Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive.
Condensation and segregation of mitotic chromosomes is a critical process for cellular propagation, and, in mammals, mitotic errors can contribute to the pathogenesis of cancer. In this report, we demonstrate that the retinoblastoma protein (pRB), a well-known regulator of progression through the G1 phase of the cell cycle, plays a critical role in mitotic chromosome condensation that is independent of G1-to-S-phase regulation. Using gene targeted mutant mice, we studied this aspect of pRB function in isolation, and demonstrate that it is an essential part of pRB-mediated tumor suppression. Cancer-prone Trp53(-/-) mice succumb to more aggressive forms of cancer when pRB's ability to condense chromosomes is compromised. Furthermore, we demonstrate that defective mitotic chromosome structure caused by mutant pRB accelerates loss of heterozygosity, leading to earlier tumor formation in Trp53(+/-) mice. These data reveal a new mechanism of tumor suppression, facilitated by pRB, in which genome stability is maintained by proper condensation of mitotic chromosomes.


Premorbid migraine history as a risk factor for vestibular and oculomotor baseline concussion assessment in pediatric athletes.
OBJECTIVEMigraine history has recently been identified as a risk factor for concussion and recovery. The authors performed a cross-sectional study examining baseline outcome measures on newly developed and implemented concussion assessment tools in pediatrics. The purpose of this study was to examine the effects of premorbid, diagnosed migraine headaches as a risk factor on vestibular and oculomotor baseline assessment in pediatric athletes.METHODSPediatric athletes between the ages of 8 and 14 years with a diagnosed history of migraine headache (n = 28) and matched controls without a history of diagnosed migraine headache (n = 28) were administered a baseline concussion assessment battery, consisting of the Vestibular/Ocular Motor Screening (VOMS), near point of convergence (NPC), and the King-Devick (K-D) tests. Between-groups comparisons were performed for vestibular symptoms and provocation scores on the VOMS (smooth pursuit, saccades, convergence, vestibular/ocular reflex, visual motion sensitivity), NPC (average distance), and K-D (time).RESULTSIndividuals diagnosed with migraine headaches reported greater VOMS smooth pursuit scores (p = 0.02), convergence scores (p = 0.04), vestibular ocular reflex scores (p value range 0.002-0.04), and visual motion sensitivity scores (p = 0.009). Differences were also observed on K-D oculomotor performance with worse times in those diagnosed with migraine headache (p = 0.02). No differences were reported on NPC distance (p = 0.06) or headache symptom reporting (p = 0.07) prior to the VOMS assessment.CONCLUSIONSPediatric athletes diagnosed with migraine headaches reported higher baseline symptom provocation scores on the VOMS. Athletes with migraine headaches also performed worse on the K-D test, further illustrating the influence of premorbid migraine headaches as a risk factor for elevated concussion assessment outcomes at baseline. Special consideration may be warranted for post-concussion assessment in athletes with migraine headaches.


Concurrent Validity and Reliability of the Transfer Assessment Instrument Questionnaire as a Self-Assessment Measure.
To evaluate the psychometric properties of the Transfer Assessment Instrument Questionnaire (TAI-Q), a self-assessment measure to evaluate transfer quality compared with clinician-reported measures. Participants self-assessed transfers from their wheelchair to a mat table using the TAI-Q. For session 1, participants self-assessed their transfer both before and after reviewing a video of themselves completing the transfer (session 1). Self-assessment was completed for another transfer after a 10-minute delay (session 2, intrarater reliability) and after a 1- to 2-day delay (session 3, test-retest reliability). Self-assessment was compared with a criterion standard of an experienced clinician scoring the same transfers with the Transfer Assessment Instrument (TAI) version 4.0 (concurrent validity). 2017 National Veterans Wheelchair Games. Convenience sample of full-time wheelchair users (N=44). Not applicable. TAI-Q and TAI. After video review of their transfer, acceptable levels of reliability were demonstrated for total TAI-Q score for intrarater (intraclass correlation [ICC], 0.627) and test-retest reliability (ICC, 0.705). Moderate to acceptable concurrent validity was demonstrated with the TAI (ICC, 0.554-0.740). Participants tended to underestimate the quality of their transfer (reported more deficient items) compared with the TAI. However, this deficit decreased and reliability improved from pre-video review to post-video review and from session 1 to session 2. The minimum detectable change indicated that a change of 1.63 to 2.21 in the TAI-Q total score is needed to detect a significant difference in transfer skills. When paired with video review, the TAI-Q demonstrates moderate to acceptable levels of reliability and validity for the total score. Self-assessment was completed quickly (<5min) and could help to potentially screen for deficiencies in transfer quality and opportunities for intervention.


Measurement and modelling of perceived slant in surfaces represented by freely viewed line drawings.
Simple pictures under everyday viewing conditions evoke impressions of surfaces oriented in depth. These impressions have been studied by measuring the slants of perceived surfaces, with probes (rotating arrowheads) designed to respect the distinctive character of depicted scenes. Converging arguments indicated that the perceived orientation of the probes was near theoretical values. A series of experiments showed that subjects formed well-defined impressions of depicted surface orientation. The literature suggests that perceived objects might be 'flattened', but that was not the general rule. Instead, both mean slant and uncertainty fitted models in which slant estimates are derived in a relatively straightforward way from local relations in the picture. Simplifying pictures tended to make orientation estimates less certain, particularly away from the natural anchor points (vertical and horizontal). The shape of the object affected all aspects of the observed-object/percept relationship. Individual differences were large, and suggest that different individuals used different relationships as a basis for their estimates. Overall, data suggest that everyday picture perception is strongly selective and weakly integrative. In particular, depicted slant is estimated by finding a picture feature which will be strongly related to it if the object contains a particular regularity, not by additive integration of evidence from multiple directly and indirectly relevant sources.


Annona muricata Leaf Extract Triggered Intrinsic Apoptotic Pathway to Attenuate Cancerous Features of Triple Negative Breast Cancer MDA-MB-231 Cells.
Annona muricata L., known as graviola, is an evergreen plant of the tropical regions and is a rich source of natural products. Graviola has various biological activities, and it is best known for its anticancer activity. This study aimed to investigate the effects of crude graviola extract in vitro on breast cancer cells; in particular, we aimed to identify an agent against triple negative breast cancer (TNBC). We used the TNBC MDA-MB-231 cell line as the experimental model and the ER(+) non-TNBC MCF-7 breast cancer cell line as the control. We identified annonaceous acetogenins, including annonacin isomers, characteristic to this plant by using liquid chromatography tandem mass spectrometry (LC/MS/MS). We observed a significant decrease in the cell viability in both cell lines within 48 h, whereas impaired cell motility and invasiveness were observed only in the MDA-MB-231 cell line. While the MCF-7 cells showed an ER-dependent mechanism of apoptosis, the apoptosis of MDA-MB-231 cells was governed by an intrinsic apoptotic pathway triggered by graviola leaf extract (GLE).


Ultrastructural analysis of chromatin in meiosis I + II of rye (Secale cereale L.).
Scanning electron microscopy (SEM) proves to be an appropriate technique for imaging chromatin organization in meiosis I and II of rye (Secale cereale) down to a resolution of a few nanometers. It could be shown for the first time that organization of basic structural elements (coiled and parallel fibers, chromomeres) changes dramatically during the progression to metaphase I and II. Controlled loosening with proteinase K (after fixation with glutaraldehyde) provides an enhanced insight into chromosome architecture even of highly condensed stages of meiosis. By selective staining with platinum blue, DNA content and distribution can be visualized within compact chromosomes as well as in a complex arrangement of fibers. Chromatin interconnecting threads, which are typically observed in prophase I between homologous and non-homologous chromosomes, stain clearly for DNA. In zygotene transversion of chromatid strands to their homologous counterparts becomes evident. In pachytene segments of synapsed and non-synapsed homologs alternate. At synapsed regions pairing is so intimate that homologous chromosomes form one filament of structural entity. Chiasmata are characterized by chromatid strands which traverse from one homolog to its counterpart. Bivalents are characteristically fused at their telomeric regions. In metaphase I and II there is no structural evidence for primary and secondary constrictions.


Effects of photodynamic therapy on dermal fibroblasts from xeroderma pigmentosum and Gorlin-Goltz syndrome patients.
PDT is widely applied for the treatment of non-melanoma skin cancer pre-malignant and malignant lesions (actinic keratosis, basal cell carcinoma and in situ squamous cell carcinoma). In photodynamic therapy (PDT) the interaction of a photosensitizer (PS), light and oxygen leads to the formation of reactive oxygen species (ROS) and thus the selective tumor cells eradication. Xeroderma pigmentosum (XP) and Gorlin-Goltz Syndrome (GS) patients are at high risk of developing skin cancer in sun-exposed areas. Therefore, the use of PDT as a preventive treatment may constitute a very promising therapeutic modality for these syndromes. Given the demonstrated role of cancer associated fibroblasts (CAFs) in tumor progression and the putative CAFs features of some cancer-prone genodermatoses fibroblasts, in this study, we have further characterized the phenotype of XP and GS dermal fibroblasts and evaluated their response to methyl-δ-aminolevulinic acid (MAL)-PDT compared to that of dermal fibroblasts obtained from healthy donors. We show here that XP/GS fibroblasts display clear features of CAFs and present a significantly higher response to PDT, even after being stimulated with UV light, underscoring the value of this therapeutic approach for these rare skin conditions and likely to other forms of skin cancer were CAFs play a major role.


Effect of Interactions between Harvester Ants on Forager Decisions.
Harvester ant colonies adjust their foraging activity to day-to-day changes in food availability and hour-to-hour changes in environmental conditions. This collective behavior is regulated through interactions, in the form of brief antennal contacts, between outgoing foragers and returning foragers with food. Here we consider how an ant, waiting in the entrance chamber just inside the nest entrance, uses its accumulated experience of interactions to decide whether to leave the nest to forage. Using videos of field observations, we tracked the interactions and foraging decisions of ants in the entrance chamber. Outgoing foragers tended to interact with returning foragers at higher rates than ants that returned to the deeper nest and did not forage. To provide a mechanistic framework for interpreting these results, we develop a decision model in which ants make decisions based upon a noisy accumulation of individual contacts with returning foragers. The model can reproduce core trends and realistic distributions for individual ant interaction statistics, and suggests possible mechanisms by which foraging activity may be regulated at an individual ant level.


[Developmental delay in breastfed children due to inadequate diet of the mother].
Two infant boys of 7 and 12 months respectively who presented with symptoms of failure to thrive and developmental delay were diagnosed with vitamin B12 deficiency. This deficiency is a rare condition in infants living in developed countries. It does occur, however, in infants who are breastfed by mothers with an inadequate diet. Both of the children studied were breastfed by vegetarian mothers. Following vitamin suppletion, both children showed signs of recovery. The importance of considering vitamin deficiencies in similar infants presenting with failure to thrive is emphasized. Moreover, maternal dietary habits in breastfed children should be checked. To prevent irreversible neurological damage, early recognition of any nutritional deficiencies is important.


Achieving equitable uptake of handwashing and sanitation by addressing both supply and demand-based constraints: findings from a randomized controlled trial in rural Bangladesh.
Supply driven programs that are not closely connected to community demand and demand-driven programs that fail to ensure supply both risk worsening inequity. Understanding patterns of uptake of behaviors among the poorest under ideal experimental conditions, such as those of an efficacy trial, can help identify strategies that could be strengthened in routine programmatic conditions for more equitable uptake. WASH Benefits Bangladesh was a randomized controlled efficacy trial that provided free-of cost WASH hardware along with behavior change promotion. The current paper aimed to determine the impact of the removal of supply and demand constraints on the uptake of handwashing and sanitation behaviors across wealth and education levels. The current analysis selected 4 indicators from the WASH Benefits trial- presence of water and soap in household handwashing stations, observed mother's hand cleanliness, observed visible feces on latrine slab or floor and reported last child defecation in potty or toilet. A baseline assessment was conducted immediately after enrolment and endline assessment was conducted approximately 2 years later. We compared change in uptake of these indicators including wealth quintiles (Q) between intervention and control groups from baseline to endline. For hand cleanliness, the poorest mothers improved more [Q1 difference in difference, DID: 16% (7, 25%)] than the wealthiest mothers [Q5 DID: 7% (- 4, 17%)]. The poorest households had largest improvements for observed presence of water and soap in handwashing station [Q1 DID: 82% (75, 90%)] compared to the wealthiest households [Q5 DID: 39% (30, 50%)]. Similarly, poorer household demonstrated greater reductions in visible feces on latrine slab or floor [Q1DID, - 25% (- 35, - 15) Q2: - 34% (- 44, - 23%)] than the wealthiest household [Q5 DID: - 1% (- 11, 8%). For reported last child defecation in potty or toilet, the poorest mothers showed greater improvement [Q1-4 DID: 50-54% (44, 60%)] than the wealthier mothers [Q5 DID: 39% (31, 46%). By simultaneously addressing supply and demand-constraints among the poorest, we observed substantial overall improvements in equity. Within scaled-up programs, a separate targeted strategy that relaxes constraints for the poorest can improve the equity of a program. WASH Benefits Bangladesh: ClinicalTrials.gov , identifier: NCT01590095 . Date of registration: April 30, 2012 'Retrospectively registered'.


A Ratiometric Near-Infrared Fluorogen for the Real Time Visualization of Intracellular Redox Status during Apoptosis.
Direct monitoring of apoptotic progression is a major step forward for the early assessment of therapeutic efficacy of certain treatments and the accurate evaluation of the spread of a disease. Here, the regulatory role of glutathione (GSH) is explored as a potential biomarker for tracking apoptosis. For this purpose, a near- infrared (NIR) squaraine dye is introduced that is capable of sensing GSH in a ratiometric manner by switching its emission from NIR (690 nm) to visible region (560 nm). The favorable biocompatible attributes of the probe facilitated the real-time monitoring of apoptotic process in line with the conventional apoptotic assay. Furthermore, the robust nature of the probe was utilized for the quantitative estimation of GSH during different stages of apoptosis. Through this study, an easy and reliable method of assaying apoptosis is demonstrated, which can provide valuable insights in translational clinical research.


Acetylcholine release from the rabbit retina mediated by kainate receptors.
The cholinergic amacrine cells of the rabbit retina may be labeled with 3H-choline (3H-Ch), and the activity of the cholinergic population may be monitored by following the release of 3H-ACh. Glutamate analogs caused massive ACh release, up to 50 times the basal efflux, with the following rank order of potency: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) greater than quisqualate (QQ) = kainate (KA) much greater than NMDA (in magnesium-free medium) much greater than glutamate greater than aspartate. In contrast, the release of 3H-Ch was unchanged. Submaximal doses of each agonist were used to establish the specifity of glutamate antagonists. Kynurenic acid was selective for KA much greater than QQ, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was selective for KA greater than QQ much greater than NMDA. At low doses, which selectively blocked the response to KA, both antagonists blocked the light-evoked release of ACh. These results suggest that ACh release may be produced via several glutamate receptors, but the physiological input to the cholinergic amacrine cells is mediated by KA receptors. Because these cells receive direct input from cone bipolar cells, this work supports previous evidence that the bipolar cell transmitter is glutamate.


Comparison between echocardiographic and non-ECG-gated CT measurements in dogs.
The aim of this study was to compare echocardiographic measurements with non-ECG-gated contrast-enhanced cardiac CT measurements in dogs. Fifty-seven dogs were included in the study. The following echocardiographic parameters were measured: M-mode interventricular septum in diastole and systole, left ventricular internal diameter in diastole and systole, left ventricular free wall in diastole and systole, 2D left atrial maximal diameter, 2D left atrium to aorta ratio in diastole, 2D aortic annulus in systole and 2D pulmonary annulus in diastole and systole. CT measurements were obtained from multiplanar reconstruction images, replicating the imaging planes used for 2D measurements on echocardiography. It was not possible to discriminate between systole and diastole. The results showed moderate Lin's concordance correlation coefficients between the left ventricular internal diameter in systole (0.77), the aortic annuli (0.84) and the pulmonary annuli in diastole (0.78) and systole (0.80). Low coefficients were obtained between the other parameters. Bland-Altman plots for the parameters with highest concordance correlation coefficients were calculated. They suggested equivalence between the measurements of the aortic annuli. Equivalence was not seen between the remaining echocardiographic and CT measurements. Therefore, non-ECG-gated CT is not a reliable way of quantitatively assessing cardiac size.


Body concerns and BMI as predictors of disordered eating and body mass in girls: An 18-year longitudinal investigation.
Body concerns (e.g., body dissatisfaction and weight preoccupation) are well-supported prospective risk factors for the development of eating disorders in women. Body concerns are psychological variables but they are partly based on actual body mass. This study tested whether (a) body concerns predict increases in eating disorder characteristics measured both continuously (via subscale scores on the Minnesota Eating Behavior Survey (MEBS) and categorically (via transition to a probable or definite eating disorder), (b) body concerns predict changes in BMI, and (c) BMI predicts changes in eating disorder symptoms or development of an eating disorder. Beginning with 762 girls at age 11, the MEBS' Body Dissatisfaction (BD) and Weight Preoccupation (WP) scales were used to predict change in the MEBS' Bulimic Behavior scale (the sum of the Binge Eating and Compensatory Behaviors scales), in BD and WP themselves and in BMI over 18 years of follow up. Baseline BMI was also used to predict BMI and MEBS change. Contrary to expectations, BD and WP predicted significantly reduced growth in all MEBS scales and also predicted significantly reduced growth in BMI. BD, WP and BMI did not predict development of an ED. This pattern was strengthened when predictors were measured at age 17 instead of 11. We consider the possibility that the divergence between the current findings and past findings on eating disorder risk factors may stem from the unusually long developmental period studied, ranging from age 11 (or 17) through age 29. Additional longitudinal research that spans a similar developmental period could shed light on the plausibility of this explanation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Biochemistry of inflammatory processes and vascular injury. Role of neutrophils: a review.
Possible mechanisms of the participation of neutrophils in inflammation and vascular damage are reviewed. The role of chemotaxis, adhesion, and neutrophil-endothelium interaction are considered. Specific attention is paid to the action of neutrophils (PMNs) in inflammation sites which can be caused by the interaction between PMN-generated proteinases and oxygen metabolites.


Weight and body mass index in relation to irradiated volume and to overall survival in patients with oropharyngeal cancer: a retrospective cohort study.
Weight loss is a common problem in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) treated with radiotherapy (RT). The aims of the present study were to determine if treated volume (TV), as a measure of the radiation dose burden, can predict weight loss in patients with oropharyngeal cancer and to analyze weight loss and body mass index (BMI) in the same patient group in relation to 5-year overall survival. The ARTSCAN trial is a prospective, randomized, multicenter trial in patients with SCCHN. Nutritional data from the ARTSCAN trial were analyzed retrospectively using univariate and multivariate statistical methods based on information on percentage weight loss from the start of RT up to five months after the termination of RT (study cohort 1, n = 232) and information on patients' BMI at the start of RT (study cohort 2, n = 203). TV was defined as the volume of the patient receiving at least 95% of the prescribed dose. TV64.6 Gy encompasses macroscopic tumor and TV43.7 Gy elective lymph nodes of the neck. TV64.6 Gy and TV43.7 Gy were both significantly correlated with higher weight loss up to five months after the termination of RT in study cohort 1 (p < 0.001 for both). BMI at the start of RT was shown to be a prognostic factor for 5-year overall survival in study cohort 2 but weight loss was not. The hazard ratios and 95% confidence intervals were 3.78 (1.46-9.75) and 2.57 (1.43-4.62) in patients with underweight and normal weight, respectively. TV can predict weight loss during RT in patients with oropharyngeal cancer regardless of clinical stage. A high BMI (>25 kg/m2) at the start of RT is positively associated with survival in patients with oropharyngeal cancer.


Venous and arterial endothelial proteomics: mining for markers and mechanisms of endothelial diversity.
Endothelial cells (ECs) line the inside of arterial and venous blood vessels in a continuous monolayer and have the important function of responding to environmental cues to regulate vascular tone and new blood vessel formation. They also have well-defined roles in supporting tumorigenesis, and alterations in their function lead to cardiovascular disease. Consequently, ECs have been studied extensively as a cellular model of both normal and abnormal physiology. Despite their importance and the increased utility of proteomic tools in medical research, there are relatively few publications on the topic of vascular endothelial proteomics. A thorough search of the literature mined 52 publications focused exclusively on arterial and/or venous endothelial proteomics. These studies mostly relied upon examination of whole-cell lysates from cultured human umbilical vein ECs to investigate in vitro effects of various molecules, such as VEGF in the context of altering human umbilical vein EC functions related to angiogenesis. Only a few of these publications focused solely on a proteomic characterization of ECs and our analysis further revealed a lack of published studies incorporating proteomic analysis of freshly isolated ECs from tissues or in vitro conditions that mimic in vivo variables, such as oxygen tension and shear stress. It is the purpose of this article to account for the diversity of vascular EC proteomic investigations and comment on the issues that have been and should be addressed in future work.


The use of oral beclomethasone dipropionate in the treatment of gastrointestinal graft-versus-host disease: the experience of the Fukuoka blood and marrow transplantation (BMT) group.
We examined the therapeutic strategies for treating mild gastrointestinal (GI) graft-versus-host disease (GVHD) using oral beclomethasone dipropionate (BDP) in 15 Japanese patients based on the donor source. The primary objective was to determine the efficacy and toxicity of oral BDP combined with/without low-dose prednisone (PSL). Oral BDP was administered with 1 mg/kg/d of PSL in patients undergoing bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT; n=11), and the dose of PSL was tapered off after 22 days. Oral BDP alone was administered in patients undergoing cord blood stem cell transplantation (CBSCT; n=4). The primary endpoint was the rate of treatment success on day 49, as measured according to the improvement or complete resolution of GI symptoms without additional treatment. The secondary endpoints included treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 3.0, the rate of treatment discontinuation due to toxicity, the rate of relapse of acute GVHD by day 100 and the incidence of bacterial, fungal or viral infection, including cytomegalovirus (CMV) antigenemia. Treatment success was achieved in seven of the 11 (64%) patients undergoing BMT or PBSCT and in all four patients (100%) undergoing CBSCT. Subsequent adverse events included herpes zoster infection, catheter-associated sepsis and CMV enteritis; all affected patients responded well to treatment. The use of a risk-stratified treatment strategy with oral BDP depending on the stem cell source is effective in patients with mild GI-GVHD.


Quality and Safety of Pediatric Inpatient Care in Community Hospitals: A Scoping Review.
Although the majority of children are hospitalized in nonchildren's hospitals, little is known about the quality and safety of pediatric care in community hospitals. The aim of this study was to conduct a scoping review and synthesize literature on the quality and safety of pediatric inpatient care in United States community hospitals. We performed a systematic literature search in October 2016 to identify pediatric studies that reported on safety, effectiveness, efficiency, timeliness, patient-centeredness, or equity set in general, nonuniversity, or nonchildren's hospitals. We extracted data on study design, patient descriptors, and quality outcomes and assessed the risk of bias using modified Newcastle-Ottawa Scales. A total of 44 articles met the inclusion criteria. Study designs, patient populations, and quality outcome measures were heterogeneous; only three clinical domains, (1) perinatal regionalization, (2) telemedicine, and (3) imaging radiation, were explored in multiple studies with consistent directionality of results. A total of 30 studies were observational, and 22 studies compared community hospital quality outcomes with other hospital types. The remaining 14 studies reported testing of interventions; 12 showed improved quality of care postintervention. All studies reported an outcome addressing safety, effectiveness, or efficiency, whereas timeliness, patient-centeredness, and equity were infrequently addressed. Risk of bias was moderate or high for 72% of studies. Literature on the inpatient care of children in community hospitals is limited, making it difficult to evaluate healthcare quality. Measures of timeliness, patient-centeredness, and equity are underrepresented. The field would benefit from more multicenter collaborations to facilitate the application of robust study designs and to enable a systematic assessment of individual interventions and community hospital quality outcomes.


Norepinephrine dialysate levels in the hypothalamic paraventricular nucleus: influence on photoperiod-driven prolactin levels in the female siberian hamster.
Basal prolactin (PRL) levels in Siberian hamsters are modulated by ambient photoperiod via the nocturnal melatonin signal. Recent evidence from our laboratory has demonstrated that norepinephrine (NE), a putative neurochemical regulator of PRL secretion shows photoperiod-dependent fluctuations in the hypothalamic paraventricular nucleus (PVN) that are independent of the pineal melatonin signal. NE content in the PVN is elevated under a short-day photoperiod with a time course that follows the short-day-induced decline in PRL. NE could thus modulate the release of a prolactin-releasing factor that subsequently drives PRL synthesis and release rates. In order to determine whether NE release in the PVN correlates with basal PRL levels, this study evaluated the relationship between extracellular NE levels in the PVN and basal PRL under long- and short-day photoperiod conditions. In addition, the profile of NE during the proestrous surge of PRL was investigated. Female Siberian hamsters were housed either in long-day or short-day photoperiods for 8 weeks. After 6 weeks of photoperiod exposure, the animals were implanted with a stainless steel guide cannula aimed at the PVN. Two weeks later, the animals were fitted with a jugular cannula for serial blood sampling and implanted with an indwelling microdialysis probe. Dialysis samples were collected every 20 min for 5 h (12.00-17.00 h) from short-day-exposed animals and from long-day-exposed animals classified as being either in diestrus or proestrus. Blood samples were collected every hour and analyzed for PRL levels by radioimmunoassay. NE and methoxy-4-hydrophenylglycol (MHPG) levels were significantly higher in short-day-exposed animals, correlating with the suppressed basal secretion of PRL. Both long-day groups had lower NE and MHPG levels, and higher PRL, than the short-day group. However, long-day animals showed a significant decline in NE in proestrus just prior to the onset of the afternoon surge of PRL. These data suggest that NE released within the PVN participates in the regulation of photoperiod effects upon PRL secretion, as well as that of the afternoon surge of PRL on proestrus.


Thyroid uptake of 67Ga-citrate is associated with thyroid autoimmunity and hypothyroidism in patients with sarcoidosis.
To evaluate the association of gallium-67 ((67)Ga)-citrate thyroid uptake with the presence of thyroid disorders in patients with sarcoidosis (S patients). Eighty-four S patients were evaluated by a complete thyroid work-up (neck ultrasound, circulating thyroid hormones and anti-thyroid antibodies, fine-needle aspiration). In S patients with (67)Ga thyroid uptake (respect those without): serum thyroid-stimulating hormone, the titre of anti-thyroid peroxidase (AbTPO) and/or anti-thyroglobulin antibodies (AbTg), and the prevalence of S patients with hypothyroidism or with positive AbTg or AbTPO was significantly higher; a thyroid hypoechoic pattern was more frequent. The prevalence of thyroid nodules was not significantly different between the two groups. Two cases of papillary thyroid cancer were observed in S patients without (67)Ga thyroid uptake, whilst no case in those with (67)Ga thyroid uptake. (67)Ga thyroid uptake is associated with the presence of aggressive autoimmune thyroiditis and hypothyroidism in S patients; thyroid function and ultrasonography should be performed in the presence of (67)Ga thyroid uptake.


Evaluation of early fetal losses on four equine farms in central Kentucky: 73 cases (2001).
To determine features of an early fetal loss (EFL) syndrome and evaluate potential risk factors for EFL in Thoroughbred broodmares on 4 farms in central Kentucky. Retrospective study. 288 pregnant broodmares. Year-2001 breeding records for 288 Thoroughbred broodmares were examined. Early fetal loss was defined as loss of a fetus that was viable at > or = 40 days of gestation but was subsequently lost by 5 months of gestation. Overall 2001 EFL rate was 25% (73/288), median gestational age at time of fetal loss was 77 days, and median date of loss was May 7. Mares on 1 farm had significantly fewer fetal losses (5%) than mares on the other 3 farms (26 to 35%). Fetal losses were higher for maiden (42%) and barren (42%) mares than for foaling mares (18%). Fetal losses were greater in young than in older mares. Effects of broodmare farm, mare age, and reproductive status were all significant. Fetal losses were not associated with sire used for mating or stud farm. Greatest risk for EFL occurred during the period from late April to May (ie, in mares bred during February through March). Higher incidence of EFL in maiden and barren mares and lower incidence of EFL on 1 farm suggest management or environmental influences may have affected outcome. Risk factors that should be investigated include environmental differences among farms and differences in management procedures used for lactating versus nonlactating mares.


Enhancing uric acid electrochemical detection with copper ion-activated mini protein mimicking uricase within ZIF-8: response surface methodology (RSM) optimization.
This study aims to investigate the influence of copper(II) ions as a cofactor on the electrochemical performance of a biocomposite consisting of a mini protein mimicking uricase (mp20) and zeolitic immidazolate framework-8 (ZIF-8) for the detection of uric acid. A central composite design (CCD) was utilized to optimize the independent investigation, including pH, deposition potential, and deposition time, while the current response resulting from the electrocatalytic oxidation of uric acid was used as the response. The statistical analysis of variance (ANOVA) showed a good correlation between the experimental and predicted data, with a residual standard error percentage (RSE%) of less than 2% for predicting optimal conditions. The synergistic effect of the nanoporous ZIF-8 host, Cu(II)-activated mp20, and reduced graphene oxide (rGO) layer resulted in a highly sensitive biosensor with a limit of detection (LOD) of 0.21 μM and a reproducibility of the response (RSD = 0.63%). The Cu(II)-activated mp20@ZIF-8/rGO/SPCE was highly selective in the presence of common interferents, and the fabricated layer exhibited remarkable stability with signal changes below 4.15% after 60 days. The biosensor's reliable performance was confirmed through real sample analyses of human serum and urine, with comparable recovery values to conventional HPLC.


Evaluating the invariance of the factor structure of the EPQ-R-N among adolescents.
We examined the factor structure of the Neuroticism scale of the Eysenck Personality Questionnaire (EPQ-R-N; S. B. G. Eysenck, Eysenck & Barrett, 1985) and its factor invariance across sex and racial/ethnic groups in a sample of 1,979 adolescents. Using confirmatory factor analyses, we compared a hierarchical model to previous models of the EPQ-R-N and to single-factor and 3-factor structures. The hierarchical factor structure in which a general factor coexists with 3 group factors (depression, social concerns, and worry) was superior to alternative models. The general factor accounted for more than 60% of the variance in EPQ-R-N total scores and was invariant across sex and ethnicity. The 3 group factors varied across ethnicity and sex. We discuss the implications of these findings for conceptualization and assessment of neuroticism using the EPQ-R-N.


Preexposure prophylaxis for HIV prevention: where have we been and where are we going?
Preexposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is an efficacious and promising new HIV prevention strategy. The past 2 years have seen significant new advances in knowledge regarding PrEP, including definitive demonstration that PrEP reduces the risk of HIV acquisition, regulatory approval of combination oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as the first PrEP agent with a label indication for sexual HIV prevention, and the development of normative guidance for clinical prescribing of PrEP. In PrEP clinical trials, HIV protection was strongly correlated with PrEP adherence; therefore, understanding and supporting adherence to PrEP are key to maximizing its public health impact. As would be expected for any new HIV prevention approach, questions remain, including how to motivate uptake of and sustain adherence to PrEP for HIV prevention in high-risk populations, how much use is sufficient to achieve HIV protection, and the potential of "next-generation" PrEP agents to improve this effective prevention strategy. At this important transition point-from demonstration of efficacy in clinical trials to thinking about implementation and effectiveness-this review addresses where we have been and where we are going with PrEP for HIV prevention.


Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program.
Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia, was based on the phase 3 RATIFY trial results. RADIUS-X (NCT02624570) was an expanded access program providing access to midostaurin during regulatory review and extending the understanding of the safety and tolerability of midostaurin. Patients aged ≥18 years received midostaurin with 1-2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy. The study enrolled 103 patients. No new safety events were observed; toxicities were not influenced by age, anthracycline choice, or coadministration of CYP3A4 inhibitors. The most common adverse events (AEs) were febrile neutropenia, nausea, and diarrhea. During maintenance, 46% of patients reported AEs. Midostaurin demonstrated a manageable safety profile and was associated with high transplant and low on-treatment relapse rates.


Magnetic resonance imaging in the evaluation of acute stroke.
The ability to use physiologic imaging with either magnetic resonance (MR) or computed tomography to help define irreversibly injured brain (the infarct core) and tissue at risk of infarct (reversible ischemic penumbra) holds great promise in the future treatment of stroke. The physiologic principles and concepts underlying the evaluation for mismatch between injured tissue and tissue at risk are similar for the 2 imaging techniques. Multimodal MR imaging (diffusion-weighted imaging/perfusion-weighted imaging/MR angiography) provides a validated penumbral selection criteria based on the results of 2 clinical trials (diffusion and perfusion imaging evaluation for understanding stroke evolution and echoplanar imaging thrombolysis evaluation). Computed tomographic perfusion parameters have also been calculated to optimize final infarct prediction. Both techniques await further study to prove their capability of selecting cases for short-term recanalization/reperfusion therapy.


Timing of proper introduction, optimization and maintenance of anti-TNF therapy in IBD: Results from a Delphi consensus.
Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBDs) with a rapidly growing worldwide incidence. The last decades presented rapid progress in pharmacological treatment leading in many cases to clinical and endoscopic remission, including biological treatment with anti-TNF agents. The exact timing of introduction, optimization and maintenance of anti-TNF therapy in IBDs is not thoroughly covered in current guidelines. We used the Delphi panel methodology to gather the IBD experts' views and achieve consensus for clinical recommendations on introducing and maintaining anti-TNF therapy for patients with IBDs. Twelve recommendations achieved a high level of consensus in two assessment rounds by 52 (1st round) and 47 (2nd round) IBD experts. In many clinical situations, the early use of anti-TNF therapy is recommended. Nowadays, the cost-efficacy profile of anti-TNF biosimilars makes them the first-line drug in a substantial proportion of patients, thus providing the opportunity to increase access to biological therapy.


Liquid-scintillation-spectrometer data processing by desk-top computer.
A desk-top computing system has been programmed to store accurately the quench curves necessary for the calculation of total disintegrations/minute (d.p.m.) of samples containing either one or two radioactive isotopes. In producing d.p.m. values background counts are subtracted, and in binary-labelled samples the counts attributable to each radioactive isotope are separated. The programme also relates d.p.m. to the weight, volume and density of the sample. Each variable is easily recalled and adjustments can be made for different batches of samples without reprogramming. Equally easily changes of radioactive isotope, quenching agent, scintillator or window setting can be accommodated. Quadratic equations are used to express the quench curves. Counting efficiencies obtained when the coefficients in the quadratic equations are derived from three carefully chosen points on a quench curve are compared with those obtained when the coefficients are derived by the method of least squares. The results of both mathematical approximations are compared with the efficiencies read by the eye from graphs.


Neuropsychiatric disorders and potentially preventable hospitalizations in a prospective cohort study of older Americans.
The relative contributions of depression, cognitive impairment without dementia (CIND), and dementia to the risk of potentially preventable hospitalizations in older adults are not well understood. To determine if depression, CIND, and/or dementia are each independently associated with hospitalizations for ambulatory care-sensitive conditions (ACSCs) and rehospitalizations within 30 days after hospitalization for pneumonia, congestive heart failure (CHF), or myocardial infarction (MI). Prospective cohort study. Population-based sample of 7,031 Americans > 50 years old participating in the Health and Retirement Study (1998-2008). The eight-item Center for Epidemiologic Studies Depression Scale and/or International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) depression diagnoses were used to identify baseline depression. The Modified Telephone Interview for Cognitive Status and/or ICD-9-CM dementia diagnoses were used to identify baseline CIND or dementia. Primary outcomes were time to hospitalization for an ACSC and presence of a hospitalization within 30 days after hospitalization for pneumonia, CHF, or MI. All five categories of baseline neuropsychiatric disorder status were independently associated with increased risk of hospitalization for an ACSC (depression alone: Hazard Ratio [HR]: 1.33, 95% Confidence Interval [95%CI]: 1.18, 1.52; CIND alone: HR: 1.25, 95%CI: 1.10, 1.41; dementia alone: HR: 1.32, 95%CI: 1.12, 1.55; comorbid depression and CIND: HR: 1.43, 95%CI: 1.20, 1.69; comorbid depression and dementia: HR: 1.66, 95%CI: 1.38, 2.00). Depression (Odds Ratio [OR]: 1.37, 95%CI: 1.01, 1.84), comorbid depression and CIND (OR: 1.98, 95%CI: 1.40, 2.81), or comorbid depression and dementia (OR: 1.58, 95%CI: 1.06, 2.35) were independently associated with increased odds of rehospitalization within 30 days after hospitalization for pneumonia, CHF, or MI. Depression, CIND, and dementia are each independently associated with potentially preventable hospitalizations in older Americans. Older adults with comorbid depression and cognitive impairment represent a particularly at-risk group that could benefit from targeted interventions.


Clarification of the blood compatibility mechanism by controlling the water structure at the blood-poly(meth)acrylate interface.
In previous studies, we reported that poly(2-methoxyethyl acrylate) (PMEA) exhibited excellent blood compatibility, although it has a simple chemical structure. Since then, we have been investigating the reasons for its blood compatibility. In this short review, we consider the reasons for this compatibility by comparing the structure of water in hydrated PMEA to the water structure of poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(meth)acrylate analogs as reference polymers. The hydrated water in PMEA could be classified into three types; free water (or freezing water), freezing-bound water (or intermediate water), and non-freezing water (or non-freezing-bound water). We found that hydrated PMEA possessed a unique water structure, observed as cold crystallization of water in differential scanning calorimetry (DSC). Cold crystallization is interpreted as ice formation at low temperature, an attribute of freezing-bound water in PMEA. The cold crystallization peak was observed for hydrated poly(ethylene glycol) (PEG), poly(vinyl methyl ether) (PVME), polyvinylpyrrolidone (PVP), poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(tetrahydrofurfuryl acrylate) (PTHFA), and newly synthesized poly(2-(2-ethoxyethoxy)ethyl acrylate), as well as various proteins and polysaccharides, which are well-known biocompatible polymers. On the other hand, cold crystallization of water was not observed in hydrated PHEMA and PMEA analogous polymers, which do not show excellent blood compatibility. Based on these findings, we hypothesized that freezing-bound water, which prevents the biocomponents from directly contacting the polymer surface or non-freezing water on the polymer surface, plays an important role in the excellent blood compatibility of PMEA.


Gapless Hamiltonians for the toric code using the projected entangled pair state formalism.
We study Hamiltonians which have Kitaev's toric code as a ground state, and show how to construct a Hamiltonian which shares the ground space of the toric code, but which has gapless excitations with a continuous spectrum in the thermodynamic limit. Our construction is based on the framework of projected entangled pair states, and can be applied to a large class of two-dimensional systems to obtain gapless "uncle Hamiltonians."


Website review: UK CropNet.
This review explores the UK CropNet site. The project is aimed at aiding the comparative mapping of cereal and other crop genomes. The site provides software tools for use by those working on genome mapping, and access to an array of databases that will be of interest to all members of the plant genomics research community, using several ACeDB interfaces. All screen views from the website are reproduced with the kind permission of Dr Sean May, Director, Nottingham Arabidopsis Stock Centre (NASC).


Separating behavioral and physiological mechanisms in testosterone-mediated trade-offs.
Testosterone often mediates trade-offs between reproduction and other life-history traits, which are usually investigated using testosterone implants. However, this approach does not distinguish between the physiological and behavioral effects of testosterone. We studied a wild game bird, the red grouse Lagopus lagopus scoticus, and took a new approach to investigate mechanisms linking elevated testosterone to increased parasite intensity. We caught males in autumn, removed their parasites, implanted them with the antiandrogen flutamide in combination with an aromatase inhibitor (FA males) or with empty implants (control males), and challenged them with parasites. The FA treatment increased testosterone concentration and physiological stress, but without enhancing testosterone-dependent behaviors, because testosterone receptors were blocked. FA males ended up with more parasites than the control males the following autumn, an effect similar to that of a testosterone treatment reported elsewhere. However, and unlike the testosterone treatment, the FA treatment did not affect home range, pairing, or breeding success. The results supported a physiological mechanism (increased susceptibility) linking elevated testosterone and increased parasite intensity. The FA treatment provided a new way of investigating testosterone-mediated trade-offs whereby testosterone concentration was increased while the effects on behavior were blocked, resulting in physiological costs without phenotypic benefits.


Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment.
Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The co-inhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PD-L1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcm-like cells.


A Review on Development and Characterization of a Cost-effective Targeted Quality-driven Antimalarial Product with an Emphasis on Phytosomes.
Malaria, a protozoan disease, led to numerous deaths and several new million cases raised due to the development of resistance as per the WHO malaria report 2019. This can be overcome by the development of an effective targeted plant-based delivery system through phytosomes that are effective in permeation and bioavailability to treat infected RBCs (parasitic cells). This review article explained the development of targeted Nanophytosomes to overcome resistance, to improve efficacy. This review paper also emphasized various quality-driven developmental approaches in developing an antimalarial product at a reasonable cost. By implementing molecular modeling techniques in development, a significant phytoconstituent with the capability of acting at the target (receptor or enzymes) of the parasite and the one with the capability to overcome drug resistance against resistant strains of parasites can be identified. Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies information provide a route to the design and formulation of a potent antimalarial agent. Efficient, targeted Nanophytosomal formulations can be formulated by functionalizing or conjugating with suitable targets to direct the phytoconstituent to the infected RBCs thereby achieving complete parasitic eradication. Artificial Neural Network technology (ANN), Quality by Design (QbD), molecular dynamics, and simulation studies implementation improves quality and reduces the cost of the product, as these malarial products are much utilized in low-income countries. Hence it can be concluded that targeted developmental quality-driven approaches implementation is essential for effective malarial treatment.


Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease.
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.


Pathogenesis of the attenuated foot-and-mouth disease virus O/JPN/2000 in experimentally infected pigs.
We examined the pathogenesis of the attenuated foot-and-mouth disease virus (FMDV) O/JPN/2000 in pigs. The virus used in this study was passaged three times in primary bovine kidney (BK) cells and once in baby hamster kidney-21 (BHK-21) cells after isolation. A plaque assay demonstrated that this virus exhibited the small plaque (SP) phenotype. There was no clinical or histological evidence of vesicular lesions in pigs intraorally inoculated with 106 50% tissue culture infectious dose (TCID50)/ml of the SP virus (SPV) of FMDV O/JPN/2000. Although fever was detected from 2 or 3 days post inoculation (dpi), there was no other prominent clinical sign up to 6 dpi. Virus shedding from saliva and nasal swab samples was not observed in any pigs inoculated with the SPV of FMDV O/JPN/2000. In the foot, mild lamellar degeneration of prickle cells in the upper layer of the stratum spinosum was histologically observed without development into vesicular or necrotic lesions. Immunohistochemical virus antigen- and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)-positive reactions observed in the foot at 1 dpi seemed to disappear after 3 and 6 dpi. Our findings suggest that the SPV of FMDV O/JPN/2000 had low pathogenicity against pigs by intraoral inoculation.


The influence of tidal cycles and freshwater inflow on the distribution and movement of an estuarine resident fish Acanthopagrus butcheri.
Movement patterns and habitat utilization by black bream Acanthopagrus butcheri (Sparidae), an estuarine resident species, were investigated using acoustic telemetry in a small estuary on the east coast of Tasmania, Australia. Thirty-four adult A. butcheri were tracked for periods of up to 187 days between August 2005 and January 2006. Although able to tolerate a wide range of salinities, the fish spent most of the time within the upper and middle regions of the estuary, where brackish conditions dominated. The species exhibited extensive movements linked to tidal cycles, with small-scale upstream movements during incoming tides and downstream movements during out going tides. The extent of these movements was positively correlated with the tidal height difference between consecutive tidal peaks and troughs. Freshwater inflows and resultant changes in salinity also significantly influenced distribution and movement patterns. Fish moved downstream during the periods of heavy inflows, returning upstream as salinities increased to c. >10. During the peak of spawning period (November to December) fish moved into the upper region of the estuary, where they aggregated to spawn. Periodic increases in freshwater discharge, however, resulted in fish leaving the spawning grounds and moving downstream. Towards the end of the spawning season (January), the fish became more dispersed throughout the entire estuarine system.


Recovery from terminal and fruit damage by dry season cotton crops in tropical Australia.
We conducted a 2-yr field study on growth and yield compensation in cotton (Gossypium hirsutum L.) after artificial pest damage in Kununurra in NW Australia. The aim was to assess the responses of cotton grown in tropical Australia to simulated Helicoverpa damage early in the season (tip damage) and during fruiting (square removal). In this region, cotton is grown in an inverse temperature regimen to cotton grown in temperate regions, and it is possible that tropical cotton crops exhibit different responses to pest damage (Yeates 2001). To examine this, we imposed manual damage treatments by excising plant tips before squaring (flower bud production) and removing all large squares at 800 degree-days DD, (at base 12 degrees C; early square loss) or 1,200 DD (mid-square loss). We found high levels of tolerance in tropical cotton to simulated pest damage (particularly early square loss) equaling or possibly surpassing the compensatory response of cotton grown in temperate Australia. While yield did not differ between damage and control treatments, the trend suggests an increase in yield resulting from tip damage and early fruit loss. Compared with temperate crops, the delay in maturity caused by damage was minimal, owing to high rates of boll opening (up to 11% d(-1)). Early season tip damage resulted in a significant increase in lateral branch growth that later contributed to a higher fruiting potential. The altered canopy of tip-damaged plants also increased light interception, particularly in the upper canopy. Both of the above factors could confer a greater tolerance to subsequent fruit damage in tipped plants.


The potential therapeutic effect of metformin in type 2 diabetic patients with severe COVID-19.
Type 2 diabetes mellitus (T2DM) is regarded as a chief risk factor for(coronavirus disease 2019 (COVID-19) owing to dysregulation of the expression of angiotensin-converting enzyme 2 (ACE2) and chronic low-grade inflammatory disorders. Metformin, an insulin-sensitizing agent for managing T2DM, has pleiotropic anti-inflammatory and oxidant potentials, which may lessen the risk of diabetic complications. So, we aimed to reveal the potential role of metformin monotherapy in treating T2DM patients with COVID-19. In this prospective cohort study, 60 hospitalized T2DM patients with COVID-19 on metformin plus standard anti-COVID-19 treatments compared to 40 hospitalized T2DM patients with COVID-19 on other diabetic pharmacotherapy like insulin and sulfonylurea, were recruited. Inflammatory and oxidative stress biomarkers and radiological and clinical outcomes were assessed at admission time and at the time of discharge. The results of this study illustrated that metformin treatment in T2DM patients with COVID-19 was more effective in reducing inflammatory and oxidative stress biomarkers with significant amelioration of radiological scores and clinical outcomes compared to T2DM patients with COVID-19 on another diabetic pharmacotherapy. Our findings highlighted that metformin efficiently managed T2DM patients with COVID-19 by reducing inflammatory and oxidative stress with mitigating effects on the radiological scores and clinical outcomes.


The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments.
Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.


Synthetic biology of protein folding.
In protein evolution amino acid replacements occur more frequently between similar than dissimilar amino acids. Accordingly, the mutations obey a simple 'similar replaces similar' rule as disruption of the resulting protein structure is minimized by the modest alterations in the amino acid side chains. At laboratory level such non-destructive modifications have to be incorporated in a controlled manner by integrating the chemical diversity achieved in synthetic chemistry into proteins. For this purpose the most straightforward route is generation of the synthetic proteins by the cellular translational apparatus via insertion of isosteric synthetic amino acid analogs during gene expression. This leads to target proteins with chemical diversity not found in nature. Such genetic code engineering does not require any DNA mutagenesis step as it produces extensive sequence variations at the level of protein translation. It is generally achieved either by expansion of the existing amino acid repertoire or by introduction of novel coding units. Here we highlight the concept of using isosteric noncanonical amino acid analogs for in vivo protein synthesis as a useful tool to dissect, study and manipulate protein folding and conformational stability with two examples, the prion protein and green fluorescent protein. In the first example, we show how alternative translation of the single gene sequence by different synthetic amino acids enables the protein to fold into stable, but differing conformations. In particular, replacement of methionine by the isosteric analogs norleucine/metoxinine provide a chemical model to dissect the role of hydrophilicity/hydrophobicity in the alpha-->beta conversion of the prion protein structure. In the second example, proline residues in green fluorescent protein are replaced with (4S)-fluoroproline which improves folding and overall stability of the protein. Indeed, fluorination of the protein matrix creates a network of favorable local interactions absent in the parent (i.e. natural) protein. The generation of these novel properties is the first demonstration of a structural preogranisation principle in one complex globular protein molecule.


Objective versus subjective outcome measures of biofeedback: what really matters?
Clinical epidemiologic studies suggest that once established, voiding dysfunction can become a lifelong condition if not treated correctly early on in life. Biofeedback is one component of a voiding retraining program to help children with voiding dysfunction. Our goal was to compare objective non-invasive urodynamic data obtained during office biofeedback sessions with patient reported voiding symptom scores. Charts of 55 children referred in 2010 for pelvic floor muscle biofeedback therapy for urinary incontinence were retrospectively reviewed. Patients with any anatomic diagnoses were excluded. Forty-seven (86%) females and eight males (14%) with a mean age of 8.2 years made up the cohort. Uroflow curves, voided volumes, and post-void residuals were recorded at each visit and served as objective data. Volumes were normalized as a percentage of expected bladder capacity according to age. The patient reported symptom score and patient reported outcome (improved, no change or worse) served as subjective measures of intervention. The primary referral diagnoses were day and night wetting in 37 (67%) and daytime incontinence in 18 (33%) children. A history of urinary tract infection (UTI) was noted in 32 (64%) patients, and 25% were maintained on antibiotic prophylaxis during the study period. Twenty-nine percent were maintained on anticholinergic medication. Patients attended an average of 2.5 biofeedback sessions. Voided volumes and post void residual volumes were unchanged, 50% of the abnormal uroflow curves normalized over the course of treatment (p < 0.05). Patient reported symptom score decreased from 12.8 ± 5.6 to 8.0 ± 6.5 (p < 0.002) over an average follow-up time of 276 days reflecting fewer daytime voiding symptoms. There was no significant change in the patient symptom score component for the night-time wetting. Patient-reported outcomes at the final session of biofeedback were rated an improved in 26 (47%), no change in 15 (27%), worse in three (5%) patients, and not rated in 11 patients (21%). Pelvic floor muscle biofeedback is associated with patient-reported improvement in symptoms, reduction in voiding symptom score, and normalization of uroflow curves, but these improvements are not correlated with objective parameters of voided volumes and post-void residual urine obtained during office visits for biofeedback. It is important to identify the most relevant outcome measures for BFB, as insurance coverage for medical interventions that cannot offer outcomes analysis that demonstrates a benefit for the patient will eventually be eliminated.


Mitochondrial subtype MB-G3 contains potential novel biomarkers and therapeutic targets associated with prognosis of medulloblastoma.
Medulloblastoma is the most common malignant brain tumor in children. There are four groups, each with different causal mutations, affected pathways and prognosis. Here, we investigated the role of mitochondria in medulloblastoma and whether there are differences between the different groups. We compared the gene expression levels in the four different medulloblastoma groups (MB-WNT, MB-SHH, MB-G3 and MB-G4), with the focus on genes associated with mitochondria. We used several tools including Salmon, Tximeta, DESeq2, BiomaRt, STRING, Ggplot2, EnhancedVolcano, Venny 2.1 and Metscape. A total of 668 genes were differentially expressed and the most abundant genes were associated with cell division pathway followed by modulation of chemical synaptic transmission. We also identified several genes (ABAT, SOX9, ALDH5A, FOXM1, ABL1, NHLH1, NEUROD1 and NEUROD2) known to play vital role in medulloblastoma. Comparative expression analysis revealed OXPHOS complex-associated proteins of mitochondria. The most significantly expressed genes in the MB-SHH and MB-G4 groups were AHCYL1 and SFXN5 while PAICS was significantly upregulated in MB-WNT group. Notably, MB-G3 contained the most downregulated genes from the OXPHOS complexes, except COX6B2 which was strongly upregulated. We show the importance of mitochondria and compare their role in the four different medulloblastoma groups.


Endosomal trafficking inhibitor EGA can control TLR7-mediated IFNα expression by human plasmacytoid dendritic cells.
Plasmacytoid dendritic cells (pDC) are the major producer of type 1 IFN in response to TLR7 agonists. Aberrant TLR7 activation and type 1 IFN expression by pDCs are linked to the pathogenesis of certain types of autoimmune diseases, including systemic lupus erythematosus (SLE). This study investigated the underlying mechanisms for TLR7-mediated cytokine expression by pDCs using a late endosome trafficking inhibitor, EGA (4-bromobenzaldehyde N-(2,6-dimethylphenyl) semicarbazone). We found that EGA treatment decreased IFNα expression by pDCs stimulated with imiquimod (R837), single-stranded RNA40, and influenza virus. EGA also decreased TNFα expression and secretion by R837-stimulated pDCs. Mechanistically, EGA treatment decreased phosphorylation of IKKα/β, STAT1, and p38, and prolonged degradation of IκBα. Furthermore, EGA treatment decreased the colocalization of 3F, a substituted adenine TLR7 agonist, with LAMP1+ compartments in pDCs. EGA was also capable of diminishing IFNα expression by SLE pDCs treated with R837 or live PR8/A/34 influenza viruses. Therefore, we concluded that trafficking of TLR7 agonists to LAMP1+ compartments is important for IFNα expression by pDCs. Data from this study support additional examinations of the potential benefits of EGA in treating type 1 IFN-associated inflammatory diseases in the future.


Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin.
Intravenous (i.v.) infusions of Ig concentrates are an effective but expensive treatment for patients with autoimmune thrombocytopenic purpura (AITP). The optimal treatment protocol and the long-term results are uncertain, and the precise mechanism by which the platelet count increases is poorly understood. Twenty adult patients with chronic AITP were enrolled in a prospective study to compare the respective efficacy of two high-dose IVIgG induction regimens (1 g v 2 g/kg body weight) and the long-term effect of six 1 g/kg body weight i.v. IgG reinfusions. An initial response was observed in all 18 evaluable patients: the platelet count increased to a mean value of 251 x 10(9)/L (range 72 to 836 x 10(9)/L) and the mean pretreatment platelet count was multiplied by 14.6. No difference in efficiency was observed between the two i.v. IgG dosages. The degree of the platelet count increment correlated in both groups with the increase in the clearance of antibody-coated red blood cells, measured by an isotopic method, but not with the serum IgG elevation. Treatment was considered to have failed in 11 patients, 90 days after the last i.v. IgG reinfusion (D90), because the platelet counts were comparable with pretreatment values. In contrast, a complete response was observed at D90 in five patients (mean platelet count: 184 x 10(9)/L; range: 150 to 250 x 10(9)/L) and a partial response at D90 was obtained in the remaining two patients (platelet counts: 70 and 104 x 10(9)/L). Five of the 7 responders at D90 kept a platelet count above 50 x 10(9)/L during the entire follow-up period (mean 33 months; range: 5 to 66) with no further treatment; unfortunately, no clinical or biologic criteria were found to be predictive of the long-term response. This study shows that an i.v. IgG infusion regimen of 1 g/kg body weight could safely replace the classical 2 g/kg body weight dosage, at least in patients who do not have life-threatening thrombocytopenia. Moreover, repeated i.v. IgG reinfusion could be an alternative for AITP patients in whom splenectomy is contraindicated.


High speed laser drilling of metals using a high repetition rate, high average power ultrafast fiber CPA system.
We present an experimental study on the drilling of metal targets with ultrashort laser pulses at high repetition rates (from 50 kHz up to 975 kHz) and high average powers (up to 68 Watts), using an ytterbium-doped fiber CPA system. The number of pulses to drill through steel and copper sheets with thicknesses up to 1 mm have been measured as a function of the repetition rate and the pulse energy. Two distinctive effects, influencing the drilling efficiency at high repetition rates, have been experimentally found and studied: particle shielding and heat accumulation. While the shielding of subsequent pulses due to the ejected particles leads to a reduced ablation efficiency, this effect is counteracted by heat accumulation. The experimental data are in good qualitative agreement with simulations of the heat accumulation effect and previous studies on the particle emission. However, for materials with a high thermal conductivity as copper, both effects are negligible for the investigated processing parameters. Therefore, the full power of the fiber CPA system can be exploited, which allows to trepan high-quality holes in 0.5mm-thick copper samples with breakthrough times as low as 75 ms.


Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis.
Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite's metabolic pathways, similarly to what has been well described in cancer cell metabolism. An example is the switch in the metabolism of cancer that blocks the conversion of pyruvate into acetyl coenzyme A in mitochondria. In this context, dichloroacetate (DCA) is an anticancer drug that reverts the tumor proliferation by inhibiting the enzymes responsible for this switch: the pyruvate dehydrogenase kinases (PDKs). DCA has also been used in the treatment of certain symptoms of malaria; however, there is no evidence of how this drug affects apicomplexan species. In this paper, we studied the metabolism of T. gondii and demonstrate that DCA also inhibits T. gondii's in vitro infection with no toxic effects on host cells. DCA caused an increase in the activity of pyruvate dehydrogenase followed by an unbalanced mitochondrial activity. We also observed morphological alterations frequently in mitochondria and in a few apicoplasts, essential organelles for parasite survival. To date, the kinases that potentially regulate the activity of pyruvate metabolism in both organelles have never been described. Here, we confirmed the presence in the genome of two putative kinases (T. gondii PDK [TgPDK] and T. gondii branched-chain α-keto acid dehydrogenase kinase [TgBCKDK]), verified their cellular localization in the mitochondrion, and provided in silico data suggesting that they are potential targets of DCA.IMPORTANCE Currently, the drugs used for toxoplasmosis have severe toxicity to human cells, and the treatment still lacks effective and safer alternatives. The search for novel drug targets is timely. We report here that the treatment of T. gondii with an anticancer drug, dichloroacetate (DCA), was effective in decreasing in vitro infection without toxicity to human cells. It is known that PDK is the main target of DCA in mammals, and this inactivation increases the conversion of pyruvate into acetyl coenzyme A and reverts the proliferation of tumor cells. Moreover, we verified the mitochondrial localization of two kinases that possibly regulate the activity of pyruvate metabolism in T. gondii, which has never been studied. DCA increased pyruvate dehydrogenase (PDH) activity in T. gondii, followed by an unbalanced mitochondrial activity, in a manner similar to what was previously observed in cancer cells. Thus, we propose the conserved kinases as potential regulators of pyruvate metabolism and interesting targets for new therapies.


The relationship of the audible pop to hypoalgesia associated with high-velocity, low-amplitude thrust manipulation: a secondary analysis of an experimental study in pain-free participants.
High-velocity, low-amplitude (HVLA) manipulation is an effective treatment of low back pain (LBP); however, the corresponding mechanisms are undetermined. Hypoalgesia is associated with HVLA manipulation and suggests specific mechanisms of action. An audible pop (AP) is also associated with HVLA manipulation; however, the influence of the AP on the hypoalgesia associated with HVLA manipulation is not established. The purpose of the current study was to observe the influence of the AP on hypoalgesia associated with HVLA manipulation. The current study represents a secondary analysis of 40 participants. All participants underwent thermal pain sensitivity testing to their leg and low back using protocols specific to A delta fiber-mediated pain and temporal summation. Next, participants received HVLA manipulation to their low back, and the examiner recorded whether an AP was perceived. Finally, participants underwent immediate follow-up thermal pain sensitivity testing using the same protocols. Separate repeated-measure analyses of variance (ANOVAs) were used to observe changes in pain sensitivity before and immediately after HVLA manipulation. Hypoalgesia of A delta fiber-mediated pain was observed in the low back after HVLA (P < .05), and this was independent of whether an AP was perceived (P > .05). Hypoalgesia of temporal summation was observed in the lower extremity after HVLA (P < .05), and this was independent of whether an AP was perceived (P = .08). However, a moderate effect size for temporal summation was observed favoring participants in whom an AP was perceived. The current study suggests hypoalgesia is associated with HVLA manipulation and occurs independently of a perceived AP. Inhibition of lower extremity temporal summation may be larger in individuals in whom an AP is perceived, but further study is necessary to confirm this finding.


In vitro biomechanical comparison of dynamic compression plates with a rough contact surface and a polished contact surface for fixation of osteotomized equine third metacarpal bones.
To compare the number of cycles to failure of 4.5 mm broad dynamic compression plates (DCP), 4.5 mm broad limited-contact dynamic compression plates (4.5-LC-DCP), and 5.5 mm broad limited-contact dynamic compression plates (5.5-LC-DCP) having a rough (denoted by a prefix R-) versus a standard smooth contact surface for the fixation of osteotomized equine 3rd metacarpal (MC3) bones. Experimental. Fifteen pairs of adult equine cadaveric MC3 bones. Fifteen pairs of equine MC3 were divided into 3 test groups (5 pairs each) for comparison of (1) R-DCP fixation with DCP fixation, (2) R-4.5-LC-DCP fixation with 4.5-LC-DCP fixation, and (3) R-5.5-LC-DCP fixation with 5.5-LC-DCP fixation to repair osteotomized equine MC3 bones under palmarodorsal 4-point bending cyclic fatigue testing. For each group an 8-hole plate with rough contact surface was applied to the dorsal surface of one randomly selected bone from each pair and a corresponding 8-hole plate with smooth contact surface was applied dorsally to the contralateral bone from each pair. All plates and screws were applied using standard ASIF techniques. All MC3 bones had mid-diaphyseal osteotomies. Mean number of cycles to failure for each method were compared using a paired t-test within each group. Significance was set at P < .05. Mean cycles to failure ± standard deviation was significantly greater for the R-DCP fixation (230,025 ± 23,129) compared with the DCP fixation (103,451 ± 14,556), for the R-4.5-LC-DCP fixation (99,237 ± 14,390) compared with the 4.5-LC-DCP fixation (46,464 ± 6325) and for the R-5.5-LC-DCP fixation (65,113 ± 7796) compared with the 5.5-LC-DCP fixation (34,224 ± 3835). For the fixation of osteotomized MC3 bones, the constructs with plates having rough contact surface were superior to the corresponding constructs with plates having standard smooth contact surfaces in resisting cyclic fatigue under palmarodorsal 4-point bending.


A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence.
Using a double-blind procedure, 68 patients with putative benzodiazepine dependence were randomly allocated to one of three groups given lorazepam (n = 22), diazepam (n = 23) or bromazepam (n = 23) in doses equivalent to those of the patients' original benzodiazepine. After four weeks the dosage was reduced in 25% quantities until no further benzodiazepines were taken. A total of 23 patients dropped out during the study, ten on lorazepam (one of whom committed suicide), seven on diazepam and six on bromazepam. There were few differences in withdrawal symptoms between the three groups but, despite the higher dropout rate, these symptoms were somewhat less marked in the lorazepam group. Withdrawal symptoms were greater in patients who had taken a benzodiazepine for greater than 5 years and were most marked in those with personality disorders, predominantly dependent ones.


Current State of Hyperspectral Remote Sensing for Early Plant Disease Detection: A Review.
The development of hyperspectral remote sensing equipment, in recent years, has provided plant protection professionals with a new mechanism for assessing the phytosanitary state of crops. Semantically rich data coming from hyperspectral sensors are a prerequisite for the timely and rational implementation of plant protection measures. This review presents modern advances in early plant disease detection based on hyperspectral remote sensing. The review identifies current gaps in the methodologies of experiments. A further direction for experimental methodological development is indicated. A comparative study of the existing results is performed and a systematic table of different plants' disease detection by hyperspectral remote sensing is presented, including important wave bands and sensor model information.


Components of late-life exercise and cognitive function: an 8-year longitudinal study.
The preventive effect of late-life physical exercise on cognitive deterioration has been reported in many cohort studies. However, the effect of exercise, independent of other cognitively demanding and social activities, is equivocal and little is known about the relative contributions of frequency, intensity, and duration of exercise. This study aimed to examine the relationships of exercise and its underlying components with cognitive function and rate of cognitive change over an 8-year period in a nationally representative sample of older Taiwanese. Data from the 1999, 2003, and 2007 phases of the nationwide longitudinal survey were used. Data from a fixed cohort of 1,268 participants aged 70 years or older in 1999 with 8 years of follow-up were analyzed. Cognitive function was assessed using the Short Portable Mental Status Questionnaire. Self-reported frequency, intensity, and duration of exercise were collected. A generalized estimating equation with multivariate adjustment for sociodemographic variables, cognitive and social leisure activities, lifestyle behaviors, and health status was calculated. Participants who were physically active during leisure time had better subsequent cognitive function (incident rate ratios [IRR] = 0.63; 95 % CI, 0.54-0.75) and a slower rate of cognitive decline (p = 0.01). Among the components of exercise, only duration emerged as a predictor of cognitive function (p = 0.01). Older adults engaging in exercise for at least 30 min or more per session are likely to reduce the risk of subsequent cognitive decline. This research supports the case for physical exercise programs for older adults in order to help prevent loss of cognitive function.


Bystander cell death is modified by sites of energy deposition within cells irradiated with a synchrotron X-ray microbeam.
Radiation-induced bystander effects are the biological responses exhibited by cells adjacent to cells that have been traversed by charged particles. Using a synchrotron X-ray microbeam irradiation system, we irradiated five cells in two different ways: by targeting the nuclei with 10 microm x 10-microm 5.35 keV X-ray beams and by irradiating the whole cells with 50 microm x 50-microm 5.35 keV X-ray beams. Then we measured the clonogenic survival of the bystander cells. When only the nuclei were irradiated, a parabolic enhancement of bystander cell death was observed in a dose-dependent manner in the low-dose region around 1 Gy. In contrast, the surviving fraction of bystander cells decreased monotonically when whole cells were irradiated. Addition of carboxy-PTIO, a specific scavenger of nitric oxide (NO), suppressed bystander cell death in both cases. These results indicate that NO is a mediator in the induction of the parabolic and monotonic types of bystander cell death. Moreover, from the spatial analysis, we found that the parabolic type of bystander cell death was induced primarily within 1 mm of irradiated cells. Our findings demonstrate that the induction of bystander cell death depends on the sites of energy deposition in irradiated cells.


Different synaptic location of mianserin and imipramine binding sites.
The high-affinity binding sites for mianserin and imipramine appear to be locate in different neurons of rat brain. Studies in which lesions were produced with 5,7-dihydroxytryptamine and other studies in which the 5-hydroxytryptamine content was decreased with p-chlorophenylalanine indicate that some of the imipramine binding sites are on serotonin axon terminals and others are on nonserotonergic synapses. The sites that bind mianserin are on postsynaptic serotonin sites as well as on synapses of other neuronal systems.


Cellular and biological therapies of gastrointestinal tumors: overview of clinical trials.
Because of the high relapse rate of resected gastrointestinal malignancies and the modest responses of metastatic disease to currently available therapies, biologic agents that harness host-tumor immunologic interactions have received increased attention. Based on promising preclinical data, current clinical trials in cellular and biologic therapies are evaluating the safety and efficacy of passive immunotherapy with tumor-reactive lymphocytes activated ex vivo and active immunotherapy with peptide, viral vector, and cellular vaccines. This review will describe the background, rationale, and experimental approach of these clinical trials. Although equally promising, antibodies, gene therapies, and antiangiogenic strategies will not be discussed.


Severe acute asthma exacerbation in children: a stepwise approach for escalating therapy in a pediatric intensive care unit.
An increasing prevalence of pediatric asthma has led to increasing burdens of critical illness in children with severe acute asthma exacerbations, often leading to respiratory distress, progressive hypoxia, and respiratory failure. We review the definitions, epidemiology, pathophysiology, and clinical manifestations of severe acute asthma, with a view to developing an evidence-based, stepwise approach for escalating therapy in these patients. Subject headings related to asthma, status asthmaticus, critical asthma, and drug therapy were used in a MEDLINE search (1980-2012), supplemented by a manual search of personal files, references cited in the reviewed articles, and treatment algorithms developed within Le Bonheur Children's Hospital. Patients with asthma require continuous monitoring of their cardiorespiratory status via noninvasive or invasive devices, with serial clinical examinations, objective scoring of asthma severity (using an objective pediatric asthma score), and appropriate diagnostic tests. All patients are treated with β-agonists, ipratropium, and steroids (intravenous preferable over oral preparations). Patients with worsening clinical status should be progressively treated with continuous β-agonists, intravenous magnesium, helium-oxygen mixtures, intravenous terbutaline and/or aminophylline, coupled with high-flow oxygen and non-invasive ventilation to limit the work of breathing, hypoxemia, and possibly hypercarbia. Sedation with low-dose ketamine (with or without benzodiazepines) infusions may allow better toleration of non-invasive ventilation and may also prepare the patient for tracheal intubation and mechanical ventilation, if indicated by a worsening clinical status. Severe asthma can be a devastating illness in children, but most patients can be managed by using serial objective assessments and the stepwise clinical approach outlined herein. Following multidisciplinary education and training, this approach was successfully implemented in a tertiary-care, metropolitan children's hospital.


Blood pressure: effect of body mass index and of waist circumference on adolescents.
Increased body mass index (BMI) and waist circumference (WC) have been associated with blood pressure elevation. To evaluate the effect of BMI and WC on blood pressure (BP) of adolescents. Cross-sectional analytical study including 536 adolescents from public and private schools. BMI was calculated and classified as high-normal (> or =50th p and < 85th p), overweight (> or =85th p and < 95th p), and obesity (> 95th p). WC was measured and considered increased if > 75th p. BP was considered elevated if > 90th p. 319 (59.5%) adolescents were girls, the mean age was 14.0+/- 1.99 years, high-normal weight was found in 39.6%, overweight in 37.1% and obesity in 23.3%. The percentage of high SBP and DBP followed the increase in BMI (p=0.000), reaching 46.4% among boys and 39.3% among obese girls for SBP and 42.0% and 44.6% for DBP, respectively. High SBP and DBP were 3.9 and 3.4 times more frequent among boys and 2.2 to 2.0 times more frequent among girls with WC > 75th p, respectively. Using simple linear regression analysis, each increment in BMI would increase SBP by 1.198 mmHg, and in WC by 0.622 mmHg. The PR for elevated SBP and DBP in relation to BMI > or =85th p was 3.9 (95% CI 2.0-7.4[p=0.000]) and 4.3(95% CI 2.2-8.5[p=0.000]), respectively; in relation to WC > 75th p was 1.8(95% CI 1.0 to 3.0 [p=0.036]) and 1.4 (95% CI 0.8 to 2.4). BP > 90th p with WC < or =75th p was found in 16/181 (8.8%) of the adolescents with high-normal weight. BMI and WC values have a strong influence on BP values in adolescents.


Gut Microbiota Markers in Obese Adolescent and Adult Patients: Age-Dependent Differential Patterns.
Obesity levels, especially in children, have dramatically increased over the last few decades. Recently, several studies highlighted the involvement of gut microbiota in the pathophysiology of obesity. We investigated the composition of gut microbiota in obese adolescents and adults compared to age-matched normal weight (NW) volunteers in order to assemble age- and obesity-related microbiota profiles. The composition of gut microbiota was analyzed by 16S rRNA-based metagenomics. Ecological representations of microbial communities were computed, and univariate, multivariate, and correlation analyses performed on bacterial profiles. The prediction of metagenome functional content from 16S rRNA gene surveys was carried out. Ecological analyses revealed a dissimilarity among the subgroups, and resultant microbiota profiles differed between obese adolescents and adults. Using statistical analyses, we assigned, as microbial markers, Faecalibacterium prausnitzii and Actinomyces to the microbiota of obese adolescents, and Parabacteroides, Rikenellaceae, Bacteroides caccae, Barnesiellaceae, and Oscillospira to the microbiota of NW adolescents. The predicted metabolic profiles resulted different in adolescent groups. Particularly, biosynthesis of primary bile acid and steroid acids, metabolism of fructose, mannose, galactose, butanoate, and pentose phosphate and glycolysis/gluconeogenesis were for the majority associated to obese, while biosynthesis and metabolism of glycan, biosynthesis of secondary bile acid, metabolism of steroid hormone and lipoic acid were associated to NW adolescents. Our study revealed unique features of gut microbiota in terms of ecological patterns, microbial composition and metabolism in obese patients. The assignment of novel obesity bacterial markers may open avenues for the development of patient-tailored treatments dependent on age-related microbiota profiles.


Protein evolution within a structural space.
Understanding of the evolutionary origins of protein structures represents a key component of the understanding of molecular evolution as a whole. Here we seek to elucidate how the features of an underlying protein structural "space" might impact protein structural evolution. We approach this question using lattice polymers as a completely characterized model of this space. We develop a measure of structural comparison of lattice structures that is analogous to the one used to understand structural similarities between real proteins. We use this measure of structural relatedness to create a graph of lattice structures and compare this graph (in which nodes are lattice structures and edges are defined using structural similarity) to the graph obtained for real protein structures. We find that the graph obtained from all compact lattice structures exhibits a distribution of structural neighbors per node consistent with a random graph. We also find that subgraphs of 3500 nodes chosen either at random or according to physical constraints also represent random graphs. We develop a divergent evolution model based on the lattice space which produces graphs that, within certain parameter regimes, recapitulate the scale-free behavior observed in similar graphs of real protein structures.


Comparative visual function in elasmobranchs: spatial arrangement and ecological correlates of photoreceptor and ganglion cell distributions.
The topographic analysis of retinal ganglion and photoreceptor cell distributions yields valuable information for assessing the visual capabilities and behavioral ecology of vertebrates. This study examines whole-mounted retinas of four elasmobranch species, the ornate wobbegong, Orectolobus ornatus; the whitetip reef shark, Triaenodon obesus; the epaulette shark, Hemiscyllium ocellatum; and the east Australia shovelnose ray, Aptychotrema rostrata, for regional specializations mediating zones of improved visual ability. These species represent a range of lifestyles: benthic, mid-water, diurnal, and nocturnal. Both photoreceptors (visualized using differential interference contrast optics) and ganglion cells (stained with cresyl violet) in the retina are extensively sampled, and their spatial distribution is found to be nonuniform, exhibiting areae or In general, the topographic distributions of both cell populations are in register and match well with respect to the location of regions of high density. However, the location of peaks in rod and cone densities can vary within a retina, indicating that preferential sampling of different regions of the visual field may occur in photopic and scotopic vision. Anatomical measures of the optical limits of resolving power, indicated by intercone spacing, range from 3.8 to 13.1 cycles/deg. Spatial limits of resolving power, calculated from ganglion cell spacing, range from 2.6 to 4.3 cycles/deg. Summation ratios, assessed by direct comparison of cell densities of photoreceptors (input cells) and ganglion cells (output cells), at more than 150 different loci across the retina, show topographic differences in signal convergence (ranging from 25:1 to over 70:1). Species-specific retinal specializations strongly correlate to the habitat and feeding behavior of each species.


Antibody responses in patients with invasive Staphylococcus aureus infections.
Correlation between antibody response and clinical outcome in Staphylococcus aureus bacteremia has yielded conflicting results. Immunization schedules have failed in clinical trials. Is the humoral response toward S. aureus of protective nature? A prospective study was performed in patients with invasive S. aureus (ISA) infections during the period 2003-2005. The antibody levels were determined at the beginning and at the end of treatment and one month later (n = 96, n = 71, and n = 51, respectively). As controls, 115 healthy individuals were used. A quantitative enzyme-linked immunosorbent assay (ELISA) against eight purified antigens was performed. Bacterial isolates were grouped as to the production of alpha-toxin, agr type, and pulsed-field gel electrophoresis (PFGE) type. Large variations were seen in the antibody levels. The levels in the second sample were the highest. A correlation between agr group, PFGE group, alpha-toxin production, and initial antibody levels was observed. Patients with fatal outcome displayed lower initial antibody levels to all antigens and significantly so in regard to teichoic acid, lipase, enterotoxin A, and scalded skin syndrome toxin. In episodes with complicated bacteremia, initial significantly low levels to teichoic acid and lipase were registered. Low initial antibody levels against several antigens were associated with increased mortality and complicated bacteremia in invasive S. aureus infections. Bacterial properties, strain, and toxin production affected the antibody response.


Osteoarthritis: research update and clinical applications.
Musculoskeletal (MS) ultrasonography (US) offers an overall assessment of the joints in OA. MSUS of the peripheral joints can be carried out at the time of consultation with high patient acceptability. This allows an immediate correlation between imaging findings and clinical data that improves diagnosis and management of patients with OA. The principal indications for MSUS in OA include detection of articular cartilage damage, bone changes, joint inflammation and adjacent soft tissue lesions. The main added value of US over clinical examination and plain radiography is its higher sensitivity for detecting synovitis and bone surface abnormalities, respectively. In addition, MSUS can be routinely used to guide accurate and safe diagnostic or therapeutic injections in the OA joints. The objective of the article is to describe the current applications of MSUS in both clinical practice and research in OA.