[Application of anterior segment optical coherence tomography for measuring the tear meniscus height in the diagnosis of dry eye diseases].
To investigate the reproducibility and repeatability of anterior segment optical coherence tomography (AS-OCT) for measuring the tear meniscus height (TMH) and to evaluate its clinical application in the diagnosis of dry eye diseases. Evaluation of diagnostic test. The inferior tear meniscus height of 36 eyes of 36 patients with dry eyes and 38 eyes of 38 normal volunteers were measured by AS-OCT and slit lamp marker lens in Zhongshan Ophthalmic Center, Sun Yat-sen University from November 2007 to August 2008. Then the paired t test, intra-class correlation coefficiency test, ANOVA and Spearman test were used for comparing TMH values between normal subjects and dry eye patients, two different examiners, two analysts, the repeated examines within a week, and AS-OCT group and slit lamp reticle lens group. There are no significant differences between different observers for the same 22 subjects [t = 1.881, P = 0.074; TMH: (0.256 +/- 0.052) mm and (0.265 +/- 0.066) mm], the same observer in different check-points for 20 subjects [ t = 1.306, P = 0.207; TMH: (0.265 +/- 0.056) mm and (0.272 +/- 0.052) mm] as well as different analyzers for the same 20 AS-OCT pictures [t = 2.048, P = 0.065; TMH: (0.266 +/- 0.059) mm and (0.259 +/- 0.062) mm]. There is a positive correlation between AS-OCT and reticule reading in measuring TMH (r = 0.713, P = 0.000); there are significant differences between normal subjects and patients with dry eye (t = 9.368, P = 0.000), and between groups of dry eye at different degree (F = 55.763, P = 0.000) [TMH: grade II, (0.228 +/- 0.036) mm; grade III, (0.145 +/- 0.056) mm; and grade IV, (0.084 +/- 0.048) mm]. The sensitivity and specificity of TMH value with AS-OCT for dry eye diagnosis was 77.8% and 71.7% when the diagnostic value was set to be 0.213 mm under the instruction of receptor operating characteristics curve (ROC). AS-OCT has excellent reproducibility and repeatability for measuring the inferior tear meniscus height, and can be taken as an objective clinical imaging method for the diagnosis of aqueous deficiency dry eye.


First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401.
To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.


Image-guided radiation therapy (IGRT) in gastrointestinal tumors.
Daily setup errors and changes in body habitus during external beam radiotherapy can result in interfraction variation, contributing to uncertainties in treatment delivery. The conventional method of patient positioning using external skin markings is inadequate in reducing these interfraction variations. To evaluate use of on-board imaging with daily kV-kV image matching to reduce interfraction variation in patients with primary gastrointestinal cancer. To evaluate interfraction variation, 13 patients underwent radiotherapy for primary non-metastatic gastrointestinal cancer as did 1 patient with renal liposarcoma. After conventional external setup, kV-kV image matching was performed using bony landmarks or radiopaque surgical clips with a Varian on-board imager. The degree of shift between the real-time patient position and the planning position were recorded in three planes, and appropriate corrections were made for treatment. Degree of shift, acute toxicity and local response were assessed. For 276 daily on-board imaging sessions, average shift was 0.30+/-0.42 cm (vertical), 0.33+/-0.34 cm (longitudinal), and 0.35+/-0.39 cm (lateral); average 3-D vector shift was 0.71+/-0.52 cm. Percentage of shift greater than or equal to 0.5 cm was 25% (vertical), 28% (longitudinal), and 30% (lateral); percentage of total vector shift greater than or equal to 0.5 cm was 64%. The pattern of shifts showed a random distribution over time. At median 6-month follow-up, 3 (21%) patients had radiographic local disease regression, ten (71%) had local disease stabilization, and 1 (7%) had local progression. Use of daily on-board imaging kV-kV matching reduced uncertainty in amount of dose delivered, potentially resulting in improvement in local control and reduction in treatment toxicity.


Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells.
Human respiratory syncytial virus (RSV) is the most important agent of serious pediatric respiratory tract disease worldwide. One of the main characteristics of RSV is that it readily reinfects and causes disease throughout life without the need for significant antigenic change. The virus encodes nonstructural protein 1 (NS1) and NS2, which are known to suppress type I interferon (IFN) production and signaling. In the present study, we monitored the maturation of human monocyte-derived myeloid dendritic cells (DC) following inoculation with recombinant RSVs bearing deletions of the NS1 and/or NS2 proteins and expressing enhanced green fluorescent protein. Deletion of the NS1 protein resulted in increased expression of cell surface markers of DC maturation and an increase in the expression of multiple cytokines and chemokines. This effect was enhanced somewhat by further deletion of the NS2 protein, although deletion of NS2 alone did not have a significant effect. The upregulation was largely inhibited by pretreatment with a blocking antibody against the type I IFN receptor, suggesting that suppression of DC maturation by NS1/2 is, at least in part, a result of IFN antagonism mediated by these proteins. Therefore, this study identified another effect of the NS1 and NS2 proteins. The observed suppression of DC maturation may result in decreased antigen presentation and T-lymphocyte activation, leading to incomplete and/or weak immune responses that might contribute to RSV reinfection.


Improved method for visualizing coated pits, microfilaments, and microtubules in cryofixed and freeze-substituted plant cells.
We have optimized the conditions for visualizing microfilaments, microtubules, and coated pits in the cortical cytoplasm of high-pressure frozen and freeze-substituted plant cells, in both tobacco root tips and onion cotyledons, individual microfilaments and the supramolecular structure of coated pits can be seen clearly in freeze-substituted samples treated with OsO4 at 40 degrees C followed by 5% uranyl acetate. Treatment with uranyl acetate alone resulted in poorly stained cytoplasmic organelles, whereas microfilaments were difficult to discern in specimen treated with OsO4 alone. The combination of a 40 degrees C OsO4 staining step followed by staining with uranyl acetate at 4 degrees C should prove useful for more detailed plant cytoskeletal/membrane studies in the future.


[Primary gastric choriocarcinoma: case report].
Primary gastric choriocarcinoma (PGC) is an extremely rare and highly invasive tumor with rapid hematogenous spread. We present the case of a 57-year-old female patient who started with hematemesis and progressive episodes of melena, weight loss and epigastralgia. It is derived from the National Institute of Neoplastic Diseases where gastroscopy and biopsy are performed. Histological analysis reported pattern suggestive of PGC; that was confirmed by immunohistochemical analysis for human chorionic gonadotrophin and fetal alpha protein. Subsequently, the patient underwent a radical D2 gastrectomy with splenic preservation and tail of the pancreas preservation. Unfortunately, her evolution was not favorable and died due to the progression of the disease.


Size dependent biological profiles of PEGylated gold nanorods.
The perspective of introducing plasmonic particles for applications in biomedical optics is receiving much interest. However, their translation into clinical practices is delayed by various factors, which include a poor definition of their biological interactions. Here, we describe the preparation and the biological profiles of gold nanorods belonging to five different size classes with average effective radii between ∼5 and 20 nm and coated with polyethylene glycol (PEG). All these particles exhibit decent stability in the presence of representative proteins, low cytotoxicity and satisfactory compatibility with intravenous administration, in terms of their interference with blood tissue. However, the suspension begins to become unstable after a few days of exposure to blood proteins. Moreover, the cytotoxicity is a little worse for smaller particles, probably because their purification is more critical, while undesirable interactions with the mononuclear phagocyte system are minimal in the intermediate size range. Overall, these findings hold implications of practical relevance and suggest that PEGylated gold nanorods may be a versatile platform for a variety of biomedical applications.


Observation of infants with SFU grades 3-4 hydronephrosis: worsening drainage with serial diuresis renography indicates surgical intervention and helps prevent loss of renal function.
Early pyeloplasty is indicated for ureteropelvic junction obstruction (UPJ) obstructions with reduced differential renal function (DRF) and/or no drainage on diuretic renography (DR). Optimal management of Society of Fetal Urology (SFU) Grades 3 and 4hydronephrosis with preservation of DRF and indeterminate drainage is less straightforward. We review our experience using serial DR to guide the management of kidneys with high-grade hydronephrosis, emphasizing preservation of DRF. After IRB approval we reviewed the charts of 1398 patients <1-year-old referred for prenatal hydronephrosis. Only patients with SFU Grades 3 and 4 hydronephrosis without ureterectasis were included in the study. Initial evaluation included a baseline DR. Follow-up included DR or ultrasound (US). 115 patients (125 kidneys) were eligible for study inclusion. 27 kidneys underwent early surgery (median 64 days) due to reduced DRF and/or severely impaired drainage. 98 kidneys were initially observed. Of these, 21 underwent delayed surgery (median 487 days) due to worsening drainage. Only 2 patients had an irreversible decrease in DRF of >5%. 77 kidneys demonstrated improved drainage and stable DRF. Comparison of observation (n = 77) and surgery groups (n = 48) revealed more kidneys with SFU Grade 3 hydronephrosis in the observation group (p = 0.0001). Infants with Grades 3 and 4 hydronephrosis and preserved DRF may be safely followed with serial DR. Patients with SFU Grade 4 hydronephosis are more likely to require surgery. Worsening drainage on serial DR is a useful indicator for surgical intervention which limits the number of pyeloplasties while preserving DRF.


Burn Chamber Test of Ex Situ Thermal Impulse Sensors.
Recently, we reported on a novel ex situ thermal impulse sensing technique (based on lanthanide-doped oxide precursor nanoparticles) for use in structural fire forensics and demonstrated its functionality in small-scale lab-based tests. As a next step we have now performed a large-scale lab test at the US Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF) Fire Research Laboratory using a burn chamber with three sand burners. In this test we demonstrate our technique's ability to determine the average temperature experienced by surfaces during the fire. While we successfully demonstrate our techniques accuracy, we also discover several previously unknown vulnerabilities. Namely, we find that: (1) our current method of embedding sensors in paint results in our sensor particles being difficult to recover (due to a large quantity of debris), (2) the current test panels have poor survivability, (3) debris from the fire tests interferes with excitation of dopant Dy ions (limiting our sensors' functionality), and (4) dispersal in paint results in suppression of the (metastable)tetragonal-to-monoclinic phase transition of ZrO2. To overcome these vulnerabilities we are evaluating new panel materials, paints, and lanthanide-dopants.


Use of complementary medicine and dietary supplements among U.S. adolescents.
Use of complementary and alternative medicine (CAM) is increasing, but some dietary supplements have potentially negative side effects. This study examines CAM and dietary supplement use among a national sample of adolescents. A total of 1280 adolescents 14-19 years old completed an online survey in 2002 about lifetime and past-30-day use of all CAM modalities, and specifically about use of herbal medicines and dietary supplements. We e-mailed invitations to 12,353 members of Harris Interactive's national Youth Query panel, and filled age/gender quotas sample targets. Data were then weighted to reflect the U.S. adolescent population by gender, race/ethnicity, urbanicity, region, parents' education, propensity to be online, and likelihood of nonresponse. Chi-square and logistic regression analyses were done using SPSS. Seventy-nine percent of adolescents had used CAM in their lifetime, 48.5% in the previous month; 46.2% had used dietary supplements in their lifetime, 29.1% in the previous month; 9.3% reported concurrent use of supplements and prescription medication in the previous month. Factors associated with CAM and supplement use included being female, positive attitudes towards CAM, and being age 16-17 years (rather than in younger or older age groups). Commonly used supplements included ginseng, zinc, echinacea, ginkgo, weight loss supplements, and creatine. Many adolescents use CAM and dietary supplements, including a significant number concurrent with prescription medications. Commonly used supplements (weight loss supplements and creatine) are closely linked to attempts to change body shape. Health care providers should be aware of CAM and supplement use by adolescents.


Cloning, sequencing and in vitro functional expression of recombinant donkey follicle-stimulating hormone receptor: a new insight into the binding specificity of gonadotrophin receptors.
Among all mammalian FSH receptors (FSH-R; including donkey (dk) FSH-R), only horse (hs) FSH-R does not bind hsLH/chorionic gonadotrophin (CG). In order to delineate the structural origin of hsFSH-R specificity precisely, we have cloned dkFSH-R cDNA from donkey testis mRNA by RT-PCR. Transiently expressed dkFSH-R endowed COS-7 cells with both hsLH/CG- and FSH-binding activity, as well as FSH-induced cAMP production. The deduced dkFSH-R amino acid sequence shares 96% identity with the hsFSH-R: notably, in the hormone-binding domain, the specificity of hsFSH-R may be ascribed to only four divergent amino acids: Thr 173, Asp 202, Asn 268 and Pro 322. Interestingly, hsAsn 268 could bear an additional N-glycosylation. According to receptor negative specificity, these amino acids could be implicated in preventing LH/CG binding to FSH-R.


Production and comparison of mature single-domain 'trefoil' peptides pNR-2/pS2 Cys58 and pNR-2/pS2 Ser58.
The preparation and purification of recombinant mature pNR-2/pS2, a single-domain member of the 'trefoil' family of cysteine-rich secreted proteins, is described. Analysis of recombinant pNR-2/pS2 by ion-exchange chromatography showed that it was heterogeneous. The heterogeneity was reduced by treatment with thiol-group-containing reagents, suggesting that it is caused by the odd number of cysteine residues in mature pNR-2/pS2, and this view was reinforced by mutation of the extra-trefoil domain cysteine residue, Cys58, to a serine residue. Electrophoresis of recombinant pNR-2/pS2 Cys58 and pNR-2/pS2 Ser58 proteins under non-denaturing conditions confirmed that the Ser58 mutant is much more homogeneous, and showed that most of pNR-2/pS2 Ser58 co-migrates as a single band with pNR-2/pS2 secreted from breast-cancer cells in culture. Treatment of recombinant pNR-2/pS2 proteins with various thiol-group-reactive reagents indicated that cysteine is the most effective at producing recombinant pNR-2/pS2 that co-migrates with pNR-2/pS2 secreted by breast-cancer cells. Dithiothreitol appeared to denature the proteins, and GSH was relatively ineffective. pNR-2/pS2 Cys58 treated with cysteine and untreated pNR-2/pS2 Ser58 had the same apparent molecular mass, measured by gel filtration, as pNR-2/pS2 secreted from breast-cancer cells. This is the first report of the production of a recombinant mature single-domain trefoil peptide and should greatly facilitate elucidation of the structure and function of pNR-2/pS2.


The Impact of Hospital Closures and Hospital and Population Characteristics on Increasing Emergency Department Volume: A Geographic Analysis.
Emergency visits are rising nationally, whereas the number of emergency departments is shrinking. However, volume has not increased uniformly at all emergency departments. It is unclear what factors account for this variability in emergency volume growth rates. The objective of this study was to test the association of hospital and population characteristics and the effect of hospital closures with increases in emergency department volume. The study team analyzed emergency department volume at New York State hospitals from 2004 to 2010 using data from cost reports and administrative databases. Multivariate regression was used to evaluate characteristics associated with emergency volume growth. Spatial analytics and distances between hospitals were used in calculating the predicted impact of hospital closures on emergency department use. Among the 192 New York hospitals open from 2004 to 2010, the mean annual increase in emergency department visits was 2.7%, but the range was wide (-5.5% to 11.3%). Emergency volume increased nearly twice as fast at tertiary referral centers (4.8%) and nonurban hospitals (3.7% versus urban at 2.1%) after adjusting for other characteristics. The effect of hospital closures also strongly predicted variation in growth. Emergency volume is increasing faster at specific hospitals: tertiary referral centers, nonurban hospitals, and those near hospital closures. This study provides an understanding of how emergency volume varies among hospitals and predicts the effect of hospital closures in a statewide region. Understanding the impact of these factors on emergency department use is essential to ensure that these populations have access to critical emergency services.


Joint Facial Action Unit Detection and Feature Fusion: A Multi-conditional Learning Approach.
Automated analysis of facial expressions can benefit many domains, from marketing to clinical diagnosis of neurodevelopmental disorders. Facial expressions are typically encoded as a combination of facial muscle activations, i.e., action units. Depending on context, these action units co-occur in specific patterns, and rarely in isolation. Yet, most existing methods for automatic action unit detection fail to exploit dependencies among them, and the corresponding facial features. To address this, we propose a novel multi-conditional latent variable model for simultaneous fusion of facial features and joint action unit detection. Specifically, the proposed model performs feature fusion in a generative fashion via a low-dimensional shared subspace, while simultaneously performing action unit detection using a discriminative classification approach. We show that by combining the merits of both approaches, the proposed methodology outperforms existing purely discriminative/generative methods for the target task. To reduce the number of parameters, and avoid overfitting, a novel Bayesian learning approach based on Monte Carlo sampling is proposed, to integrate out the shared subspace. We validate the proposed method on posed and spontaneous data from three publicly available datasets (CK+, DISFA and Shoulder-pain), and show that both feature fusion and joint learning of action units leads to improved performance compared to the state-of-the-art methods for the task.


DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system.
Down syndrome (DS), a major cause of mental retardation, is characterized by subtle abnormalities of cortical neuroanatomy, neurochemistry and function. Recent work has shown that chromosome band 21q22 is critical for many of the neurological phenotypes of DS. A gene, DSCAM (Down syndrome cell adhesion molecule), has now been isolated from chromosome band 21q22.2-22.3. Homology searches indicate that the putative DSCAM protein is a novel member of the immunoglobulin (Ig) superfamily that represents a new class of neural cell adhesion molecules. The sequence of cDNAs indicates alternative splicing and predicts two protein isoforms, both containing 10 Ig-C2 domains, with nine at the N-terminus and the tenth located between domains 4 and 5 of the following array of six fibronectin III domains, with or without the following transmembrane and intracellular domains. Northern analyses reveals the transcripts of 9.7, 8.5 and 7.6 kb primarily in brain. These transcripts are differentially expressed in substructures of the adult brain. Tissue in situ hybridization analyses of a mouse homolog of the DSCAM gene revealed broad expression within the nervous system at the time of neuronal differentiation in the neural tube, cortex, hippocampus, medulla, spinal cord and most neural crest-derived tissues. Given its location on chromosome 21, its specific expression in the central nervous system and neural crest, and the homologies to molecules involved in neural migration, differentiation, and synaptic function, we propose that DSCAM is involved in neural differentiation and contributes to the central and peripheral nervous system defects in DS.


Effects of stimulus features and instruction on response coding, selection, and inhibition: evidence from repetition effects under task switching.
The coding of stimuli and responses is crucial for human behaviour. Here, we focused primarily on the response codes (or response categories). As a method, we applied a combined dual-task and task-switch paradigm with a fixed task-to-hand mapping. Usually, negative effects (i.e., costs) are observed for response category repetitions under task switching. However, in several previous studies it has been proposed that such repetition effects do not occur, if the stimulus categories (e.g., "odd" if digits have to be classified according to their parity feature) are unequivocally mapped to specific responses. Our aim was to test this hypothesis. In the present experiments, we were able to distinguish between three different types of possible response codes. The results show that the participants generally code their responses according to abstract response features (left/right, or index/middle finger). Moreover, the spatial codes were preferred over the finger-type codes even if the instructions stressed the latter. This preference, though, seemed to result from a stimulus-response feature overlap, so that the spatial response categories were primed by the respective stimulus features. If there was no such overlap, the instructions determined which type of response code was involved in response selection and inhibition.


Imparied atrial receptor modulation or renal nerve activity in dogs with chronic volume overload.
Left atrial receptors with vagal afferents are reset and become less sensitive in dogs with chronic high output congestive heart failure (Zucker et al J Clin Invst 1977;60:323). We determined if the normal reflex inhibition of renal sympathetic nerve activity (RNA) which occurs in response to left atrial distension is altered in dogs with chronic volume overload produced by an aorto-vena caval fistula (AVF). In addition, we examined the ability of the arterial baroreflex to alter RNA. In normal dogs, left atrial distension decreased RNA by 6.8 +/- 1.8% per mmHg change in left atrial pressure (LAP). After carotid sinus denervation (CSD), this inhibition was increased to 10.9 +/- 1.4% per mmHg change in RNA in response to left atrial distension. Vagotomy completely abolished any change in RNA in response to left atrial distension. In contrast, dogs with chronic AVF's demonstrated an increase in RNA in response to left atrial distension by 4.5 +/- 3.9% per mmHg change in LAP. The response of the AVF dogs was significantly different from the normal dogs (P less than 0.005). This was also the case after CSD. Loading and unloading of the arterial baroreceptors with norepinephrine and nitroprusside demonstrated that the modulation of RNA by arterial baroreceptors was similar in AVF dogs compared with normal dogs. The present study demonstrates that chronic volume overload results in a decrease in the peripheral sympathetic inhibitory effects of left atrial receptor stimulation at a time when arterial baroreceptor function is preserved.


Asthma symptoms among Chinese children: the role of ventilation and PM10 exposure at school and home.
Respiratory symptoms in relation to environment in Taiyuan, China. To study associations between school/home exposure and prevalence of respiratory symptoms and self-reported respiratory infections (RIs) among students. A total of 2134 pupils from 10 schools answered a questionnaire; air pollution at school was measured. The prevalence of current wheeze, daytime attacks of breathlessness, nocturnal cough, nocturnal respiratory symptoms and RI was respectively 4.4%, 18.7%, 11.6%, 3.6% and 32.3%. Environmental tobacco smoke (ETS) at home was associated with daytime attacks of breathlessness (OR 1.41), nocturnal cough (OR 1.41) and RI (OR 1.26). Redecoration or indoor painting at home was associated with wheeze (OR 2.02), daytime attacks of breathlessness (OR 1.57) and nocturnal symptoms (OR 1.83). Dampness or mould at home was associated with daytime attacks of breathlessness (OR 1.68), nocturnal cough (OR 1.68) and RI (OR 1.69). Particulate matter of diameter  10 microns (PM10) in the classroom was associated with nocturnal cough (OR 1.20/10 μg/m3). PM10 outside school was associated with daytime attacks of breathlessness (OR 1.07/10 μg/m3) and nocturnal cough (OR 1.13/10 μg/m3). Indoor carbon dioxide, a marker of poor ventilation (OR 1.52/1000 parts per million), and relative humidity (RH) (OR 1.33/10%) were associated with nocturnal cough. Dampness, redecoration and ETS at home, as well as poor ventilation flow, and high RH and PM10 concentration at school may influence respiratory health.


[Treatment of local recurrent melanomas by isolated limb perfusion: value of Doppler ultrasonography].
To assess the effectiveness of Color Doppler Ultrasound (US) in the follow-up of recurrent melanoma of the limbs treated by isolated limb perfusion (ILP). A retrospective study was done looking at 18 patients treated by isolated perfusion of the limb. Number, size and vascularity of subcutaneous metastases were examined for all patients. The results of pre and post therapeutic examinations were compared with clinical data and evolution. US was superior to clinical examination in the detection and measurement of subcutaneous metastases. Decrease in tumor size and early disappearance of tumoral vascularity were associated with an effective tumor response to treatment. Early disappearance of vascularity was associated with early complete response. Initial presence or persistence of vascularity before the third month after treatment were not poor prognostic factors. The appearance of vascularity seemed to be an indicator of early failure of the treatment. Color Doppler US is highly effective for the follow-up of patients with recurrent melanoma of the limbs. It provides prognostic factors of treatment failure, which may lead to early modification of the treatment strategy.


Bimetallic metal-organic framework as an efficient sorbent for the extraction of tacrolimus and cyclosporine from plasma before HPLC-MS/MS analysis.
This study investigated the application of pores-size protocols into metal-organic frameworks that can lead to improved adsorption capacity of sorbents. A selective, fast, and sensitive analytical procedure based on dispersive solid phase extraction using a bimetallic metal organic framework named ZrZnMOF coupled with high-performance liquid chromatography-tandem mass spectrometry was established for the simultaneous quantification of tacrolimus and cyclosporine in plasma. The effects of several parameters, such as the dosage of sorbent, separation and elution times, volume and type of elution solvent, were investigated. Under optimal conditions, high extraction recovery (70 and 89 for tacrolimus and cyclosporine, respectively), low limits of detection (0.15 and 0.31 μg L-1 for tacrolimus and cyclosporine, respectively) and quantification (1.0 and 0.51 μg L-1 for tacrolimus and cyclosporine, respectively) wide linearity (1.0-1000 and 0.51-500 μg L-1 for tacrolimus and cyclosporine, respectively), and acceptable repeatability (n = 5, relative standard deviation less than 5.6 %) were attained. The validated method was successfully applied to quantify tacrolimus and cyclosporine A in plasma samples obtained from different volunteers.


Systemic excretion of benzo(a)pyrene in the control and microsomally induced rat: the influence of plasma lipoproteins and albumin as carrier molecules.
In vitro studies have previously indicated that benzo(a)pyrene distributes primarily into the plasma lipoprotein fraction when incubated with whole plasma. Hydroxylated metabolites of benzo(a)pyrene distribute increasingly into the albumin fraction as the degree of metabolite hydroxylation increases. This report assesses the influence of plasma lipoproteins and albumin as carriers for benzo(a)pyrene on carcinogen excretion in the control and microsomally induced rat. Male Sprague-Dawley rats cannulated in the bile duct received i.v. injections of radiolabeled benzo(a)pyrene noncovalently bound to the very-low-density, low-density, or high-density lipoproteins in equimolar amounts. Bile was collected and measured for radioactivity. Cumulative biliary excretions of benzo(a)pyrene complexed with rat lipoproteins were 39.6 +/- 9.7 (S.D.), 24.6 +/- 1.3, and 21.2 +/- 8.8% for very low-density, low-density, and high-density lipoprotein, respectively. Values for excretion of benzo(a)pyrene complexed with rat or human lipoproteins were comparable. These data suggest that the transport molecule can effect a 2-fold difference in benzo(a)pyrene excretion under conditions of the present study. We infer that metabolism of the plasma lipoprotein molecules determines, in part, the extent of benzo(a)pyrene excretion. Cumulative biliary excretions of albumin-bound benzo(a)pyrene, 3-hydroxybenzo(a)pyrene, benzo(a)pyrene 7,8-dihydrodiol, and benzo(a)pyrene-4,5-epoxide were 28.0 +/- 2.7, 39.8 +/- 0.5, 46.9 +/- 2.5, and 49.8 +/- 1.2%, respectively. Thus, excretion increased as the degree of benzo(a)pyrene hydroxylation increased. The effect of microsomal enzyme induction on excretion of lipoprotein-bound benzo(a)pyrene was also assessed. Contrary to expectation, excretion of benzo(a)pyrene bound to the very-low-density, low-density, or high-density lipoproteins in Aroclor-induced rats was not greater than that of control animals. Hence, under the conditions of the present study, 60 to 80% of the injected benzo(a)pyrene and 50 to 60% of the injected benzo(a)pyrene metabolites were not excreted immediately in control or microsomally induced animals. This benzo(a)pyrene may represent a carcinogen pool that is slowly excreted.


Juvenile-type granulosa theca cell tumour producing precocious pseudopuberty. A case report.
The juvenile-type of granulosa theca cell tumour in a young girl is reported. The child presented with pain, vaginal bleeding, distension of the abdomen and enlarged breasts and exhibited pubic and axillary hair, i.e. signs of oestrogenic and androgenic effects and overproduction of luteinizing hormone--an unusual phenomenon. Discussion includes the differences between the juvenile and adult types of this tumour. Salpingo-oophorectomy of the affected side is recommended in such cases. A recurrence many years after surgery has been reported, so long-term follow-up is envisaged in this case.


Auditory-nerve rate responses are inconsistent with common hypotheses for the neural correlates of loudness recruitment.
A number of perceptual phenomena related to normal and impaired level coding can be accounted for by the degree of compression in the basilar-membrane (BM) magnitude response. However, the narrow dynamic ranges of auditory-nerve (AN) fibers complicate these arguments. Because the AN serves as an information bottleneck, an improved understanding of the neural coding of level may clarify some of the limitations of current hearing aids. Here three hypotheses for the neural correlate of loudness recruitment were evaluated based on AN responses from normal-hearing cats and from cats with a noise-induced hearing loss (NIHL). Auditory-nerve fiber rate-level functions for tones were analyzed to test the following hypotheses: Loudness recruitment results from steeper AN rate functions after impairment. This hypothesis was not supported; AN rate functions were not steeper than normal following NIHL, despite steeper estimated BM responses based on the AN data. Loudness is based on the total AN discharge count, and recruitment results from an abnormally rapid spread of excitation after impairment. Whereas abnormal spread of excitation can be observed, steeper growth of total AN rate is not seen over the range of sound levels where recruitment is observed in human listeners. Loudness of a narrowband stimulus is based on AN responses in a narrow BF region, and recruitment results from compression of the AN-fiber threshold distribution after impairment. This hypothesis was not supported because there was no evidence that impaired AN threshold distributions were compressed and the growth of AN activity summed across BFs near the stimulus frequency was shallower than normal.Overall, these results suggest that loudness recruitment cannot be accounted for based on summed AN rate responses and may depend on neural mechanisms involved in the central representation of intensity.


[The cubito-carpal region in gibbons].
As a continuation of our studies concerning the structure and fetal development of the human carpal articular disc (KAUER, 1968, 1975, 1976) we have investigated the disc-homologue in the Gibbon. For this purpose we have used the serial sectioned hand of a late-fetal specimen. The stratigraphical position of the os Daubentonii has been established comparing the situation in the Gibbon with that of the human ulno-carpal region. The homology presumed by others of the os Daubentonii with the cartilaginous primordium frequently found in the developing carpal articular disc in man, was found questionable. We have tried to give the os Daubentonii a functional interpretation as a sesamoid bone supporting the mechanical loaded pronation and supination of the hand in the Gibbon.


[Adiposis dolorosa (Dercum's disease)].
Adiposis dolorosa (Dercum's disease) is a rare fat-tissue malady most frequently presenting in middle-aged women as fatty lumps in the body. Its etiology and pathogenesis isn't known. Two female patients are reported who had symptomatic adiposis dolorosa (32 and 62-year-old).


Left atrial volume and function assessed by cardiac magnetic resonance imaging are markers of subclinical atrial fibrillation as detected by continuous monitoring.
We aimed to investigate whether left atrial (LA) markers from cardiovascular magnetic resonance (CMR) were able to predict atrial fibrillation (AF) in elderly patients with risk factors for stroke. At baseline, 203 participants with stroke risk factors but without history of AF underwent advanced CMR and received an implantable loop recorder. During a median of 40 (37-42) months of continuous monitoring, incident AF was detected in 79 patients (39%). With regards to CMR markers, a steep increase in incidence rate of AF was seen with LA maximum volume (LAmax) above 55 mL/m2, LA minimum volume (LAmin) above 30 mL/m2, LA total emptying fraction (LA TEF) below 45%, LA active emptying fraction (LA AEF) below 37%, LA strain S below 25%, LA strain A below 17%, and LA strain rate A above -1.7 s-1. After multivariate adjustment, the above-mentioned CMR markers remained associated with AF incidence: hazard ratio (95% confidence interval) 1.25 (1.06-1.48) and 1.51 (1.22-1.87) per 10 mL/m2 increase of LAmax and LAmin, respectively, 1.49 (1.26-1.76) and 1.46 CI (1.25-1.71) per 5% decrease in LA TEF and LA AEF, respectively, 1.23 (1.05-1.44) and 1.56 (1.18-2.06) per 5% decrease in LA strain S and A, respectively, and 2.06 (1.31-3.23) per s-1 increase in LA strain rate A. In prediction analyses, LA functional indices increased area under the receiver operating characteristic curve significantly. The risk of AF, including asymptomatic AF, increases significantly with increasing LA volumes and worsening LA function.


Examination of Sexual Identity Differences in the Prevalence of Hypertension and Antihypertensive Medication Use Among US Adults: Findings From the Behavioral Risk Factor Surveillance System.
Recent evidence suggests that sexual minority (eg, gay/lesbian, bisexual) adults might be at increased risk of hypertension compared with heterosexual adults. However, disparities by sexual identity in antihypertensive medication use among adults with hypertension have not been comprehensively examined. We analyzed data from the Behavioral Risk Factor Surveillance System (2015-2019), to examine sexual identity differences in the prevalence of hypertension and antihypertensive medication use among adults. We ran sex-stratified logistic regression models to estimate the odds ratios of diagnosis of hypertension and antihypertensive medication use among sexual minority (ie, gay/lesbian, bisexual, and other) and heterosexual adults (reference group). The sample included 420 340 participants with a mean age of 49.7 (±17.0) years, of which 66.7% were Non-Hispanic White. Compared with heterosexual participants of the same sex, bisexual women (adjusted odds ratio, 1.19 [95% CI, 1.03-1.37]) and gay men (adjusted odds ratio, 1.18 [95% CI, 1.03-1.35]) were more likely to report having been diagnosed with hypertension. Among women with diagnosed hypertension, bisexual women had lower odds of current antihypertensive medication use (adjusted odds ratio, 0.71 [95% CI, 0.56-0.90]). Among men with diagnosed hypertension, gay men were more likely than heterosexual men to report current antihypertensive medication use (adjusted odds ratio, 1.39 [95% CI, 1.10-1.78]). Compared with heterosexual participants of the same sex, there were no differences in hypertension or antihypertensive medication use among lesbian women, bisexual men, and participants who reported their sexual identity as other. Clinical and public health interventions are needed to reduce the risk of hypertension among bisexual women and gay men. Bisexual women were at higher risk of untreated hypertension, which may be attributed to lower health care utilization due to fear of discrimination from health care providers and socioeconomic disadvantage. Future research is needed to better understand factors that may contribute to untreated hypertension among bisexual women with hypertension.


The inhibitory effect of bran on iron absorption in man.
The effects of whole wheat bran and its components on the absorption of nonheme dietary iron were measured using a double isotope technique in human volunteers. When 12 g bran was added to a light meal, absorption decreased by 51 to 74%; this inhibitory effect of bran was shown for meals of both high and low iron availability. Inhibition was not explained by monoferric phytate, the major form of iron in bran, because labeled iron from monoferric phytate was absorbed at least as well as the common pool of nonheme dietary iron. Furthermore, removal of phytate from bran by endogenous phytase did not in itself alter the inhibitory effect of the bran on iron absorption. Studies in which dephytinized bran was separated into a soluble, phosphate-rich fraction and an insoluble, high-fiber fraction indicated that the soluble fraction was more inhibitory than the insoluble fraction.


The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome.
Many different environmental and genetic sex-determination mechanisms are found in nature. Closely related species can use different master sex-determination switches, suggesting that these developmental pathways can evolve very rapidly. Previous cytological studies suggest that recently diverged species of stickleback fish have different sex chromosome complements. Here, we investigate the genetic and chromosomal mechanisms that underlie sex determination in the threespine stickleback (Gasterosteus aculeatus). Genome-wide linkage mapping identifies a single chromosome region at the distal end of linkage group (LG) 19, which controls male or female sexual development in threespine sticklebacks. Although sex chromosomes are not cytogenetically visible in this species, several lines of evidence suggest that LG 19 is an evolving sex chromosome system, similar to the XX female/XY male system in many other species: (1) males are consistently heterozygous for unique alleles in this region; (2) recombination between loci linked to the sex-determination region is reduced in male meiosis relative to female meiosis; (3) sequence analysis of X- and Y-specific bacterial artificial chromosome (BAC) clones from the sex-determination region reveals many sequence differences between the X- and Y-specific clones; and (4) the Y chromosome has accumulated transposable elements and local duplications. Taken together, our data suggest that threespine sticklebacks have a simple chromosomal mechanism for sex determination based on a nascent Y chromosome that is less than 10 million years old. Further analysis of the stickleback system will provide an exciting window into the evolution of sex-determination pathways and sex chromosomes in vertebrates.


Pityriasis lichenoides chronica: an association with autoimmune hepatitis?
Pityriasis lichenoides is an uncommon, benign skin disorder with two major variants: acute and chronic. Autoimmune hepatitis comprises heterogeneous forms of chronic hepatitis that are generally progressive and often fluctuating. Two major forms of this entity are recognized. Herein, we report the concurrence of pityriasis lichenoides chronica with type I autoimmune hepatitis in a child, which, to the best of our knowledge, has not been previously reported. Although it is hard to say whether an etiologic relationship or coincidental coexistence occurred between the two entities in our patient, some common mechanisms may be involved in both diseases.


Pattern recognition assisted infrared library searching.
Pattern recognition methods have been used to develop search prefilters for infrared (IR) library searching. A two-step procedure has been employed. First, the wavelet packet tree is used to decompose each spectrum into wavelet coefficients that represent both the high and low frequency components of the signal. Second, a genetic algorithm for pattern recognition analysis is used to identify wavelet coefficients characteristic of functional group. Even in challenging trials involving carboxylic acids, compounds that possess both carbonyl and hydroxyl functionalities can be readily differentiated from carboxylic acids. The proposed search prefilters allow for the use of more sophisticated and correspondingly more time-consuming algorithms in IR spectral library matching because the size of the library can be culled down for a specific match using information from the search prefilter about the presence or absence of specific functional groups in the unknown.


An efficient probabilistic methodology for incorporating uncertainty in body segment parameters and anatomical landmarks in joint loadings estimated from inverse dynamics.
Inverse dynamics is a standard approach for estimating joint loadings in the lower extremity from kinematic and ground reaction data for use in clinical and research gait studies. Variability in estimating body segment parameters and uncertainty in defining anatomical landmarks have the potential to impact predicted joint loading. This study demonstrates the application of efficient probabilistic methods to quantify the effect of uncertainty in these parameters and landmarks on joint loading in an inverse-dynamics model, and identifies the relative importance of the parameters and landmarks to the predicted joint loading. The inverse-dynamics analysis used a benchmark data set of lower-extremity kinematics and ground reaction data during the stance phase of gait to predict the three-dimensional intersegmental forces and moments. The probabilistic analysis predicted the 1-99 percentile ranges of intersegmental forces and moments at the hip, knee, and ankle. Variabilities, in forces and moments of up to 56% and 156% of the mean values were predicted based on coefficients of variation less than 0.20 for the body segment parameters and standard deviations of 2 mm for the anatomical landmarks. Sensitivity factors identified the important parameters for the specific joint and component directions. Anatomical landmarks affected moments to a larger extent than body segment parameters. Additionally, for forces, anatomical landmarks had a larger effect than body segment parameters, with the exception of segment masses, which were important to the proximal-distal joint forces. The probabilistic modeling approach predicted the range of possible joint loading, which has implications in gait studies, clinical assessments, and implant design evaluations.


Attitudes of physicians and patients towards disclosure of genetic information to spouse and first-degree relatives: a case study from Turkey.
When considering the principle of medical confidentiality, disclosure of genetic information constitutes a special case because of the impact that this information can have on the health and the lives of relatives. The aim of this study is to explore the attitudes of Turkish physicians and patients about sharing information obtained from genetic tests. The study was carried out in Kocaeli, Turkey. Participants were either paediatricians and gynaecologists registered in Kocaeli, or patients coming to the genetic diagnosis centre for karyotype analysis in 2008. A self-administered paper questionnaire was given to the physicians, and face-to-face structured interviews were conducted with patients. We used a case study involving a man who was found to be a balanced chromosome carrier as a result of a test conducted after his first baby was born with Down's syndrome. However, he refused to share this information with his wife or his siblings. Percentages of characteristics and preferences of the participants were calculated, and the results were analysed using Kruskal-Wallis test. A total of 155 physicians (68% response rate) and 104 patients (46% response rate) were participated in the study. Twenty-six percent of physicians and 49% of patients believed that genetic information belongs to the whole family. When participants were asked with whom genetic information should be shared for the case study, most of the physicians and patients thought the physician should inform the spouse (79%, 85%, respectively). They were less likely to support a physician informing a sibling (41%, 53%, respectively); whereas, many thought the testee has an obligation to inform siblings (70%, 94%, respectively). Although Turkey's national regulations certainly protect the right of privacy of the testee, the participants in our study appear to believe that informing the spouse, who is not personally at risk of serious damage, is the physician's responsibility, while informing siblings, is the testee's responsibility. Therefore we believe that opening ethical discussions with clinicians about the sharing of genetic information, establishing guidelines for practice and sharing these guidelines and the reasons behind them with the wider population, will help to pre-empt ethical dilemmas.


Evaluation of fibrinolytic and antioxidant effects of Allium elburzense bulb extracts.
Allium elburzense is an endemic plant of the family Amaryllidaceae that grows wild in northern Iran with some nutritional and medicinal applications. The present study was aimed to investigate the fibrinolytic and antioxidant effects of A. elburzense bulb extracts. Hydroalcoholic, aqueous, chloroformic and butanolic extracts were evaluated in this research. In vitro antioxidant assays were performed using total phenolic, DPPH, and FRAP methods. In the in vivo analysis, animals received i.p. injection of A. elburzense hydroalcoholic extract for 21 days and hydroperoxides level, FRAP value, PT and aPTT were determined in serum samples. The fibrinolytic activity of different extracts was quantitatively evaluated by measurement of clot weight. In vitro antioxidant assay showed that A. elburzense aqueous extract had the highest DPPH scavenging and the highest total antioxidant capacity. In the in vivo assay, A. elburzense hydroalcoholic extract reduced serum hydroperoxides level and increased serum total antioxidant capacity in rats. In vitro fibrinolytic assay revealed remarkable thrombolytic activity for this plant with the highest effect for the aqueous extract. However, coagulation parameters including PT and aPTT were not affected by administration of A. elburzense hydroalcoholic extract in rats. In conclusion, the results of this study revealed the potential antioxidant and fibrinolytic effects of A. elburzense bulb extracts. For developing novel thrombolytic agents, further investigations for isolation of bioactive constituents and finding the underlying mechanisms are suggested.


[The circulation of the California encephalitis complex and Batai viruses in the Lake Baikal region (serological research data)].
The serological materials of the indigenous population and cattle suggest that there are viral foci of a complex of California encephalitis with the circulation of viruses of Inkoo, Tahyna [correction of Tyagin], and the white hare. The results of examining the residents of Irkutsk also suggest that there are urban viral foci of a complex of California encephalitis. The epidemiological potential of the natural foci of Batai virus is insignificant in the Baikal region.


Comment on "Compromised birth outcomes and infant mortality among racial and ethnic groups".
Frisbie, Forbes, and Pullum (1996) show that it is meaningful to account for low birth weight, preterm delivery, and intrauterine growth-retardation when analyzing differences in compromised birth outcomes and infant mortality among racial and ethnic groups. I compare their findings for the 1987 U.S. birth cohort with findings for the 1988 U.S. birth cohort, using linked birth and infant death vital statistics from the National Center for Health Statistics. I focus on their calculation of fetal growth curves, which are highly at odds with the curves commonly used in the obstetric and pediatric literature. I compare birth outcome distributions and infant death probabilities using Frisbie et al.'s method and other standards. I conclude that Frisbie et al.'s method is not suited for the study of intrauterine growth-retardation at the population level because of the major flaws in gestational age measurement that exist in the type of data they use. An appropriate alternative is to apply a standard of normal intrauterine growth derived from antenatal estimation of fetal weight-for-gestational-age to the vital statistics data.


[Modern classification approach to central nervous system tumors].
Central nervous system (CNS) tumors cannot be, for a number of reasons, organically included into the existing tumor classification system - TNM. This hampers the registration and systematization of CNS tumors, the acquisition of valid data on their prevalence, and the organization of treatment in patients with CNS tumors. A variant of a classification of CNS tumors is proposed, which takes into account the specific features of this group of neoplasms.


Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: a population controlled study.
The role of blood viscosity and haemostasis has been investigated in mixed groups of patients with branch and central retinal vein occlusion (CRVO) with conflicting results. This may have partly been due to the different aetiologies of these two types of vein occlusion. In this study viscosity and coagulation (including activated protein C resistance) were examined in 87 patients with CRVO and compared with the results from an age-matched, population based control group. Viscosity variables were higher in CRVO than in controls which suggested that reduced red cell deformability was associated with the occurrence of CRVO. A higher percentage of the patients with CRVO (12%) had activated protein C resistance than controls (5%). Patients who developed the complication of iris neovascularisation had relatively low antithrombin III, factor VII, and tissue plasminogen activator indicating both a tendency to thrombus formation and a reduction in fibrinolytic activity. Increased blood viscosity may contribute to the production of CRVO by inducing stasis of blood flow, with thrombus formation in at risk individuals who go on to develop iris neovascularisation.


Recurrence of inflammatory myofibroblastic tumor in bladder secondary to prostate treated with laparoscopic radical cystectomy.
Inflammatory myofibroblastic tumor (IMT) is a rare borderline tumor. The nomenclature of this disease is confused in the literature. In this report, the case of a 62-year-old man with IMT recurrence of bladder secondary to prostate is presented. The possible etiology of IMT is discussed, along with its clinical manifestation and pathological features. The patient received a laparoscopic bladder radical resection. The pathology finding demonstrated the diagnosis of IMT and no regional lymph node involvement. IMT is a borderline tumor and unlikely to metastasize to regional lymph nodes. The patient has been observed for 2 years without recurrence.


Disulfide- and thiol-incorporating copper catenanes: synthesis, deposition onto gold, and surface studies.
Two new copper-complexed [2]catenanes have been prepared, both of which consist of two different interlocking rings. In both cases, one of the rings incorporates a disulfide bridge. The other ring contains either a single chelate (phen=1,10-phenanthroline, a bidentate ligand) or two different chelates (phen and terpy, 2,2',6',2"-terpyridine, a tridentate chelate). Deposition of these two complexes on a gold electrode surface was carried out by standard procedures, leading to reductive cleavage of the S-S bridge. The adsorbed species can be viewed as [2]catenanes for which the gold atoms of the electrode surface are an integral fragment of one of the two rings. They yield clear electrochemical responses, but no motion is observed for the catenane incorporating a phen unit and a terpy fragment in one of the two rings, regardless of the metal oxidation state. This is at odds with the behavior of the parent compound in solution, which undergoes ring-gliding motions upon electrochemical reduction or oxidation of the copper center. Near-field microscopy was used to study the deposited layers (STM and AFM). STM images suggest that the molecules do not tend to order at long range on the surface. Polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS) led to promising results: the two catenanes deposited are likely to be oriented perpendicular to the gold surface. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2111/2002/f3636_s.pdf or from the author. 1: Infrared spectra of [Cu.2]+ as a powder (black line, transmission IR spectroscopy) and as a SAM on gold (dotted line, PM-IRRAS). (Spectra offset and scaled for clarity; significant peaks marked with an asterisk.) 2: STM image (819x819 nm2) of a monolayer of [Cu.3]+ on Au(111) on mica.


Regulation of GLUT4 expression in vivo and in vitro.
The GLUT4 gene is subject to complex tissue-specific and metabolic regulation that has a profound impact on insulin-mediated glucose disposal. The regulation of this gene is of special clinical interest because insulin-mediated glucose homeostasis is highly sensitive to the levels of GLUT4 protein in muscle and adipose tissue. For this reason, the mechanisms of regulated expression of the GLUT4 gene have been intensively studied over the past decade. Understanding the transcriptional mechanisms that underlie the regulated expression of this highly differentiated gene have been slow to emerge, due to the paucity of suitable model systems available for detailed investigation. The development of transgenic mouse models to understand the mechanisms of transcriptional regulation has greatly enhanced our understanding of this gene. Information gained about the regulation of the GLUT4 gene has provided insight into mechanisms by which complex gene regulation occurs through a small number of cis-acting regulatory elements.


Critical behaviors of nonlinear contagion models with recurrent mobility patterns.
Recently, there has been a lot of discussion about the nonlinearity property of contagion processes in epidemic spreading on social networks with various structures. In this paper, we propose a nonlinear contagion model in networked metapopulations to investigate the critical behavior of epidemics with recurrent mobility patterns. First, we build up a discrete-time Markovian chain model to formulate the spreading of susceptible-infected-susceptible-like diseases. Additionally, we develop a practicable framework to analyze the impact of mobility on the epidemic threshold and derive the theoretical condition for the transition of an epidemic from a local to a global scale. This transition is associated with multiple discontinuous phase changes. We validate our analytical results through extensive numerical simulations on both regular and heterogeneous networks. Our findings offer a useful tool to discuss the implementation of prevention strategies such as quarantine and lockdown.


Measurement of gray and white matter atrophy in dementia with Lewy bodies using diffeomorphic anatomic registration through exponentiated lie algebra: A comparison with conventional voxel-based morphometry.
DLB is recognized as the second major form of dementia in the elderly. The regional pattern of GM atrophy in DLB highly overlaps that in AD. The aim of this study was to identify the critical pattern of atrophy in DLB by using DARTEL, which provides improved registration accuracy compared with that of conventional VBM. We evaluated 51 patients with probable AD, 43 patients with probable DLB, and 40 age-matched healthy controls. The pattern of GM atrophy in each group was compared by using conventional VBM and VBM-DARTEL. Regional patterns of atrophy identified by using conventional VBM differed significantly from those identified by using VBM-DARTEL. A decrease in GM volume in the MTLs in both AD and DLB was identified with VBM-DARTEL; the decrease was greater in patients with AD than in those with DLB. Comparisons with healthy controls revealed that the WM volume of the whole brain was preserved in patients with DLB. In contrast, a severe bilateral decrease in WM in the MTLs was detected in patients with AD. VBM-DARTEL provided more accurate results, and it enabled the identification of more localized morphologic alterations than did conventional VBM. Analysis of WM preservation in DLB could help to differentiate this condition from AD.


Acute and fractionated exposure to high-LET (56)Fe HZE-particle radiation both result in similar long-term deficits in adult hippocampal neurogenesis.
Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreER(T2)/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy (56)Fe-particle exposure or five fractionated 20 cGy (56)Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of (56)Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed.


Comparing dairy farm milk yield and components, somatic cell score, and reproductive performance among United States regions using summer to winter ratios.
Heat stress abatement is a challenge for dairy producers in the United States, especially in the southern states. Thus, managing heat stress is critical to maintain dairy cow performance in the summer. The ability to employ a metric to measure heat stress and evaluate abatement strategies may benefit dairy producers by providing meaningful feedback on the effectiveness of current and future management strategies with the goal of improving heat stress management. Therefore, this study aimed to explore the use of the summer to winter performance ratio metric to quantify and compare farm performance variables among regions of the United States. Monthly performance data recorded by the Dairy Herd Improvement Association from 2007 to 2016, for all US Dairy Herd Improvement Association herds processing records through Dairy Records Management Systems (Raleigh, NC), were obtained. Season dates were based on the astronomical definition of the Northern Hemisphere with summer as June 21 to September 21 and winter as December 21 to March 19. States were grouped into regions based on climate zone classification. Performance records included a total of 16,573 herds [Northeast (n = 7,955), Midwest (n = 6,555), Northern Plains (n = 305), Southeast (n = 1,370), and Southern Plains (n = 388) regions]. Herd test day performance variables energy-corrected milk, somatic cell score, milk fat and protein percentage, conception rate, heat detection rate, and pregnancy rate in summer and winter were used to calculate summer to winter ratios for each region. The MIXED procedure of SAS 9.4 (SAS Institute Inc., Cary, NC) was used to compare test day performance variables. The effects of year, mean days in milk, mean 150-d milk, mean herd size, and number of milkings per day were included as covariates in the models. Dairy cattle performance in all climate regions was negatively affected by summer heat stress, but some regions greater than others. A difference was also observed among regions when comparing summer to winter ratios for each performance parameter. This indicates that summer performance varies by climate region identified by the summer to winter ratio and demonstrates usefulness of the metric to monitor degree of heat stress based on performance.


Blood separation on microfluidic paper-based analytical devices.
A microfluidic paper-based analytical device (μPAD) for the separation of blood plasma from whole blood is described. The device can separate plasma from whole blood and quantify plasma proteins in a single step. The μPAD was fabricated using the wax dipping method, and the final device was composed of a blood separation membrane combined with patterned Whatman No.1 paper. Blood separation membranes, LF1, MF1, VF1 and VF2 were tested for blood separation on the μPAD. The LF1 membrane was found to be the most suitable for blood separations when fabricating the μPAD by wax dipping. For blood separation, the blood cells (both red and white) were trapped on blood separation membrane allowing pure plasma to flow to the detection zone by capillary force. The LF1-μPAD was shown to be functional with human whole blood of 24-55% hematocrit without dilution, and effectively separated blood cells from plasma within 2 min when blood volumes of between 15-22 μL were added to the device. Microscopy was used to confirm that the device isolated plasma with high purity with no blood cells or cell hemolysis in the detection zone. The efficiency of blood separation on the μPAD was studied by plasma protein detection using the bromocresol green (BCG) colorimetric assay. The results revealed that protein detection on the μPAD was not significantly different from the conventional method (p > 0.05, pair t-test). The colorimetric measurement reproducibility on the μPAD was 2.62% (n = 10) and 5.84% (n = 30) for within-day and between day precision, respectively. Our proposed blood separation on μPAD has the potential for reducing turnaround time, sample volume, sample preparation and detection processes for clinical diagnosis and point-of care testing.


Universal screening for meticillin-resistant Staphylococcus aureus: interim results from the NHS Scotland pathfinder project.
Following recommendations from a Health Technology Assessment (HTA), a prospective cohort study of meticillin-resistant Staphylococcus aureus (MRSA) screening of all admissions (N=29 690) to six acute hospitals in three regions in Scotland indicated that 7.5% of patients were colonised on admission to hospital. Factors associated with colonisation included re-admission, specialty of admission (highest in nephrology, care of the elderly, dermatology and vascular surgery), increasing age, and the source of admission (care home or other hospital). Three percent of all those who were identified as colonised developed hospital-associated MRSA infection, compared with only 0.1% of those not colonised. Specialties with a high rate of colonisation on admission also had higher rates of MRSA infection. Very few patients refused screening (11 patients, 0.03%) or had treatment deferred (14 patients, 0.05%). Several organisational issues were identified, including difficulties in achieving complete uptake of screening (88%) or decolonisation (41%); the latter was largely due to short duration of stay and turnaround time for test results. Patient movement resulted in a decision to decolonise all positive patients rather than just those in high risk specialties as proposed by the HTA. Issues also included a lack of isolation facilities to manage patients with MRSA. The study raises significant concerns about the contribution of decolonisation to reducing risks in hospital due to short duration of stay, and reinforces the central role of infection control precautions. Further study is required before the HTA model can be re-run and conclusions redrawn on the cost and clinical effectiveness of universal MRSA screening.


[Changes in viability of two Antarctic marine bacteria exposed to solar radiation in the water column: influence of vertical mixing].
The effect of UV radiation on two Antarctic marine bacterial strains (UVps and UVvi) was studied in the water column of Potter Cove (South Shetland, Antarctica). Quartz flasks were filled with the bacterial suspensions and exposed to solar radiation at 0 m, 1 m and 3 m depth. Assays using flasks exposed to direct solar radiation and others using flasks covered with/by interferential filters which discriminate between UVA and UVB, were performed. In other assays, a vertical mixing of 4 m/h was simulated. Both strains showed a significant decrease in viability (expressed as colony - forming units) when exposed to a surface UVB dose of 8.4 kJ m(-2). Studies with interferential filters showed a significant decrease at 0 and 1 m depth under both UV treatments. The UVps strain appeared to be more sensitive to UVB than to UVA. Damage produced by UVB was attenuated by the vertical mixing when the surface UVB dose was 4.8 kJ m(-2). This effect was not observed when surface UVB dose was 7.7 kJ m(-2). These results show that the negative effect caused by UVB radiation on the bacterioplankton would be significant only in the first meter of water column of the Antarctic coastal waters with high levels of suspended particulate material.


Gefitinib Inhibits Rifampicin-Induced CYP3A4 Gene Expression in Human Hepatocytes.
During multidrug combination chemotherapy, activation of the nuclear receptor and the transcription factor human pregnane xenobiotic receptor (hPXR) has been shown to play a role in the development of chemoresistance. Mechanistically, this could occur due to the cancer drug activation of hPXR and the subsequent upregulation of hPXR target genes such as the drug metabolism enzyme, cytochrome P450 3A4 (CYP3A4). In the context of hPXR-mediated drug resistance, hPXR antagonists would be useful adjuncts to PXR-activating chemotherapy. However, there are currently no clinically approved hPXR antagonists in the market. Gefitinib (GEF), a tyrosine kinase inhibitor used for the treatment of advanced non-small-cell lung cancer and effectively used in combinational chemotherapy treatments, is a promising candidate owing to its hPXR ligand-like features. We, therefore, investigated whether GEF would act as an hPXR antagonist when combined with a known hPXR agonist, rifampicin (RIF). At therapeutically relevant concentrations, GEF successfully inhibited the RIF-induced upregulation of endogenous CYP3A4 gene expression in human primary hepatocytes and human hepatocells. Additionally, GEF inhibited the RIF induction of hPXR-mediated CYP3A4 promoter activity in HepG2 human liver carcinoma cells. The computational modeling of molecular docking predicted that GEF could bind to multiple sites on hPXR including the ligand-binding pocket, allowing for potential as a direct antagonist as well as an allosteric inhibitor. Indeed, GEF bound to the ligand-binding domain of the hPXR in cell-free assays, suggesting that GEF directly interacts with the hPXR. Taken together, our results suggest that GEF, at its clinically relevant therapeutic concentration, can antagonize the hPXR agonist-induced CYP3A4 gene expression in human hepatocytes. Thus, GEF could be a potential candidate for use in combinational chemotherapies to combat hPXR agonist-induced chemoresistance. Further studies are warranted to determine whether GEF has sufficient hPXR inhibitor abilities to overcome the hPXR agonist-induced chemoresistance.


Intestinal microbiota in allergic and nonallergic 1-year-old very low birth weight infants after neonatal glutamine supplementation.
Previously, glutamine-enriched enteral nutrition in very low birth weight infants (VLBW) decreased the incidence of atopic dermatitis at age 1 year. The aim of this study was to determine whether this effect is related to changes in intestinal bacterial species that are associated with allergy, such as bifidobacteria, clostridium histolyticum, clostridium lituseburense (Chis/lit group) and Escherichia coli at age 1 year. Eighty-nine infants were eligible for this follow-up study, conducted at a Tertiary care hospital. Bifidobacteria, Chis/lit group and E. coli were measured by fluorescent in situ hybridization in faecal samples collected at age 1 year. Information on allergic and infectious diseases was previously determined by questionnaire. Seventy-two of 89 (81%) infants were participated. Prevalence of all studied species was not different between glutamine-supplemented and control groups. Allergic infants were less frequently colonized with bifidobacteria than nonallergic infants (p =0.04). Between neonatal period and 1 year, prevalence of bifidobacteria was increased (p < 0.001), of Chis/lit group was unchanged (p=0.84), and of E. coli was decreased (p < 0.001). The beneficial effect of glutamine-enriched enteral nutrition on the incidence of atopic dermatitis in the first year of life in VLBW infants is not related to changes in bifidobacteria, Chis/lit group or E. coli. Allergic VLBW infants are less frequently colonized with bifidobacteria compared to nonallergic VLBW infants.


Correlation between rpoB gene mutation in Mycobacterium avium subspecies paratuberculosis and clinical rifabutin and rifampicin resistance for treatment of Crohn's disease.
To investigate overlapping regions of the rpoB gene previously involved with rifamycin resistance in M. tuberculosis and seek correlation between rpoB mutations in clinical MAP strains with susceptibility to RIF and RFB. We designed a molecular-based PCR method for the evaluation of rifabutin (RFB) and rifampicin (RIF) resistance based on probable determinant regions within the rpoB gene of MAP, including the 81 bp variable site located between nucleotides 1363 and 1443. The minimum inhibitory concentration (MIC) for RIF was also determined against 11 MAP isolates in attempt to seek correlation with rpoB sequences. We determined that MAP strain 18 had an MIC of > 30 mg/L and <or= 5 mg/L for RIF and RFB respectively, and a significant and novel rpoB mutation C1367T, compared to an MIC of <or= 1.0 mg/L for both drugs in the wild type MAP. The 30-fold increase in the MIC was a direct result of the rpoB mutation C1367T, which caused an amino acid change Thr456 to Ile456 in the drug's binding site; the beta subunit of RNA polymerase. In addition, MAP strain 185 contained five silent rpoB mutations and exhibited an MIC comparable to the wild-type. Moreover, our in vitro selected mutation in MAP strain UCF5 resulted in the generation of a new resistant strain (UCF5-RIF16r) that possessed T1442C rpoB mutation and an MIC > 30 mg/L and > 10 mg/L for RIF and RFB respectively. Sequencing of the entire rpoB gene in MAP strains UCF4, 18, and UCF5-RIF16r revealed an rpoB mutation A2284C further downstream of the 81 bp variable region in UCF4, accounting for observed slight increase in MIC. In addition, no other significant mutations were found in strains 18 and UCF-RIF16r. The data clearly illustrates that clinical and in vitro-selected MAP mutants with rpoB mutations result in resistance to RIF and RFB, and that a single amino acid change in the beta subunit may have a significant impact on RIF resistance. Unconventional drug susceptibility testing such as our molecular approach will be beneficial for evaluation of antibiotic effectiveness. This molecular approach may also serve as a model for other drugs used for treatment of MAP infections.


Subclinical anxiety symptoms, sleep, and daytime dysfunction in older adults with primary insomnia.
"Both Insomnia complaints and anxiety-related distress are common in older adults, and are associated with poor daytime functioning. We investigated whether subclinical levels of anxiety were associated with sleep disturbance and daytime functioning in older adults who met diagnostic criteria for primary insomnia, and therefore but did not meet criteria for depression or an anxiety disorder. After adjustment for depressive symptoms, elevated state anxiety was associated with higher levels of wake after sleep onset (measured by both actigraphy and sleep log) and shorter sleep sleep onset latency (measured by sleep log). Higher levels of trait anxiety were associated with greater wake after sleep onset (measured by sleep log). Elevated state and trait anxiety were associated with worse and social functioning, and higher levels of trait anxiety were associated with worse role functioning. Thus, subclinical anxiety symptoms may be an important target for clinical intervention to improve sleep and functioning in older adults with primary insomnia."


Liver stiffness and the prediction of clinically significant portal hypertension and portal hypertensive complications.
Clinically significant portal hypertension (CSPH) is associated with increased risk of liver disease complications, but its identification requires invasive methods. Liver stiffness (LS) measurement via transient elastography correlates with the presence of CSPH. We, therefore, evaluated LS as a noninvasive tool in the prediction of CSPH and portal hypertensive complications. Ninety-five consecutive patients successfully underwent measurement of hepatic venous pressure gradient (HVPG) and LS on the same day. Recent laboratory tests were correlated. Patients were followed up for development of portal hypertensive complications. Predictors of CSPH and complications were identified. Seventy-six (80%) were male and mean age was 56.8 ± 9.3 years. Ninety-three percent and 72% of patients had cirrhosis and esophageal varices, respectively. Only LS (r(2) = 0.38; p < 0.0001) and international normalized ratio (r(2) = 0.21; p = 0.02) were independently associated with HVPG. An LS >29.0 kilopascal (kPa) predicted CSPH with 71.9% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 56.0% negative predictive value (NPV). An LS <25.0 kPa in those with platelet count >150 × 10(9)/L excluded CSPH with 91.7% sensitivity, 100% specificity, 100% PPV, and 90% NPV. Ninety patients were followed up for a median duration of 15.1 months. CSPH and LS >34.5 kPa predicted portal hypertensive complications with 100% and 75.0% sensitivity, 40.3% and 69.4% specificity, 43.1% and 52.5% PPV, and 100% and 86.2% NPV, respectively. LS shows promise as a noninvasive marker of CSPH and portal hypertensive complications. Combining LS with platelet count improves diagnostic accuracy in the exclusion of CSPH.


Signal Dynamics and Interactions during Flooding Stress.
Flooding is detrimental for nearly all higher plants, including crops. The compound stress elicited by slow gas exchange and low light levels under water is responsible for both a carbon and an energy crisis ultimately leading to plant death. The endogenous concentrations of four gaseous compounds, oxygen, carbon dioxide, ethylene, and nitric oxide, change during the submergence of plant organs in water. These gases play a pivotal role in signal transduction cascades, leading to adaptive processes such as metabolic adjustments and anatomical features. Of these gases, ethylene is seen as the most consistent, pervasive, and reliable signal of early flooding stress, most likely in tight interaction with the other gases. The production of reactive oxygen species (ROS) in plant cells during flooding and directly after subsidence, during which the plant is confronted with high light and oxygen levels, is characteristic for this abiotic stress. Low, well-controlled levels of ROS are essential for adaptive signaling pathways, in interaction with the other gaseous flooding signals. On the other hand, excessive uncontrolled bursts of ROS can be highly damaging for plants. Therefore, a fine-tuned balance is important, with a major role for ROS production and scavenging. Our understanding of the temporal dynamics of the four gases and ROS is basal, whereas it is likely that they form a signature readout of prevailing flooding conditions and subsequent adaptive responses.


Evaluation and Reduction of Artifacts Generated by 4 Different Root-end Filling Materials by Using Multiple Cone-beam Computed Tomography Imaging Settings.
After endodontic surgery, radiographic assessment is the method of choice to monitor bone defect healing. Cone-beam computed tomography scans are useful to check and identify the reasons of failure of surgical intervention or confirm healing; however, the artifact generated by some root-end filling material might compromise this task. The objective of the study was to compare the amount of artifacts generated by 4 root-end filling materials and to test multiple exposure settings used with these materials, when the effective dose generated by each protocol was taken into consideration. Twenty central incisors were endodontically treated with retrograde obturation by using amalgam, Biodentine, MTA, and Super-EBA (5 of each). They were placed in a skull with soft tissue simulation and scanned by using the Planmeca Promax Max with different kilovolt peaks (kVp): 66, 76, 84, and 96 with and without the use of metal artifact reduction (MAR) algorithm and with low, normal, and high resolution and high definition. The Dose Area Product was registered, and the effective dose was calculated. Amalgam generated the highest amount of artifacts, whereas MAR and low resolution created fewer artifacts than other settings. The artifacts were also reduced with 96 kVp. The effective dose calculated with low resolution was remarkably lower than other resolutions. When used as root-end filling material, Biodentine, MTA, and Super-EBA generated fewer artifacts than amalgam. The use of 96 kVp with MAR and low resolution also reduced artifacts on the image and at the same time generated the lowest effective dose.


Clinical and analytical relevance of NNRTIs minority mutations on viral failure in HIV-1 infected patients.
The objective of this study was to assess the analytical and clinical relevance of minority variants using a new pyrosequencing (PSQ) assay and to detect minor variants with frequencies below the current 20% clinical setting limit. A PSQ approach for detecting and quantifying mutations was developed for the analysis of 14 codons of the human immunodeficiency virus (HIV) reverse transcriptase (RT) gene below the limit of conventional sequencing. Ten patients who experienced virological failure (VF) after a first-line regimen of lamivudine, tenofovir, and either efavirenz, nevirapine, or etravirine, as well as 10 controls patients without VF, were included in this retrospective study. Baseline plasma and plasma from the time of VF were assessed using Sanger sequencing and PSQ methods. The analytical sensitivity for the detection of minor sequence variants is 5%. At baseline, no minority variant was detected in 10/10 patient controls using both the Sanger sequencing and PSQ assays, whereas, two patients who failed therapy had baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations that were not detected by the standard genotyping. At the time of VF, standard genotyping detected mutations in four out of the 10 VF patients, whereas, PSQ detected mutations in five out of the 10 VF patients. Clinically, minority mutations at a 10% level of detection can be assessed efficiently by pyrosequencing and used as a suitable predictor of the evolution of viral populations. These traits allow for a better interpretation of data analysis, which can help clinicians in providing a suitable treatment for HIV.


Visual space-time interactions: effects of adapting to spatial frequencies on temporal sensitivity.
To study how adaptation to spatial frequency patterns affects temporal sensitivity in vision, observers were selectively adapted for 4 min to either a high- or a low-spatial-frequency sinusoidal grating (12 and 2 cpd, respectively). Their sensitivities to modulation of a blurred patch at high or low temporal frequencies (12 Hz and 2 Hz, respectively) were measured, before and after the adaptation period, by using the yes/no task of signal detection theory. The data consistently indicated that spatial adaptation differentially affected the observers' sensitivities to temporal signals. Specifically, when the observers were adapted to low spatial frequencies, their sensitivity to low temporal frequencies was reduced; when they were adapted to high spatial frequencies, their sensitivity to high temporal frequencies was increased. These results have implications for the psychophysical measurements of temporal and spatial sensitivity, as well as for the issue of the separability of spatial and temporal properties of individual channels.


Amount of peptidoglycan in cell walls of gram-negative bacteria.
The amount of diaminopimelic acid (Dap) in the cell wall of Escherichia coli was measured in two ways. A radiochemical method first described by us in 1985 (F. B. Wientjes, E. Pas, P. E. M. Taschner, and C. L. Woldringh, J. Bacteriol. 164:331-337, 1985) is based on the steady-state incorporation of [3H]Dap during several generations. Knowing the cell concentration and the specific activity of the [3H]Dap, one can calculate the number of Dap molecules per sacculus. The second method measures the Dap content chemically in sacculi isolated from a known number of cells. With both methods, a value of 3.5 x 10(6) Dap molecules per sacculus was obtained. Combined with electron microscopic measurements of the surface area of the cells, the data indicate an average surface area per disaccharide unit of ca. 2.5 nm2. This finding suggests that the peptidoglycan is basically a monolayered structure.


Analysis of expressed sequence tags from Prunus mume flower and fruit and development of simple sequence repeat markers.
Expressed Sequence Tag (EST) has been a cost-effective tool in molecular biology and represents an abundant valuable resource for genome annotation, gene expression, and comparative genomics in plants. In this study, we constructed a cDNA library of Prunus mume flower and fruit, sequenced 10,123 clones of the library, and obtained 8,656 expressed sequence tag (EST) sequences with high quality. The ESTs were assembled into 4,473 unigenes composed of 1,492 contigs and 2,981 singletons and that have been deposited in NCBI (accession IDs: GW868575 - GW873047), among which 1,294 unique ESTs were with known or putative functions. Furthermore, we found 1,233 putative simple sequence repeats (SSRs) in the P. mume unigene dataset. We randomly tested 42 pairs of PCR primers flanking potential SSRs, and 14 pairs were identified as true-to-type SSR loci and could amplify polymorphic bands from 20 individual plants of P. mume. We further used the 14 EST-SSR primer pairs to test the transferability on peach and plum. The result showed that nearly 89% of the primer pairs produced target PCR bands in the two species. A high level of marker polymorphism was observed in the plum species (65%) and low in the peach (46%), and the clustering analysis of the three species indicated that these SSR markers were useful in the evaluation of genetic relationships and diversity between and within the Prunus species. We have constructed the first cDNA library of P. mume flower and fruit, and our data provide sets of molecular biology resources for P. mume and other Prunus species. These resources will be useful for further study such as genome annotation, new gene discovery, gene functional analysis, molecular breeding, evolution and comparative genomics between Prunus species.


Ecological mechanisms explaining interactions within plant-hummingbird networks: morphological matching increases towards lower latitudes.
Interactions between species are influenced by different ecological mechanisms, such as morphological matching, phenological overlap and species abundances. How these mechanisms explain interaction frequencies across environmental gradients remains poorly understood. Consequently, we also know little about the mechanisms that drive the geographical patterns in network structure, such as complementary specialization and modularity. Here, we use data on morphologies, phenologies and abundances to explain interaction frequencies between hummingbirds and plants at a large geographical scale. For 24 quantitative networks sampled throughout the Americas, we found that the tendency of species to interact with morphologically matching partners contributed to specialized and modular network structures. Morphological matching best explained interaction frequencies in networks found closer to the equator and in areas with low-temperature seasonality. When comparing the three ecological mechanisms within networks, we found that both morphological matching and phenological overlap generally outperformed abundances in the explanation of interaction frequencies. Together, these findings provide insights into the ecological mechanisms that underlie geographical patterns in resource specialization. Notably, our results highlight morphological constraints on interactions as a potential explanation for increasing resource specialization towards lower latitudes.


Abnormal bone collagen morphology and decreased bone strength in growth hormone-deficient rats.
Patients with growth hormone deficiency (GHD) have an increased risk of bone fractures. In these patients, the well-described decrease in bone mineral density (BMD) and content (BMC) may, however, not alone explain the increase in fracture rate. Accordingly, the aim of this study was to evaluate collagen morphology and bone mineralisation in cortical bone as well as bone strength in GHD rats to try to clarify the explanation for the increased fracture rate. The Dw-4 rat was used as a model for GHD. This strain of rats has an autosomal recessive disorder, reducing GH synthesis to approximately 10% and growth rate to approximately 40-50% when compared to normal control rats. Five male Dw-4 rats were examined at age 12 weeks and five healthy Lewis rats served as age-matched controls. The animals were examined for (1) bone mineral status by dual energy X-ray absorptometry (DXA) and ash weight/bone volume, (2) biomechanical properties, (3) serum insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and (4) collagen morphology of cortical bone from the right femurs was examined by scanning and transmission electron microscopy. A significant decrease was found in serum IGF-I, IGFBP-3 and biomechanical properties in GHD rats compared to controls (P < 0.009). While DXA-derived BMD was decreased, no significant difference was found in ash weight/bone volume. Electron microscopy showed a significant decrease in the number and a significant increase in the diameter of collagen microfibrils in GHD rats as compared to their controls (P < 0.009). In conclusion, we report for the first time that collagen morphology in bone is markedly altered in rats with isolated GHD. Whether similar conditions are present in GHD patients need further investigations. The changes described, however, may provide a co-explanation for the increased fracture rate in GHD.


The impact of integrated care on health care utilization and costs in a socially deprived urban area in Germany: A difference-in-differences approach within an event-study framework.
We investigated the impact of an integrated care initiative in a socially deprived urban area in Germany. Using administrative data, we empirically assessed the causal effect of its two sub-interventions, which differed by the extent to which their instruments targeted the supply and demand side of healthcare provision. We addressed confounding using propensity score matching via the Super Learner machine learning algorithm. For our baseline model, we used a two-way fixed-effects difference-in-differences approach to identify causal effects. We then employed difference-in-differences analyses within an event-study framework to explore the heterogeneity of treatment effects over time, allowing us to disentangle the effects of the sub-interventions and improve causal interpretation and generalizability. The initiative led to a significant increase in hospital and emergency admissions and non-hospital outpatient visits, as well as inpatient, non-hospital outpatient, and total costs. Increased utilization may indicate that the intervention improved access to care or identified unmet need.


Route of antibiotic prophylaxis for prevention of cerebrospinal fluid-shunt infection.
The main complication of cerebrospinal fluid (CSF) shunt surgery is shunt infection. Prevention of these shunt infections consists of the perioperative use of antibiotics that can be administered in five different ways: orally; intravenously; intrathecally; topically; and via the implantation of antibiotic-impregnated shunt catheters. To determine the effect of different routes of antibiotic prophylaxis (i.e. oral, intravenous, intrathecal, topical and via antibiotic-impregnated shunt catheters) on CSF-shunt infections in persons treated for hydrocephalus using internalised CSF shunts. We conducted a systematic electronic search without restrictions on language, date or publication type. We performed the search on the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and Embase, with the help of the Information Specialist of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group. The search was performed in January 2018. All randomised and quasi-randomised controlled trials that studied the effect of antibiotic prophylaxis, in any dose or administration route, for the prevention of CSF-shunt infection in patients that were treated with an internal cerebrospinal fluid shunt. Patients with external shunts were not eligible. Two review authors independently extracted data from included studies. We resolved disagreements by discussion or by referral to an independent researcher within our department when necessary. Analyses were also performed by at least two authors. We included a total of 11 small randomised controlled trials, containing 1109 participants, in this systematic review. Three of these studies included solely children, and the remaining eight included participants of all ages. Most studies were limited to the evaluation of ventriculoperitoneal shunts. However, five studies included participants with ventriculoatrial shunts, of which one study contained four participants with a subduroperitoneal shunt. We judged four out of 11 (36%) trials at unclear risk of bias, while the remaining seven trials (64%) scored high risk of bias in one or more of the components assessed.We analysed all included studies in order to estimate the effect of antibiotic prophylaxis on the proportion of shunt infections regardless of administration route. Although the quality of evidence in these studies was low, there may be a positive effect of antibiotic prophylaxis on the number of participants who had shunt infections (RR 0.55, 95% CI 0.36 to 0.84), meaning a 55% reduction in the number of participants who had shunt infection compared with standard care or placebo.Within the different administration routes, only within intravenous administration of antibiotic prophylaxis there may be evidence of an effect on the risk of shunt infections (RR 0.55, 95% CI 0.33 to 0.90). However, this was the only route that contained more than two studies (8 studies; 797 participants). Evidence was uncertain for both, intrathecal administration of antibiotics (RR 0.73, 95% CI 0.28 to 1.93, 2 studies; 797 participants; low quality evidence) and antibiotic impregnated catheters (RR 0.36, 95% CI 0.10 to 1.24, 1 study; 110 participants; very low quality evidence) AUTHORS' CONCLUSIONS: Antibiotic prophylaxis may have a positive effect on lowering the number of participants who had shunt infections. However, the quality of included studies was low and the effect is not consistent within the different routes of administration that have been analysed. It is therefore uncertain whether prevention of shunt infection varies by different antibiotic agents, different administration routes, timing and doses; or by characteristics of patients, e.g. children and adults. The results of the review should be seen as hypothesis-generating rather than definitive, and the results should be confirmed in adequately powered trials or large multicentre studies in order to obtain high-quality evidence in the field of ventricular shunt infection prevention.


Diphtheria in the south of France, March 2011.
In March 2011, a 40 year-old French man was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. Fifty-three close contacts were identified from whom throat samples were analysed. C. diphtheriae was found only in the asymptomatic partner of the index case. The two cases had travelled in Spain during the incubation period of the index case. Investigation around the second case identified 13 new close contacts.None of them was found to be infected.