ions and the recoil target atoms they generate is directly measured. We find that the total electronic energy deposition and the ratio of the total nuclear to electronic stopping powers for the incident ions and their recoils each follow a simple, universal representation, thus enabling systematic prediction of ion-induced effects in silicon. We also observe a velocity threshold at 0.05 a.u. for the onset of electronic stopping.


Hunter syndrome: prenatal diagnosis in maternal serum.
Iduronate sulfate sulfatase (ISS), the deficient hydrolase in Hunter syndrome, consistently increases in the serum of pregnant women, reaching a three- to fourfold increase from pre-pregnancy levels toward the end of pregnancy. In Hunter carriers, a correlation occurs between the status of the fetus with regard to Hunter syndrome and the ISS increase in maternal serum. Thus, in pregnancies with Hunter-affected fetuses, enzyme levels did not change in the serum of heterozygous mothers until abortion was performed, while in nonaffected fetuses, ISS increased usually very early in pregnancy--as early as the 6th-12th week. In heterozygote female fetuses, this increase might be delayed. These data imply that a prenatal diagnosis of Hunter syndrome might be accomplished in maternal serum at early conventional procedures for the prenatal diagnosis of Hunter syndrome.


Secondary bone grafting in cleft lip and palate with eruption of tooth into the graft: a case report.
Secondary bone grafting in cleft lip and palate patients is performed preferably before the eruption of permanent canine in order to provide adequate periodontal support for eruption and preservation of the teeth adjacent to the cleft. Presented here with is a case of unilateral cleft lip and palate, which was followed up from birth to 15 years of age. The role of an orthodontist in the team approach for management of such anomalies is described. Also discussed in detail is the entire range of treatment procedures the child underwent, especially the role of secondary bone grafting.


Coevolution between flight morphology, vertical stratification and sexual dimorphism: what can we learn from tropical butterflies?
Occurrence patterns are partly shaped by the affinity of species with habitat conditions. For winged organisms, flight-related attributes are vital for ecological performance. However, due to the different reproductive roles of each sex, we expect divergence in flight energy budget, and consequently different selection responses between sexes. We used tropical frugivorous butterflies as models to investigate coevolution between flight morphology, sex dimorphism and vertical stratification. We studied 94 species of Amazonian fruit-feeding butterflies sampled in seven sites across 3341 ha. We used wing-thorax ratio as a proxy for flight capacity and hierarchical Bayesian modelling to estimate stratum preference. We detected a strong phylogenetic signal in wing-thorax ratio in both sexes. Stouter fast-flying species preferred the canopy, whereas more slender slow-flying species preferred the understorey. However, this relationship was stronger in females than in males, suggesting that female phenotype associates more intimately with habitat conditions. Within species, males were stouter than females and sexual dimorphism was sharper in understorey species. Because trait-habitat relationships were independent from phylogeny, the matching between flight morphology and stratum preference is more likely to reflect adaptive radiation than shared ancestry. This study sheds light on the impact of flight and sexual dimorphism on the evolution and ecological adaptation of flying organisms.


Stimulation of the human immunodeficiency virus type 1 enhancer by the human T-cell leukemia virus type I tax gene product involves the action of inducible cellular proteins.
The human immunodeficiency virus type 1 (HIV-1) preferentially infects CD4+ T lymphocytes and may exist as a latent provirus within these cells for extended periods. The transition to a productive retroviral infection results in T-cell death and clinically may lead to the acquired immune deficiency syndrome. Accelerated production of infectious HIV-1 virions appears to be closely linked to a heightened state of T-cell activation. The transactivator (Tax) protein of the type I human T-cell leukemia virus (HTLV-I) can produce such an activated T-cell phenotype and augments activity of the HIV-1 long terminal repeat. One Tax-responsive region within the HIV-1 long terminal repeat has been mapped to a locus composed of two 10-base-pair direct repeats sharing homology with the binding site for the eucaryotic transcription factor NF-kappaB (GGGACTTTCC). Tax-expressing Jurkat T cells contain one or more inducible cellular proteins that specifically associate with the HIV-1 enhancer at these binding sites. Microscale DNA affinity precipitation assays identified a Tax-inducible 86-kilodalton protein, HIVEN86A, as one of these HIV-1 enhancer-binding factors. The interaction of HIVEN86A, and presumably other cellular proteins, with the HIV-1 enhancer appears functionally important as oligonucleotides corresponding to this enhancer were sufficient to impart Tax inducibility to an unresponsive heterologous promoter. These findings suggest that the Tax-inducible cellular protein HIVEN86A plays an important role in the transcriptional activation of the HIV-1 enhancer. These specific protein-DNA interactions may also be important for the transition of HIV-1 from a latent to a productive mode of infection. Furthermore, these findings highlight an intriguing biological interplay between HTLV-1 and HIV-1 through a cellular transcriptional pathway that is normally involved in T-cell activation and growth.


Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice.
The endoplasmic reticulum (ER) stress results from disrupted protein folding triggered by protein mutation or oxidation, reduced proteasome activity, and altered Ca2+ homeostasis. ER stress is accompanied by activation of the unfolded protein response (UPR) and cell death pathway. We examined if the UPR and cell death pathway would be activated in Alzheimer's disease (AD). RT-PCR experiments revealed increased splicing of X-box binding protein-1 (XBP-1), an UPR transcription factor, in AD compared with age-matched control. Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose-regulated protein 78 (GRP78), was increased in AD, suggesting disturbed activation of the UPR in AD. C/EBP homologous protein (CHOP), caspase-3, caspase-4, and caspase-12, downstream mediators of cell death pathway, were activated in AD. Neither the UPR nor cell death pathway was induced in aged Tg2576 mice, a transgenic mouse model of Alzheimer's disease that reveals both plaque pathology and some cognitive deficits. The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid beta and senile plaque.


Stochasticity in host-parasitoid models informs mechanisms regulating population dynamics.
Population dynamics of host-parasitoid interactions have been traditionally studied using a discrete-time formalism starting from the classical work of Nicholson and Bailey. It is well known that differences in parasitism risk among individual hosts can stabilize the otherwise unstable equilibrium of the Nicholson-Bailey model. Here, we consider a stochastic formulation of these discrete-time models, where the host reproduction is a random variable that varies from year to year and drives fluctuations in population densities. Interestingly, our analysis reveals that there exists an optimal level of heterogeneity in parasitism risk that minimizes the extent of fluctuations in the host population density. Intuitively, low variation in parasitism risk drives large fluctuations in the host population density as the system is on the edge of stability. In contrast, high variation in parasitism risk makes the host equilibrium sensitive to the host reproduction rate, also leading to large fluctuations in the population density. Further results show that the correlation between the adult host and parasitoid densities is high for the same year, and gradually decays to zero as one considers cross-species correlations across different years. We next consider an alternative mechanism of stabilizing host-parasitoid population dynamics based on a Type III functional response, where the parasitoid attack rate accelerates with increasing host density. Intriguingly, this nonlinear functional response makes qualitatively different correlation signatures than those seen with heterogeneity in parasitism risk. In particular, a Type III functional response leads to uncorrelated adult and parasitoid densities in the same year, but high cross-species correlation across successive years. In summary, these results argue that the cross-correlation function between population densities contains signatures for uncovering mechanisms that stabilize consumer-resource population dynamics.


PRIME-MD: its utility in detecting mental disorders in American Indians.
To examine the utility of using PRIME-MD (Primary Care Evaluation of Mental Disorders) for diagnosing mental disorders in American Indians. One hundred randomly selected, adult, American-Indian patients who receive health care services at an urban Indian Health Service primary care clinic were evaluated for mental disorder by three primary care physicians using the PRIME-MD diagnostic assessment procedure. The main outcome measures were PRIME-MD diagnoses, diagnoses by an independent mental health professional, and treatment/referral decisions. Eighteen percent of the patients had a threshold (met full DSM-IV criteria ) PRIME-MD diagnosis, and an additional 17 percent had a subthreshold PRIME-MD diagnosis. The most frequently occurring PRIME-MD diagnoses were: probable alcohol abuse/dependence, major depressive disorder, and generalized anxiety disorder. Over 60 percent of the patients with a PRIME-MD diagnosis who were known "somewhat" or "fairly well" to their physician had not been recognized as having that psychiatric disorder prior to the PRIME-MD assessment. Therapy and/or referral was initiated for nineteen of the twenty-seven patients with a PRIME-MD diagnosis who were not previously receiving treatment. The primary care physicians were able to complete the PRIME-MD evaluations within an average of 7.8 minutes. There was a fair agreement between the PRIME-MD diagnoses and the diagnoses of the mental health professional (kappa = 0.56; overall accuracy rate = 79%). The present study represents the first formal examination of the use of PRIME-MD with American Indians. The results are encouraging. Further studies using PRIME-MD with other urban groups and reservation populations are recommended.


Targeted recombination of homologous chromosomes using CRISPR-Cas9.
CRISPR mutagenesis is an efficient way to disrupt specific target genes in many model organisms. We previously devised a targeted CRISPR recombination method to generate intragenic recombinants of alleles in Drosophila. Here, we assessed the applicability of CRISPR targeting-induced recombination to different genetic loci. We compared the ectopic recombination rates in the male germline by CRISPR targeting at two neighboring genetic loci within the genomic region that consists of the repressed chromatin domain of the Lobe gene, and the transcriptionally active domain of PRAS40. Targeting around the transcription initiation of PRAS40 resulted in higher recombination rates of homologous chromosomes than targeting at the Lobe intron. Based on the efficient homologous recombination by CRISPR targeting observed around transcriptionally active loci, we further investigated targeted recombination between P-elements that are inserted at different genomic locations. Male recombination by CRISPR targeting of P-elements located proximally and distally to the ebony gene produced recombinants deficient for the intervening region of ebony transcription. Taken together, we suggest that targeted homologous recombination by CRISPR targeting may have specific genetic applications, such as generation of allelic combinations or chromosomal variations.


The C-terminal portion of the Hrs protein interacts with Tsg101 and interferes with human immunodeficiency virus type 1 Gag particle production.
The human immunodeficiency virus type 1 (HIV-1) Gag protein recruits Tsg101 to facilitate HIV-1 particle budding and release. In uninfected cells, the Hrs protein recruits the ESCRT-I complex to the endosome, also through an interaction with Tsg101, to promote the sorting of host proteins into endosomal vesicles and multivesicular bodies. Here, we show that the overexpression of the C-terminal fragment of Hrs (residues 391 to 777) or Hrs mutants lacking either the N-terminal FYVE domain (mutant dFYVE) or the PSAP (residues 348 to 351) motif (mutant ASAA) all efficiently inhibit HIV-1 Gag particle production. Expression of the dFYVE or ASAA mutants of Hrs had no effect on the release of Moloney murine leukemia virus. Coimmunoprecipitation analysis showed that the expression of Hrs mutant dFYVE or ASAA significantly reduced or abolished the HIV-1 Gag-Tsg101 interaction. Yeast-two hybrid assays were used to identify two new and independent Tsg101 binding sites, one in the Hrs coiled-coil domain and one in the proline/glutamic acid-rich domain. Scanning electron microscopy of HeLa cells expressing HIV-1 Gag and the Hrs ASAA mutant showed viral particles arrested in "lump-like" structures that remained attached to the cell surface. Together, these data indicate that fragments of Hrs containing the C-terminal portion of the protein can potently inhibit HIV-1 particle release by efficiently sequestering Tsg101 away from the Gag polyprotein.