DNA cleavage activity of the V(D)J recombination protein RAG1 is autoregulated.
RAG1 and RAG2 catalyze the first DNA cleavage steps in V(D)J recombination. We demonstrate that the isolated central domain of RAG1 has inherent single-stranded (ss) DNA cleavage activity, which does not require, but is enhanced by, RAG2. The central domain, therefore, contains the active-site residues necessary to perform hydrolysis of the DNA phosphodiester backbone. Furthermore, the catalytic activity of this domain on ss DNA is abolished by addition of the C-terminal domain of RAG1. The inhibitory effects of this latter domain are suppressed on substrates containing double-stranded (ds) DNA. Together, the activities of the reconstituted domains on ss versus mixed ds-ss DNA approximate the activity of intact RAG1 in the presence of RAG2. We propose how the combined actions of the RAG1 domains may function in V(D)J recombination and also in aberrant cleavage reactions that may lead to genomic instability in B and T lymphocytes.


Gastrocnemius flaps in the surgical treatment of sarcomas of the knee.
The authors discuss their experience with the pediculated gastrocnemius flap used in the oncological surgery of the knee, in 27 patients. Three groups of patients are evaluated: in one group the method was used in patients affected with bone sarcoma and associated with reconstruction of the resected bone segment; in another group the method was used after infection had occurred as a result of reconstructive surgery; in the third group the method was used at the same time as excision of sarcomas of the soft tissues. The gastrocnemius flap may be used to cover sufficiently wide areas of loss of skin and muscular substance around the knee, and may be effectively used to cover metallic prostheses or composite reconstructive implants (bone-cement-metal). We recommend using the covering technique at the same time as resection and reconstruction are performed in order to avoid the risk of infection, and thus reduce any changes in chemotherapy protocols that postoperative infection would require in these patients. The use of the gastrocnemius flap associated with excision of sarcomas of the soft tissues must be reserved for selected cases. The high incidence of local recurrence after such excisions indicates that either wider excisions using distant free flaps or the association of radiotherapy should be considered.


Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins.
The role of inflammation in diabetic retinal amage is well accepted. While a number of cytokines and inflammatory mediators are responsible for these changes, upstream regulators are less well studied. Additionally, the role for these upstream mediators in retinal health is unclear. In this study, we hypothesized that inhibition of high mobility group box 1 (HMGB1) could restore normal insulin signaling in retinal endothelial cells (REC) grown in high glucose, as well as protect the retina against ischemia/reperfusion (I/R)-induced retinal damage. REC were grown in normal (5mM) or high glucose (25mM) and treated with Box A or glycyrrhizin, two different HMGB1 inhibitors. Western blotting was done for HMGB1, toll-like receptor 4 (TLR4), insulin receptor, insulin receptor substrate-1 (IRS-1), and Akt. ELISA analyses were done for tumor necrosis factor alpha (TNFα) and cleaved caspase 3. In addition, C57/B6 mice were treated with glycyrrhizin, both before and after ocular I/R. Two days following I/R, retinal sections were processed for neuronal changes, while vascular damage was measured at 10 days post-I/R. Results demonstrate that both Box A and glycyrrhizin reduced HMGB1, TLR4, and TNFα levels in REC grown in high glucose. This led to reduced cleavage of caspase 3 and IRS-1Ser307 phosphorylation, and increased insulin receptor and Akt phosphorylation. Glycyrrhizin treatment significantly reduced loss of retinal thickness and degenerate capillary numbers in mice exposed to I/R. Taken together, these results suggest that inhibition of HMGB1 can reduce retinal insulin resistance, as well as protect the retina against I/R-induced damage.


Iron Catalyzed Dual-Oxidative Dehydrogenative (DOD) Tandem Annulation of Glycine Derivatives with Tetrahydrofurans.
A novel iron-catalyzed dual-oxidative dehydrogenative (DOD) tandem annulation of glycine derivatives with tetrahydrofurans (THFs) for the synthesis of high value quinoline fused lactones has been developed. The reactions were performed under mild reaction conditions. And the use of cheap substrates (glycine derivatives and THF) and an even cheaper simple inorganic iron salt as the catalyst makes this protocol very attractive for potential synthetic applications.


Intraocular lens power calculation in eyes after myopic laser refractive surgery and radial keratotomy: Bayesian network meta-analysis.
To compare the accuracy of formulas for calculating intraocular lens power in eyes after myopic laser refractive surgery or radial keratotomy. Bayesian network meta-analysis. PubMed, EMBASE, the Cochrane Data Base of Systematic Reviews, and the Cochrane Central Register of Controlled Trials databases were searched for retrospective and prospective clinical studies published from Jan 1, 2012 to Aug 24, 2022. The outcome measurement was the percentage of eyes with a predicted error within the target refractive range (± 0.50 diopter [D] or ± 1.00 D). Our meta-analysis includes 24 studies of 1172 eyes after myopic refractive surgery that use 12 formulas for intraocular lens power calculation. (1)A network meta-analysis showed that Barrett true-K no history, the OCT formula, and the Masket formula had a significantly higher percent of eyes within ± 0.50 D of the goal than the Haigis-L formula, while the Wang-Koch-Maloney formula showed the poor predictability. Using an error criterion of within ± 1.00 D, the same three formulas performed slightly better than the Haigis-L formula. Based on performance using both prediction error criteria, the Barrett true-K no history formula, OCT formula, and Masket formula showed the highest probability of ranking as the top three among the 12 methods. (2)A direct meta-analysis with a subset of four studies and five formulas indicated that formulas did not differ in percent success for either the ± 0.5 D or ± 1.0 D error range in eyes that had undergone radial keratotomy. The OCT, Masket, and Barrett true-K no history formulas are more accurate for eyes with previous myopic laser refractive surgery, whereas no significant difference was found among the formulas for eyes that had undergone radial keratotomy.


Critical Illness Associated Fatal Hypoglycemia in a Nondiabetic Male.
We present here the case of a 55-year-old male who presented to the emergency department with severe abdominal pain and respiratory distress secondary to mesenteric ischemia. His critical illness on preexisting chronic kidney disease, previously undiagnosed alcoholic cirrhosis, and congestive heart failure led to a rare yet fatal consequence of refractory hypoglycemia. Critical illness associated hypoglycemia generally occurs as a result of high metabolic consumption with relative insulin excess and insufficient nutritional intake that is seen frequently in critically ill patients. This, along with reduced hepatic and renal gluconeogenesis seen in preexisting liver and renal disease, can cumulate to life-threatening hypoglycemia and is seen as a poor prognostic factor in the ICU setting.


Laparoscopic treatment of symptomatic endometriosis.
From their experience and from data in the literature, the authors try to define the respective place of the different treatments for endometriosis, especially those of operative laparoscopy. In cases of endometriosis-associated infertility, operative laparoscopy is the first line treatment and assisted reproductive technology (ART) the second one. Gonadotrophin-releasing hormone (GnRH) analogues are only useful in cases of extensive endometriosis to render surgery easier, and for ART. The average pregnancy rate following laparoscopic treatment is approximately 50% (range 34-80%). It is poorly related to the type of endometriosis except in cases of large adhesions and tubal involvement. However, duration of infertility, age and sperm quality have a direct influence on it. Therefore the authors propose a scheme for the management of endometriosis-associated infertility. In cases of pain, laparoscopic surgery can also be used; however, drugs have a more important role in these cases, to avoid recurrent surgery.


Alterations in regional shape on ipsilateral and contralateral cortex contrast in children with unilateral cerebral palsy and are predictive of multiple outcomes.
Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P < 0.004), as well as on the apparently uninjured hemisphere, illustrating potential compensatory mechanisms in these children. Furthermore, these shape measures were significantly correlated with several functional outcomes, including motor, cognition, vision, and communication (P < 0.012), with three out of these four models performing well on test set validation. This study highlights that cortical neuroplastic effects may be quantified using MR imaging, allowing morphological changes to be studied longitudinally, including any influence of treatment. Ultimately, such approaches could be used for the long term prediction of outcomes and the tailoring of treatment to individuals. Hum Brain Mapp 37:3588-3603, 2016. © 2016 Wiley Periodicals, Inc.


A model of autoregulated blood flow in the cerebral vasculature.
The circle of Willis is a ring-like arterial structure located in the base of the brain, and is responsible for the distribution of oxygenated blood throughout the cerebral mass. Among the general population, approximately 50 per cent have a complete circle of Willis; for the others a multitude of possible anatomical variations are present, with absent or hypoplastic vessels being common. Certain conditions such as a build-up of atherosclerotic plaque on the arterial wall can result in ischaemic damage and stroke-like symptoms. A three-dimensional computer model has been developed based on the results of magnetic resonance imaging data, incorporating a numerical algorithm to simulate the body's autoregulation mechanism, such that oxygen delivery to the cerebral territories can be predicted in response events, leading to a reduction in cerebral blood flow. Sample results are presented for combinations of occlusion and stenosis.


Measurements, phantoms, and standardization.
The last 25 years has seen a number of significant developments in the establishment of a measurement infrastructure supporting medical applications of ultrasound. This has allowed manufacturers and users of medical ultrasonic equipment to undertake and compare measurements of key parameters describing the magnitude or strength of the applied ultrasonic field in a meaningful and traceable way: for equipment development, standards compliance, and quality assurance purposes. This paper describes the current state of the art for measurement techniques used to determine the key properties of an ultrasonic field, principally acoustic pressure and acoustic power. Measurement tools and methodologies are described in detail, alongside considerations of how these are likely to develop, shaped by user need. The way that these measurement methods underpin a range of international and national specification standards enabling equipment manufacturers to demonstrate that their equipment is safe and fit for purpose is covered.


Pulmonary artery catheter placement for elective coronary artery bypass grafting: before or after anesthetic induction?
Pulmonary arterial catheters (PACs) are often used during and after coronary artery bypass grafting. We hypothesized that placement of a PAC would be faster in anesthetized patients. We further hypothesized that the presence or absence of a PAC during the induction of anesthesia would make no difference in hemodynamics, vasoactive drug use, or IV fluid administration during the induction. Patients (n = 200) undergoing elective coronary artery bypass grafting were assigned to PAC insertion either before or after the induction of anesthesia. Total time for PAC insertion, number of finder needle and venous catheter insertion attempts, incidence of carotid artery puncture, arrhythmias or ST segment changes, arterial blood gas analysis, hemodynamic variables, IV fluids, and vasoactive drugs required during and after the anesthetic induction were recorded. Thirty-two different physicians placed the PACs. PAC placement was faster (10 versus 12 min, P = 0.0003) and required fewer punctures with a finder needle (P = 0.0107) in anesthetized patients. There were no significant differences between groups in hemodynamic values or use of vasoactive or anesthetic drugs or IV fluids during the induction. There were also no significant differences between groups in the incidence of myocardial ischemia, arterial hypoxemia, or hypercarbia. Placement of a PAC before the induction of anesthesia consumes more time and fails to improve hemodynamic stability or lessen vasoactive drug use during the induction of anesthesia. Insertion of pulmonary artery catheters (PACs) before the induction of anesthesia requires more needle sticks and takes longer than insertion after the induction of anesthesia; moreover, previous PAC insertion has no significant effect on hemodynamics or use of vasoactive drugs or IV fluid associated with the induction of anesthesia.


The Virtual Bulletin Board: A Strategy for Creating an Inclusive Learning Environment.
No single strategy can meet the unique needs of all learners; however, Padlet, a virtual bulletin board, offers multiple modes for engaging learners in activities and making them feel welcome, valued, and respected. Padlet can be added to a professional development specialist's toolbox to create a more inclusive learning environment. [J Contin Educ Nurs. 2022;53(4):155-156.].


Catalogue of the Egyptian Ephydroidea (Diptera: Schizophora: Acalyptratae).
We present a catalogue of all known taxa of the superfamily Ephydroidea in Egypt. Old World synonymies, type localities, type depositories, world distributions by biogeographic realm(s) and country, Egyptian localities and dates of collection are provided. A total number of 117 species belonging to 45 genera, 18 tribes, 7 subfamilies, and representing 3 families has been catalogued. The treated families are: Ephydridae (shore flies or brine flies), Drosophilidae (vinegar flies or fruit flies) and Braulidae (bee lice). One shore fly species, Psilopa clara (Wollaston, 1858), is recorded for the first time from Egypt. Two new synonyms of shore flies are proposed, namely: Philotelma ulianai Raffone, 2011 = Ephydra (Ephydra) macellaria Egger, 1862 and Notiphila rufitarsis Macquart, 1851 = Allotrichoma biroi Cresson, 1929. Lectotypes are designated for three shore fly species, namely: Psilopa pectinata Hendel, 1931; Rhynchopsilopa nitidissima Hendel, 1931 and Notiphila rufitarsis Macquart, 1851.


[Renal failure and insulin resistance: effect of the dialysis dose].
The main cause of death in patients undergoing hemodialysis are cardiovascular events. We have analyzed the association between intradialysis fractional clearance of urea or Kt/V index in patients with chronic renal failure in hemodialysis as an indicator of adequate dialysis and the classical factors of cardiovascular risk. A total of 47 patients with chronic renal failure on hemodialysis were included. Diabetes mellitus was considered an exclusion criteria. Optimization of dialysis was analyzed by Kt/v index in accordance with the Daugirdas formula. The cardiovascular risk factors evaluated were: insulin resistance, calculated according to the HOMA method, total cholesterol, LDL-cholesterol, triglycerides, arterial hypertension, obesity and metabolic syndrome. The relationship between cardiovascular risk factors and Kt/V index was analyzed with the variant and multivariant analysis. The HOMA median (interquartile range) of the patients was 1.16 (0.53-5.77). HOMA was correlated with triglycerides and HDL-cholesterol levels. HOMA was significantly greater in those who had less adapted dialysis (Kt/V < 1.4) (1.9 +/- 1.3 vs 1.0 +/- 0.3, p = 0.02). Furthermore, a negative correlation was found between HOMA and Kt/V. The multivariant analysis of the factors associated to HOMA demonstrated that the only associated parameters were Kt/V greater than 1.4, body mass index and age. In patients with chronic renal failure, adapted dialysis, determined by the Kt/V index, correlated negatively with insulin resistance. Based on these data, we suggest the need for longitudinal studies that consider this index as a predictive variable of cardiovascular events in this type of patients.


Congenital infiltrating lipomatosis of the face: case report and literature review.
Congenital infiltrating lipomatosis of the face comprises a subgroup of lipomatous tumors. While rare, it remains a definite clinical entity. Its etiology is unknown. The tumor is congenital in origin and occurs in infancy or early childhood. It is poorly enveloped and characterized by diffuse infiltration of mature adipose tissue over normal muscle fibers, rapid growth, associated osseous hyperplasia, and a high recurrence rate after surgical intervention. Due to its diffuse infiltration and involvement of important facial structures, complete surgical excision is often impossible. A total of 14 cases of congenital infiltrating lipomatosis of the face was found in a literature review. Herein we present an additional case who had both diffuse infiltrating lipomatosis and a well-encapsulated lipoma on her left cheek.


Heparin-induced thrombocytopenia in the setting of perioperative bridging for podiatric surgery: a case report.
Heparin is an anticoagulant commonly used to treat and prevent deep venous thrombosis. Heparin-induced thrombocytopenia and possible thrombosis are serious complications associated with its use. This can occasionally complicate treatment of patients undergoing podiatric surgery. Heparin-induced thrombocytopenia is often not immediately recognized and is underreported in podiatric medicine literature. The goal of this case report is to highlight the multiple risk factors associated with the development of heparin-induced thrombocytopenia and to aid with early recognition, understanding of pathogenesis, and treatment options.


Problems related to postmenopausal women.
The most consistently troublesome symptom of the menopause is the hot flush. It can occur without warning or may be triggered off by emotion, exercise or change of environment or temperature. It is estimated that about 50% of women suffer from hot flushes, but only 5-10% of these seek medical advice. The cause is ascribed to excessive production of follicle-stimulating hormone. There is an increased sensitivity to the effect of locally released dilator substances in the peripheral vasculature.


Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis.
Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as causes of morbidity and mortality. Dendritic cell (DC) loss has been observed in septic patients and in experimental sepsis models, but the role of DCs in sepsis, and the mechanisms and significance of DC loss, are poorly understood. Here, we report that mice with selective deletion of the glucocorticoid receptor (GR) in DCs (GR(CD11c-cre)) were highly susceptible to LPS-induced septic shock, evidenced by elevated inflammatory cytokine production, hypothermia, and mortality. Neutralizing anti-IL-12 antibodies prevented hypothermia and death, demonstrating that endogenous GC-mediated suppression of IL-12 is protective. In LPS-challenged GR(CD11c-cre) mice, CD8(+) DCs were identified as the major source of prolonged IL-12 production, which correlated with elevations of NK cell-derived IFN-γ. In addition, the loss of GR in CD11c(+) cells rescued LPS-induced loss of CD8(+) DCs but not other DC subsets. Unlike wild-type animals, exposure of GR(CD11c-cre) mice to low-dose LPS did not induce CD8(+) DC loss or tolerance to subsequent challenge with high dose, but neutralization of IL-12 restored the ability of low-dose LPS to tolerize. Therefore, endogenous glucocorticoids blunt LPS-induced inflammation and promote tolerance by suppressing DC IL-12 production.


Stent strut streamlining and thickness reduction promote endothelialization.
Stent thrombosis (ST) carries a high risk of myocardial infarction and death. Lack of endothelial coverage is an important prognostic indicator of ST after stenting. While stent strut thickness is a critical factor in ST, a mechanistic understanding of its effect is limited and the role of haemodynamics is unclear. Endothelialization was tested using a wound-healing assay and five different stent strut models ranging in height between 50 and 150 µm for circular arc (CA) and rectangular (RT) geometries and a control without struts. Under static conditions, all stent strut surfaces were completely endothelialized. Reversing pulsatile disturbed flow caused full endothelialization, except for the stent strut surfaces of the 100 and 150 µm RT geometries, while fully antegrade pulsatile undisturbed flow with a higher mean wall shear stress caused only the control and the 50 µm CA geometries to be fully endothelialized. Modest streamlining and decrease in height of the stent struts improved endothelial coverage of the peri-strut and stent strut surfaces in a haemodynamics dependent manner. This study highlights the impact of the stent strut height (thickness) and geometry (shape) on the local haemodynamics, modulating reendothelialization after stenting, an important factor in reducing the risk of stent thrombosis.


Cold adaptation regulated by cryptic prophage excision in Shewanella oneidensis.
Among the environmental stresses experienced by bacteria, temperature shifts are one of the most important. In this study, we discovered a novel cold adaptation mechanism in Shewanella oneidensis that occurs at the DNA level and is regulated by cryptic prophage excision. Previous studies on bacterial cold tolerance mainly focus on the structural change of cell membrane and changes at the RNA and protein levels. Whether or not genomic change can also contribute to this process has not been explored. Here we employed a whole-genome deep-sequencing method to probe the changes at DNA level in a model psychrotrophic bacteria strain. We found that temperature downshift induced a 10 000-fold increase of the excision of a novel P4-like cryptic prophage. Importantly, although prophage excision only occurred in a relatively small population of bacteria, it was able to facilitate biofilm formation and promote the survival of the entire population. This prophage excision affected cell physiology by disrupting a critical gene encoding transfer-messenger RNA (tmRNA). In addition, we found that the histone-like nucleoid-structuring protein (H-NS) could silence prophage excision via binding to the promoter of the putative excisionase gene at warm temperatures. H-NS level was reduced at cold temperatures, leading to de-repression of prophage excision. Collectively, our results reveal that cryptic prophage excision acts as a regulatory switch to enable the survival of the host at low temperature by controlling the activity of tmRNA and biofilm formation.


Causes and consequences of time perception differences in overweight and normal weight people.
Three experiments considered whether there are differences between overweight and normal weight subjects in time perception which represent the obese subjects' lack of internal responsiveness as well as heightened external reactivity in a noneating setting. In the first study, no time-relevant cues were provided, and overweight subjects were inaccurate in their temporal judgments and showed significantly higher group variability than did normals. In the second study, the effects of differential temporal information generated by interesting and boring cues was considered. The presentation of these time-relevant external cues reduced the judgment variability of the overweight subjects and influenced their perceived passage of time significantly more than normals. The third study examined the influence, on eating behavior, of differences in perceived passage of time as a consequence of manipulating cues for interest or boredom. When bored, overweight subjects perceived time to pass more slowly than did normals and thus ate sooner. Similarly, they delayed eating, judging time to have passed more quickly than it actually had, when they were attending to interesting cues. The implications of a generalized lack of internal sensitivity for a theory about the development and consequences of obesity are discussed.


Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite.
Malaria is estimated to cause 0.7 to 2.7 million deaths per year, but the actual figures could be substantially higher owing to under-reporting and difficulties in diagnosis. If no new control measures are developed, the malaria death toll is projected to double in the next 20 years. Efforts to control the disease are hampered by drug resistance in the Plasmodium parasites, insecticide resistance in mosquitoes, and the lack of an effective vaccine. Because mosquitoes are obligatory vectors for malaria transmission, the spread of malaria could be curtailed by rendering them incapable of transmitting parasites. Many of the tools required for the genetic manipulation of mosquito competence for malaria transmission have been developed. Foreign genes can now be introduced into the germ line of both culicine and anopheline mosquitoes, and these transgenes can be expressed in a tissue-specific manner. Here we report on the use of such tools to generate transgenic mosquitoes that express antiparasitic genes in their midgut epithelium, thus rendering them inefficient vectors for the disease. These findings have significant implications for the development of new strategies for malaria control.


[Migraine headache and mitochondrial DNA abnormality].
Migraine headache is a heterogenous group of neurologic disorders with high prevalence in the general population and strong familial aggregation. Epidemiologic evidence for frequent maternal transmission has long suggested a role for an altered mitochondrial genetic background. This is supported by the observation of impaired energy metabolism and mitochondrial function in migraine patients as well as by the frequent association of migraine headache in MELAS. In the literature, some patients having migraine headache are reported to have mitochondrial DNA abnormalities, however, systematic screening studies have failed to demonstrate the clear relationship between migraine headache and mitochondrial DNA abnormalities. Migraine may be associated with mutations of nuclear genes which encode respiratory chain enzymes.


Autoimmune rat T lymphocytes monospecific for acetylcholine receptors: purification and fine specificity.
We prepared highly purified acetylcholine receptor (AChR)-specific T lymphocytes from rats with experimental autoimmune myasthenia gravis (EAMG). Inbred rats were primed with AChR frm 3 different sources: from the electric organs of Electrophorus electricus and Torpedo californica and from denervated rat muscle. After 20 to 30 days, lymphocytes from regional lymph nodes (primary cells) were challenged with soluble AChR in vitro. The activated blast cells were isolated by density gradient centrifugation and allowed to revert back to small secondary lymphocytes in the absence of antigen. These secondary anti-AChR cells were highly responsive to the type of AChR with which they had been primed. Their reactivity critically depended on help by syngeneic accessory cells. Anti-Electrophorus AChR primary and secondary cells cross-reacted detectably with rat AChR and vice versa, whereas anti-Torpedo AChR primary and secondary cells did not significantly cross-react with Electrophorus or rat AChR. Secondary T cells strongly reactive against rat AChR could be selected in vitro from Electrophorus AChR-primed populations by using rat AChR as selecting stimulant. These cells responded equally well against Electrophorus and rat AChR and thus include autoreactive T cell clones.


The status of screening measures for bipolar disorder.
Screening measures for bipolar disorder are positioned as playing an important role in improving diagnostic accuracy. This review considers the principal screening measures developed over the past decade. Although the development and evaluation of bipolar screening measures were distinct between 2000 and 2010, there has been a decrease in research and evaluation in recent years. This article considers the main impetus for the development of screening measures for bipolar disorder and provides a description and critique of the principal measures used in both clinical and community settings. Screening measures have an important role in identifying bipolar disorder but are best positioned as a first-stage strategy rather than as definitive diagnostic measures. Although several have been developed and well validated in clinical settings, there is a distinct need for extension studies exploring their classificatory properties in community settings as well as clinical impact studies to determine their 'real world' utility.


[Nursing care of elderly persons: reactions to the use of a security blanket to prevent falling out of bed].
This article presents the results of the first part of a survey aiming at assessing the chances for adoption and use of the safety blanket, a new device preventing the falls from the beds. In this part, the resarchers wanted to know how the caretakers reacted to the use of this material. Thirty four people with five beneficiaries among them, nine family members, fifteen contributors and five managers, interacting in the context of a care unit for elderly people of a hospital centre were interviewed. The data of the interviews were analysed according to a six step procedure: listening to the interviews and reading the descriptions; deriving the significant statements, analysing and reformulating the meaning of the statements; regrouping the signification units under more global themes; gathering the analysis results and describing exhaustively the studied phenomenon; validating the exhaustive description. As a whole, the reactions recorded were positive and indicate that the safety blanket has big chances to be adopted by the healthcare units.


The morphogen Decapentaplegic employs a two-tier mechanism to activate target retinal determining genes during ectopic eye formation in Drosophila.
Understanding the role of morphogen in activating its target genes, otherwise epigenetically repressed, during change in cell fate specification is a very fascinating yet relatively unexplored domain. Our in vivo loss-of-function genetic analyses reveal that specifically during ectopic eye formation, the morphogen Decapentaplegic (Dpp), in conjunction with the canonical signaling responsible for transcriptional activation of retinal determining (RD) genes, triggers another signaling cascade. Involving dTak1 and JNK, this pathway down-regulates the expression of polycomb group of genes to do away with their repressive role on RD genes. Upon genetic inactivation of members of this newly identified pathway, the canonical Dpp signaling fails to trigger RD gene expression beyond a threshold, critical for ectopic photoreceptor differentiation. Moreover, the drop in ectopic RD gene expression and subsequent reduction in ectopic photoreceptor differentiation resulting from inactivation of dTak1 can be rescued by down-regulating the expression of polycomb group of genes. Our results unravel an otherwise unknown role of morphogen in coordinating simultaneous transcriptional activation and de-repression of target genes implicating its importance in cellular plasticity.


The influence of maxillary incisor torque on the esthetic perception of the smile.
An esthetically pleasing smile is one of our patients' main goals. However, it is not always clear that the esthetic perceptions of patients and clinicians are the same. The purpose of this study was to evaluate and quantify the discrepancies in the esthetic perception of maxillary incisor torque among professionals, and between professionals and the general public. A photograph of a 30-year-old woman was digitally manipulated to obtain nine smile images and nine full-profile images with various maxillary incisor torques, while maintaining the overjet. The images were evaluated in an online survey by three different groups: laypersons (LP, n = 21), orthodontists (OR, n = 20), and specialists in dental esthetics (SDE, n = 19). From among the smile images, the LP group preferred the 80-degree option (the angle that forms the tangent between the crown of the maxillary incisor and the functional occlusal plane), the SDE group preferred the 75-degree option, and the OR group preferred the 70-degree option. From among the full-profile images, both the LP and the SDE groups preferred the 80-degree option, while the OR group preferred the 75-degree option. To analyze the data and verify or reject the hypotheses of normality and homoscedasticity, ANOVA and Kruskal-Wallis tests were used. The LP and SDE groups coincided, in contrast to the OR group, which preferred more protrusive torques and was less tolerant of retroclined maxillary incisors.


Expression and regulation of alarmin cytokine IL-1α in human retinal pigment epithelial cells.
Human retinal pigment epithelial (hRPE) cells play important immune-regulatory roles in a variety of retinal pathologic processes, including the production of inflammatory cytokines that are essential mediators of the innate immune response within the ocular microenvironment. The pro-inflammatory "alarmin" cytokine IL-1α has been implicated in both infectious and non-infectious retinal diseases, but its regulation in the retina is poorly understood. The purpose of this study was to elucidate the expression and regulation of IL-1α within hRPE cells. To do this, IL-1α mRNA and protein in hRPE cells was assessed by RT-PCR, qPCR, ELISA, Western blot, and immunofluorescence following treatment with a variety of stimuli and inhibitors. ER stress, LPS, IL-1β, and TLR2 activation all significantly increased intracellular IL-1α protein. Increasing intracellular calcium synergized both LPS- and Pam3CSK4-induced IL-1α protein production. Accordingly, blocking calcium signaling and calpain activity strongly suppressed IL-1α protein expression. Significant but more moderate inhibition occurred following blockage of TLR4, caspase-4, or caspase-1. Neutralizing antibodies to IL-1β and TLR2 partially eliminated LPS- and TLR2 ligand Pam3CSK4-stimulated IL-1α protein production. IFN-β induced caspase-4 expression and activation, and also potentiated LPS-induced IL-1α expression, but IFN-β alone had no effect on IL-1α protein production. Interestingly, all inhibitors targeting the PI3K/Akt pathway, with the exception of Ly294002, strongly increased IL-1α protein expression. This study improves understanding of the complex mechanisms regulating IL-1α protein expression in hRPE cells by demonstrating that TLR4 and TLR2 stimulation and exposure to IL-1β, ER stress and intracellular calcium all induce hRPE cells to produce intracellular IL-1α, which is negatively regulated by the PI3K/Akt pathway. Additionally, the non-canonical inflammasome pathway was shown to be involved in LPS-induced hRPE IL-1α expression through caspase-4 signaling.


Clinical manifestations of mutations in RAS and related intracellular signal transduction factors.
Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations. Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches. Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.


MR imaging diagnosis of triangular fibrocartilage pathology with arthroscopic correlation.
The goal of this study was to compare MR imaging with arthroscopy in evaluating triangular fibrocartilage (TFC) pathology. The results of 178 MR imaging examinations of the wrist were independently reviewed by two musculoskeletal radiologists who were unaware of the the clinical history, including any subsequent surgery. One hundred forty-nine of these studies were obtained from symptomatic patients. Of these patients, 56 underwent arthroscopic evaluation of the TFC. The remaining 29 studies were obtained from control volunteers and duplicate cases to reduce bias. The data were divided into categories based on Palmer's classification of TFC injury. Diagnostic sensitivity, specificity, and accuracy were calculated for each category. Of the 56 patients who underwent arthroscopic evaluation of the TFC, 27 had TFCs that were intact at surgery. Also, 27 complete perforations and two partial defects were found at surgery. Sensitivity for detecting central degenerative perforations was 91% for both observers I and II. Sensitivity for detecting radial slitlike tears was 100% and 86% for observers I and II, respectively. Sensitivity for detecting ulnar-sided avulsions was 25% and 50% for observers I and II, respectively. MR imaging is accurate in revealing TFC perforations.


Women sexually abused as children: implications for orthopaedic nursing care.
Because an experience of childhood sexual abuse may affect a woman's symptom presentation and response to treatment, it is recommended that orthopaedic nurses be aware of the long-term effects of sexual abuse and inquire about abuse if a patient exhibits problems and symptoms that may be suggestive of an abuse history. Patients in orthopaedic settings who have been sexually abused may have particular difficulty trusting health care providers, undergoing invasive or confining procedures, and tolerating pain or somatic discomfort. Recommended nursing interventions are aimed at establishing a trusting relationship, increasing survivors' sense of personal control and minimizing threatening intrusions, facilitating pain management, and if indicated, referring for psychotherapy.


Clustering Cloud-Like Model-Based Targets Underwater Tracking for AUVs.
Autonomous underwater vehicles (AUVs) rely on a mechanically scanned imaging sonar that is fixedly mounted on AUVs for underwater target barrier-avoiding and tracking. When underwater targets cross or approach each other, AUVs sometimes fail to track, or follow the wrong target because of the incorrect association of the multi-target. Therefore, a tracking method adopting the cloud-like model data association algorithm is presented in order to track underwater multiple targets. The clustering cloud-like model (CCM) not only combines the fuzziness and randomness of the qualitative concept, but also achieves the conversion of the quantitative values. Additionally, the nearest neighbor algorithm is also involved in finding the cluster center paired to each target trajectory, and the hardware architecture of AUVs is proposed. A sea trial adopting a mechanically scanned imaging sonar fixedly mounted on an AUV is carried out in order to verify the effectiveness of the proposed algorithm. Experiment results demonstrate that compared with the joint probabilistic data association (JPDA) and near neighbor data association (NNDA) algorithms, the new algorithm has the characteristic of more accurate clustering.


Kinetics and mechanism of water substitution in the low-spin Fe(II) complex of 4-octasulfophenylpyrazinoporphyrazine.
The substitution reaction of the axial-coordinated water by pyridine, pyrazine and 4-CN-pyridine in the low-spin Fe(II) complex of octasulfophenyltetrapyrazinoporphyrazine was studied. Kinetic and thermodynamic parameters for the different reaction steps of the process were determined. On the basis of NMR data and spectrophotometric titrations, a pronounced non-equivalence of the two coordinated N-donor ligands was observed. The substitution of water by pyridine and 4-CN-pyridine is shown to include the formation of a precursor outer-sphere complex, whereas substitution by pyrazine follows a limiting dissociative mechanism.


Medicinal herbs Fructus corni and Semen cuscutae suppress allograft rejection via distinct immune mechanisms.
Achieving long-term allograft survival without continuous global immunosuppression is highly desirable because constant immunosuppression causes severe side effects. Traditional Chinese medicine (TCM) has been utilized to treat numerous diseases for centuries. To seek novel immunosuppressive agents, we investigated several Chinese herbal formulas that have been shown to be effective in treating autoimmune diseases. C57BL/6 mice were transplanted with a skin graft from Balb/C donors and treated orally with the TCM. IL-12-expressing dendritic cells and CD4+FoxP3+ Tregs were quantified by flow cytometer while intragraft IL-12 gene expression was measured by real-time PCR. Here we identified a unique TCM, San Si formula, which contains three herbs: Fructus corni (FC), Fructus ligustri lucidi (FLL) and Semen cuscutae (SC). We found that either SC or FC, but not FLL, significantly prolonged skin allograft survival while SC plus FC or San Si formula further delayed allograft rejection compared to SC or FC alone. SC and FC, which did not contain cyclosporine and rapamycin, reduced graft-infiltrating T cells and suppressed their proliferation. Importantly, it was SC, but not FC, that induced CD4+FoxP3+ Tregs in recipients. Tregs induced by SC were also more potent in suppression. In contrast, FC repressed both intracellular IL-12 expression by intragraft DCs and IFNγ expression by graft-infiltrating T cells. Moreover, FC inhibited intragraft IL-12 gene expression. Depleting Tregs and providing exogenous IL-12 completely reversed allograft survival induced by SC plus FC. Thus, SC and FC synergistically suppress allograft rejection via distinct mechanisms.


Hemodynamic effects of the nitric oxide donor DETA/NO in mice.
(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) is a recently synthesized member of NO-releasing, polyamine zwitterions, the so-called NONOates, that spontaneously liberate NO in aqueous solutions. The aim of this study was to determine the hemodynamic effects of DETA/ NO in normotensive and hypertensive mice. Male Swiss Outbred mice were implanted with TA11PA-C20 blood pressure devices (Data Sciences International, USA). After recovery (7-10 days), blood pressure was monitored for 10 days while mice were receiving saline (0.1 ml/20 g/day, s.c.). Mice were then treated every four hours for 1 day with either DETA/NO 60 mg/kg i.p. or the inactive metabolite, diethylenetriamine 38 mg/kg (molar equivalent) i.p. After a 2 week wash-out period, mice were treated with adrenocorticotrophic hormone (ACTH: 500 microg/kg/day, s.c.) for 10 days and re-challenged with DETA/NO or diethylenetriamine. Results were expressed as mean +/- SEM. After 10 days of saline treatment, baseline systolic and diastolic blood pressure (BP) were similar for animals subsequently receiving DETA/NO or the amine (123 +/- 1/95 +/- 3 and 124 +/- 1/92 +/- 0.2 mmHg) respectively. DETA/NO induced a profound fall in BP [Systolic: 74 +/- 4 mmHg (-40 +/- 3%); Diastolic: 46 +/- 4 mmHg (-52 +/- 4%)] and an increase in heart rate [729 +/- 33 bpm (32 +/- 2%)] within the first 80 minutes. Diethylenetriamine had no effect. ACTH treatment increased BP in both groups (137 +/- 16/108 +/- 12 and 161 +/- 1/142 +/- 1 mmHg) respectively. DETA/ NO induced a profound fall in blood pressure [Systolic: 92 +/- 11 mmHg (-32 +/- 7%); Diastolic: 68 +/- 10 mmHg (-35 +/- 10%)] and an increase in heart rate [613 +/- 36 bpm (18 +/- 6%)] within the first 80 minutes. Again diethylenetriamine had no significant effect. There was no significant effect on body weight with any treatment. Thus DETA/NO has potent blood pressure lowering effects in both normotensive and hypertensive mice.


Alexithymia and Facial Mimicry in Response to Infant and Adult Affect-Expressive Faces.
Facial mimicry is the automatic tendency to imitate facial expressions of emotions. Alexithymia is associated with a reduced facial mimicry ability to affect expressions of adults. There is evidence that the baby schema may influence this process. In this study it was tested experimentally whether facial mimicry of the alexithymic group (AG) is different from the control group (CG) in response to dynamic facial affect expressions of children and adults. A multi-method approach (20-point Toronto Alexithymia Scale and Toronto Structured Interview for Alexithymia) was used for assessing levels of alexithymia. From 3503 initial data sets, two groups of 38 high and low alexithymic individuals without relevant mental or physical diseases were matched regarding age, gender, and education. Facial mimicry was induced by presentation of naturalistic affect-expressive video sequences (fear, sadness, disgust, anger, and joy) taken from validated sets of faces from adults (Averaged Karolinska Directed Emotional Faces) and children (Picture-Set of Young Children's Affective Facial Expressions). The videos started with a neutral face and reached maximum affect expression within 2 s. The responses of the groups were measured by facial electromyographic activity (fEMG) of corrugator supercilii and zygomaticus major muscles. Differences in fEMG response (4000 ms) were tested in a variance analytical model. There was one significant main effect for the factor emotion and four interaction effects for the factors group × age, muscle × age, muscle × emotion, and for the triple interaction muscle × age × emotion. The participants of AG showed a decreased fEMG activity in response to the presented faces of adults compared to the CG but not for the faces of children. The affect-expressive faces of children induced enhanced zygomatic and reduced corrugator muscle activity in both groups. Despite existing deficits in the facial mimicry of alexithymic persons, affect-expressive faces of children seem to trigger a stronger positive emotional involvement even in the AG.


Single Residue Acts as Gate in OccK Channels.
The OccK protein subfamily located in the outer membrane of Pseudomonas aeruginosa contains dynamic channels with several conformational states that range from open to closed forms. The molecular determinants of the OccK channels that contribute to the diverse gating have, however, remained elusive so far. Performing molecular dynamics (MD) simulations on OccK5 (OpdH) as an example, local fluctuations of loop L7 mediated by a single residue were identified that effectively gate the channel. The features of this gate residue were studied by single-channel electrophysiology and site-directed mutagenesis demonstrating that this gate residue indeed confers unique gating properties to the OccK channels. In support of these functional measurements, MD simulations highlight the correlations between the size of the side-chain belonging to the gate residue on one side and the pore size as well as the L7 flexibility on the other side.


Utility of the method using the tsukisui device to control intraoperative bleeding applied to neurofibroma resection.
The resection of neurofibromas in Von Recklinghausen's disease [neurofibromatosis type 1 (NF-1)] is frequently complicated due to size, location, hypervascularity, and tissue friability. A repeat resection, however, is necessary for patients with functional problems such as unexpected tumor bleeding or with changes in esthetic appearance. This report describes application of the method using the Tsukisui device to resecting NF-1 tumors while minimizing blood loss. The method using the Tsukisui device was applied for the resection of 8 NF-1 tumors (5 patients), and intraoperative blood loss, operative time, and postoperative complications were recorded. In all cases employing this method, intraoperative blood loss was <360 ml (10-360 ml), and none of the patients developed postoperative hematoma or other notable bleeding complications. The method using the Tsukisui device, which provided excellent hemostasis and was associated with few complications, shows promise for application to neurofibroma resection.


Installation of a Thermoswitchable Hydrophobic Domain into a Unimer Polyion Complex for Enhanced Cellular Uptake of siRNA.
Whereas small siRNA nanocarriers with a size of 10-20 nm exert high tissue-permeability, they encounter the challenge of inefficient adsorption on the cell surface, resulting in poor cellular uptake of siRNA. To solve this dilemma, this study aims to control the hydrophobicity of a small siRNA nanocarrier, unimer polyion complex (uPIC), with a size of ∼10 nm. The uPICs are fabricated to consist of a single pair between siRNA and a smart triblock copolymer comprising hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx), thermoswitchable poly(2-n-propyl-2-oxazoline) (PnPrOx), and cationic poly(l-lysine) (PLL). The PnPrOx segment is dehydrated at 37 °C (>lower critical solution temperature) to enhance the hydrophobicity of uPICs. The uPICs with a hydrophobic domain facilitates cellular uptake of the siRNA payload through stronger binding to the cell surface, compared with control uPICs without a PnPrOx segment, leading to a significantly enhanced gene silencing effect in cultured cancer cells.


Identification of essential arginyl residues in cytoplasmic malate dehydrogenase with butanedione.
The inactivation of cytoplasmic malate dehydrogenase (L-malate: NAD+ oxidoreductase, EC 188.8.131.52) from porcine heart and the specific modification of arginyl residues have been found to occur when the enzyme is inhibited with the reagent butanedione in sodium borate buffer. The inactivation of the enzyme was found to follow pseudo-first order kinetics. This loss of enzymatic activity was concomitant with the modification of 4 arginyl residues per molecule of enzyme. All 4 residues could be made inaccessible to modification when a malate dehydrogenase-NADH-hydroxymalonate ternary complex was formed. Only 2 of the residues were protected by NADH alone and appear to be essential. Studies of the butanedione inactivation in sodium phosphate buffer and of reactivation of enzymatic activity, upon the removal of excess butanedione and borate, support the role of borate ion stabilization in the inactivation mechanism previously reported by Riordan (Riordan, J.F. (1970) Fed. Proc. 29, Abstr. 462; Riordan, J.F. (1973) Biochemistry 12, 3915-3923). Protection from inactivation was also provided by the competitive inhibitor AMP, while nicotinamide exhibited no effect. Such results suggest that the AMP moiety of the NADH molecule is of major importance in the ability of NADH to protect the enzyme. When fluorescence titrations were used to monitor the ability of cytoplasmic malate dehydrogenase to form a binary complex with NADH and to form a ternary complex with NADH and hydroxymalonate, only the formation of ternary complex seemed to be effected by arginine modification.


Effects of pressure on hydrogen diffusion behaviors in MgO.
Hydrogen, as the smallest atom and a key component of water, can penetrate into materials in various forms (e.g., atoms, molecules), which has significant effects on their properties; hence, the diffusion behavior of hydrogen has aroused widespread attention. One of the major compositions in the Earth's interior is MgO. Thus, the diffusion behavior of hydrogen in MgO under high pressure is vital for understanding the water cycle in the Earth's interior. However, the hydrogen diffusion behavior in MgO under high pressure is still poorly understood. Herein, the hydrogen diffusion behaviors in MgO with increasing pressure are systematically investigated in the framework of first-principles methods. Our results show that separated H atoms tend to converge to form H2 molecules, and H2 molecules tend to gather together. The energy barriers of both H and H2 diffusion in MgO increase with pressure. Notably, our results illustrate that hydrogen prefers to diffuse in solid MgO in its molecular state even under high pressure. Furthermore, the attempt frequency of hydrogen in MgO increases with temperature, while it decreases with pressure. This study will deepen our understanding of hydrogen diffusion behavior in MgO under high pressure and provide guidance for studies on particle diffusion in solid materials under extreme conditions.


Effect of cold exposure on energy metabolism in the young pig.
Twenty-four piglets were weaned at 3 weeks of age and received 615 kJ metabolizable energy/(kg body weight X day). The temperature was reduced from 29 to 25 degrees C by 4 weeks of age. Six pigs were exposed to cold by reducing the temperature to 10 degrees C by 5 weeks of age while the other six were exposed to 23 degrees C. These two temperatures were maintained for 3 weeks. Each week the three pigs closest to the mean weight of each group were used for measurements of heat production for 23 h by open-circuit calorimetry and glucose turnover by continuous infusion of [6-3H]- and [U-14C]-glucose. The animals were sacrificed at 8 weeks of age, a sample of their intercostal muscle was used for in vitro measurement of muscle respiration, and the carcass was analyzed. There was no change in heat production, glucose turnover, and rectal temperature during the 3 weeks of cold exposure, so the data were pooled. Cold exposure increased heat production by 50%, forced mobilization of fat reserves (1000 g over the 3 weeks), and increased glucose replacement rate by 20%. The decline in rectal temperature to 37.6 from 38.8 degrees C could be regarded as a strategy to reduce energy needed to regulate body temperature. In the cold, heat production equalled metabolizable energy intake, but protein deposition was maintained at the same level as that in the pigs at the thermoneutral temperature, using the energy derived from the mobilization of body fat. The increase in Na+-K+ ATPase dependent respiration accounted for 70% of the increase in O2 consumption of muscle from cold-exposed pigs and thus is potentially an important component of cold-induced thermogenesis in the pig.


Does More Compression Mean More Pressure? A New Classification for Muscle Tension Dysphonia.
Objective The aims of this study were to test the hypothesis that greater supraglottic compression (anteroposterior or lateral) correlates with higher subglottic pressure (SGP) and to develop a classification of muscle tension dysphonia (MTD), based on the degree of supraglottic compression during speech. Method A prospective, cross-sectional study was conducted in a series of 37 consecutive patients diagnosed with MTD with an altered aerodynamic profile characterized by high SGP (more than 90 mmH2O). Supraglottic anteroposterior and lateral compression were categorized in three grades and assessed during the laryngoscopic examination. All patients completed the Spanish Voice Handicap Index (VHI) questionnaire and completed an acoustic and aerodynamic voice assessment. The relationship between compression grade and VHI with SGP was analyzed. Results More than 90% of patients demonstrated some degree of anteroposterior compression, and 67% had some degree of lateral compression. The mean (SD) SGP was 111.03 (16.7) mmH2O, and the mean VHI was 27.86 (12.5). The degree of SGP was statistically different in the different grades of anteroposterior compression, and also anteroposterior compression correlated with an SGP (p < .05). The degree of lateral compression was not correlated with SGP. Neither the degree of anteroposterior or lateral compression nor the value of SGP was found to correlate with VHI. Conclusions Because grade of anteroposterior compression correlates with SGP, these grades can be used for diagnosis and follow-up of MTD patients. To this end and on this basis, we propose a new classification for MTD. Unlike the established classification, our proposed one makes it possible to combine different laryngoscopic features, improving the description of the larynx during phonation.


Endothelial IL-33 Expression Is Augmented by Adenoviral Activation of the DNA Damage Machinery.
IL-33, required for viral clearance by cytotoxic T cells, is generally expressed in vascular endothelial cells in healthy human tissues. We discovered that endothelial IL-33 expression was stimulated as a response to adenoviral transduction. This response was dependent on MRE11, a sensor of DNA damage that can also be activated by adenoviral DNA, and on IRF1, a transcriptional regulator of cellular responses to viral invasion and DNA damage. Accordingly, we observed that endothelial cells responded to adenoviral DNA by phosphorylation of ATM and CHK2 and that depletion or inhibition of MRE11, but not depletion of ATM, abrogated IL-33 stimulation. In conclusion, we show that adenoviral transduction stimulates IL-33 expression in endothelial cells in a manner that is dependent on the DNA-binding protein MRE11 and the antiviral factor IRF1 but not on downstream DNA damage response signaling.


Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase Inhibitory Evaluations of Benzenesulfonamide Derivatives Containing Thiazolidinone.
To find novel human carbonic anhydrase (hCA) inhibitors, we synthesized thirteen compounds by combining thiazolidinone with benzenesulfonamide. The result of the X-ray single-crystal diffraction experiment confirmed the configuration of this class of compounds. The enzyme inhibition assays against hCA II and IX showed desirable potency profiles, as effective as the positive controls. The docking studies revealed that compounds (2) and (7) efficiently bound in the active site cavity of hCA IX by forming sufficient interactions with active site residues. The fragment of thiazolidinone played an important role in the binding of the molecules to the active site.


Molecular cloning of the cDNAs encoding pituitary glycoprotein hormone alpha- and gonadotropin II beta-subunits of the Japanese eel, Anguilla japonica, and increase in their mRNAs during ovarian development induced by injection of chum salmon pituitary homogenate.
cDNAs encoding the glycoprotein hormone alpha- and gonadotropin (GTH) II beta-subunits of Japanese eel (Anguilla japonica) pituitary were cloned using the polymerase chain reaction. The nucleotide sequence of the glycoprotein hormone alpha-subunit cDNA was 364 base pairs (bp) long, encoding 117 amino acids, and that of the GTH II beta-subunit cDNA was 433 bp long, encoding 140 amino acids. The deduced amino acid sequence of each mature subunit showed high homology with those of other teleosts, indicating that the structure of GTH subunits has been conserved during the evolution of teleosts. Changes in the expression of these subunit genes during ovarian development induced artificially by the injection of chum salmon pituitary homogenate were examined using Northern blot analysis. Glycoprotein hormone alpha-subunit mRNA increased almost linearly during ovarian development, whereas GTH II beta-subunit mRNA was detected only at the late vitellogenic and migratory nucleus stages. These data indicate that eel GTH II is synthesized mainly at the late vitellogenic and migratory nucleus stages, and suggest that GTH II plays an important role in final oocyte maturation of Japanese eel. Changes in the expression of glycoprotein hormone alpha- and GTH II beta-subunits mRNA correlate with the serum estradiol-17 beta (E(2)) and testosterone profile during ovarian development. The increase in mRNA of both subunits is probably due to positive feedback of E(2) and testosterone produced by ovarian follicles in response to the GTH contained in chum salmon pituitary homogenate.


Ultrasonography for the diagnosis of patients with clinically suspected skin and soft tissue infections: a systematic review of the literature.
In patients presenting with skin and soft tissue infections (SSTI), the use of ultrasound may lead to a more accurate distinction between cellulitis and abscess compared with clinical assessment alone. This systematic review aims to determine the diagnostic accuracy of ultrasound for detecting skin abscesses. In addition, it aims to assess the impact of using ultrasound on management decisions in patients with SSTI. We searched relevant electronic databases for primary studies including MEDLINE, EMBASE, and CINAHL. We searched conference proceedings, checked references of retrieved articles, and contacted field experts. Two reviewers assessed the quality of each full-text publication using a modified QUADAS-2 tool. Five studies (n=710) fulfilled our inclusion criteria. Four studies compared the diagnostic accuracy of ultrasound with clinical examination alone (n=584). Most studies reported an improvement in diagnostic accuracy. The sensitivity of ultrasound ranged from 89 to 98% and the specificity ranged from 64 to 88%. However, the sensitivity of clinical assessment ranged from 75 to 90% and the specificity ranged from 55 to 83%; most of these results did not reach statistical significance. Sensitivity was further improved in cases of indeterminate clinical assessment. Two studies (n=176) examined the impact of ultrasound on management decisions. Use of ultrasound has led to significant and appropriate changes in management decisions in 16 to 39% of patients. The use of ultrasound could potentially improve diagnostic accuracy and lead to improved management decisions in patients with SSTI, especially in cases of indeterminate clinical assessment. Most of our findings did not achieve statistical significance. Further research is required to confirm these findings.


Deep-Precognitive Diagnosis: Preventing Future Pandemics by Novel Disease Detection With Biologically-Inspired Conv-Fuzzy Network.
Deep learning-based Computer-Aided Diagnosis has gained immense attention in recent years due to its capability to enhance diagnostic performance and elucidate complex clinical tasks. However, conventional supervised deep learning models are incapable of recognizing novel diseases that do not exist in the training dataset. Automated early-stage detection of novel infectious diseases can be vital in controlling their rapid spread. Moreover, the development of a conventional CAD model is only possible after disease outbreaks and datasets become available for training (viz. COVID-19 outbreak). Since novel diseases are unknown and cannot be included in training data, it is challenging to recognize them through existing supervised deep learning models. Even after data becomes available, recognizing new classes with conventional models requires a complete extensive re-training. The present study is the first to report this problem and propose a novel solution to it. In this study, we propose a new class of CAD models, i.e., Deep-Precognitive Diagnosis, wherein artificial agents are enabled to identify unknown diseases that have the potential to cause a pandemic in the future. A de novo biologically-inspired Conv-Fuzzy network is developed. Experimental results show that the model trained to classify Chest X-Ray (CXR) scans into normal and bacterial pneumonia detected a novel disease during testing, unseen by it in the training sample and confirmed to be COVID-19 later. The model is also tested on SARS-CoV-1 and MERS-CoV samples as unseen diseases and achieved state-of-the-art accuracy. The proposed model eliminates the need for model re-training by creating a new class in real-time for the detected novel disease, thus classifying it on all subsequent occurrences. Second, the model addresses the challenge of limited labeled data availability, which renders most supervised learning techniques ineffective and establishes that modified fuzzy classifiers can achieve high accuracy on image classification tasks.


Luminal leptin enhances CD147/MCT-1-mediated uptake of butyrate in the human intestinal cell line Caco2-BBE.
In the intestine, butyrate constitutes the major energy fuel for colonocytes. However, little is known about the transport of butyrate and its regulation in the intestine. In this study we demonstrate that the monocarboxylate transporter (MCT-1) is apically polarized in model human intestinal epithelia and is involved in butyrate uptake by Caco2-BBE cell monolayers. The butyrate uptake by Caco2-BBE cell monolayers displayed conventional Michaelis-Menten kinetics and was found to be pH-dependent, Na(+)-independent, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive, and inhibited by the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamate and by an excess of unlabeled butyrate. We show that MCT-1 associates with CD147 at the apical plasma membrane in Caco2-BBE cell monolayers. Using antisense CD147, we demonstrate that the association of CD147 with MCT-1 is critical for the butyrate transport activity. Interestingly, we show for the first time hormonal regulation of CD147/MCT-1 mediated butyrate uptake. Specifically, luminal leptin significantly up-regulates MCT-1-mediated butyrate uptake by increasing its maximal velocity (V(max)) without any modification in the apparent Michaelis-Menten constant (K(m)). Finally, we show that luminal leptin up-regulates butyrate uptake in Caco2-BBE monolayers by two distinct actions: (i) increase of the intracellular pool of MCT-1 protein without affecting CD147 expression and (ii) translocation of CD147/MCT-1 to the apical plasma membrane of Caco2-BBE cell monolayers.


[Case-only study on the relationship between genetic polymorphisms in toxicant metabolizing enzymes and risk of occupational chronic benzene poisoning].
To explore the effects of interaction between environmental exposure factors and genetic polymorphism in toxicant metabolizing enzymes on risk of occupational chronic benzene poisoning. One hundred and fifty-two cases of chronic benzene poisoning were analyzed for the risk by case-only study. The frequency of non-null GSTT1 gene in benzene poisoning workers with moderate benzene exposure level was higher than that in cases with lower benzene exposure (68.63% vs 38.00%, OR(adj) = 4.32, 95% CI 1.75 - 10.66, P = 0.002). The frequency of NQO1 C.609T/T gene in alcohol drinking group was higher than that in non-drinking group (61.11% vs 20.00%, OR(adj) = 8.03, 95% CI 2.28 - 28.25, P = 0.001), moreover, it was higher in workers with smoking and drinking than that in the rest group, and in drinking x exposure level workers than that in non-drinking x exposure level workers (85.71% vs 22.76%, OR(adj) = 18.62, 95% CI 2.01 - 172.72, P = 0.01 and 61.11% vs 20.00%, OR(adj) = 3.18, 95% CI 1.55 - 6.52, P = 0.002 respectively). The frequency of non-null GSTM1 gene was also higher in drinking x exposure level workers than that in non-drinking x exposure level workers (66.67% vs 47.06%, OR(adj) = 1.99, 95% CI 1.05 - 3.76, P = 0.036). There is interaction between the polymorphism of GSTT1 gene and moderate benzene exposure level; non-null GSTM1 gene and drinking x exposure level increase the risk of occupational chronic benzene poisoning; polymorphism of NQO1 gene C.609 also interacts with drinking, while polymorphism of NQO1 gene and drinking x smoking may further increase the risk of occupational chronic benzene poisoning.


Congenital heart disease and heterotaxy: upper gastrointestinal fluoroscopy can be misleading and surgery in an asymptomatic patient is not beneficial.
Heterotaxy syndrome is associated with intestinal abnormalities. We sought to define the gastrointestinal anatomy and determine both the risk of volvulus and benefit of screening upper gastrointestinal fluoroscopy (UGI) in these patients. Medical records from 2003 until 2011 at Children's Hospital Los Angeles were reviewed in patients with heterotaxy for cardiovascular diagnosis, gastrointestinal symptoms, imaging and surgical arrangement of viscera, perioperative morbidities, and overall mortality. 224 patients were identified. Fifteen had polysplenia, 41 had asplenia, 50 had normal splenic morphology, 13 had inversus, and 104 were uncharacterized. UGI was performed in 4 patients for suspected volvulus and 20 for obstructive symptoms. Sixty-two had "screening" UGIs. Of 138 asymptomatic patients without imaging, none developed volvulus during the study period. In 30 patients with duodenojejunal malposition (DJM) who underwent surgery, none had malrotation or narrow mesentery. Eleven developed complications, with 8 requiring reoperation for obstruction. Of 8 patients with malrotation, 7 received a Ladd's procedure, and 2 had volvulus with viable bowel. One patient required reoperation and resection for obstruction. While rotational abnormalities are common in heterotaxy, risk of volvulus is low. Following operation, the risk of bowel obstruction and of need for reoperation is higher. We advocate avoiding operation in the asymptomatic patient.


Whole genome sequence analysis of Australian avian pathogenic Escherichia coli that carry the class 1 integrase gene.
Avian pathogenic Escherichia coli (APEC) cause widespread economic losses in poultry production and are potential zoonotic pathogens. Genome sequences of 95 APEC from commercial poultry operations in four Australian states that carried the class 1 integrase gene intI1, a proxy for multiple drug resistance (MDR), were characterized. Sequence types ST117 (22/95), ST350 (10/95), ST429 and ST57 (each 9/95), ST95 (8/95) and ST973 (7/95) dominated, while 24 STs were represented by one or two strains. FII and FIB repA genes were the predominant (each 93/95, 98 %) plasmid incompatibility groups identified, but those of B/O/K/Z (25/95, 26 %) and I1 (24/95, 25 %) were also identified frequently. Virulence-associated genes (VAGs) carried by ColV and ColBM virulence plasmids, including those encoding protectins [iss (91/95, 96 %), ompT (91/95, 96 %) and traT (90/95, 95 %)], iron-acquisition systems [sitA (88/95, 93 %), etsA (87/95, 92 %), iroN (84/95, 89 %) and iucD/iutA (84/95, 89 %)] and the putative avian haemolysin hylF (91/95, 96 %), featured prominently. Notably, mobile resistance genes conferring resistance to fluoroquinolones, colistin, extended-spectrum β-lactams and carbapenems were not detected in the genomes of these 95 APEC but carriage of the sulphonamide resistance gene, sul1 (59/95, 63 %), the trimethoprim resistance gene cassettes dfrA5 (48/95, 50 %) and dfrA1 (25/95, 27 %), the tetracycline resistance determinant tet(A) (51/95, 55 %) and the ampicillin resistance genes blaTEM-1A/B/C (48/95, 52 %) was common. IS26 (77/95, 81 %), an insertion element known to capture and mobilize a wide spectrum of antimicrobial resistance genes, was also frequently identified. These studies provide a baseline snapshot of drug-resistant APEC in Australia and their role in the carriage of ColV-like virulence plasmids.


Short and long-term effects of hVEGF-A(165) in Cre-activated transgenic mice.
We have generated a transgenic mouse where hVEGF-A(165) expression has been silenced with loxP-STOP fragment, and we used this model to study the effects of hVEGF-A(165) over-expression in mice after systemic adenovirus mediated Cre-gene transfer. Unlike previous conventional transgenic models, this model leads to the expression of hVEGF-A(165) in only a low number of cells in the target tissues in adult mice. Levels of hVEGF-A(165) expression were moderate and morphological changes were found mainly in the liver, showing typical signs of active angiogenesis. Most mice were healthy without any major consequences up to 18 months after the activation of hVEGF-A(165) expression. However, one mouse with a high plasma hVEGF-A(165) level died spontaneously because of bleeding into abdominal cavity and having liver hemangioma, haemorrhagic paratubarian cystic lesions and spleen peliosis. Also, two mice developed malignant tumors (hepatocellular carcinoma and lung adenocarcinoma), which were not seen in control mice. We conclude that long-term uncontrolled hVEGF-A(165) expression in only a limited number of target cells in adult mice can be associated with pathological changes, including possible formation of malignant tumors and uncontrolled bleeding in target tissues. These findings have implications for the design of long-term clinical trials using hVEGF-A(165) gene and protein.


Horseradish peroxidase: the analyst's friend.
HRP is a calcium-containing, extensively glycosylated, stable haemoprotein possessing four disulphide bridges and weighing 44 kDa. It is an oxidoreductase which can use a wide variety of hydrogen donors to reduce hydrogen peroxide. This gives rise to a range of colorimetric, fluorimetric, chemiluminescent and electrochemical assays for HRP activity. HRP is very widely used as an indicator in immunoassays, non-isotopic DNA probes, cytochemistry, bi-enzyme systems and biosensors. This is owing to its stability, high catalytic rates, ease of conjugation to other molecules and wide choice of assays of activity.


The reconstruction of "complex" ureteral lesions.
A total of 13 patients with ureteral lesions wider than 12 cm in length and/or previous radiation treatment have been submitted to reconstructive treatment. Four patients with lesions after radiation therapy were treated with ileal ureter and contemporary bladder augmentation, one with ureteroneocystostomy combined with psoas hitch procedure and one combining psoas hitch and Boori Flap technique. The association of psoas hitch with Boari Flap technique were also used to treat two patients with the undesired outcome of vascular procedure. A patient after complete ureteral stripping following ureteroscopy was submitted to ileal bladder substitution. Two renal autotransplantations were performed in a patient with extensive stricture of the ureter following multiple endourological procedure and in a patient with negative outcome of previous attempt of open ureteral defect reconstruction following abdominal trauma.


Advanced Maternal Age and Assisted Reproductive Technologies in an Irish Population.
In recent decades the amount of women over 40 seeking assisted reproductive technology (ART) interventions in order to become pregnant has dramatically increased, both in Ireland and worldwide. This is due to an increase in the average age at which women are choosing to have their first child while additionally, many couples are choosing to have a second family later in life. However, as with natural conception, ART success rates decrease with maternal age. In the present study, we perform a 16 year retrospective analysis on our clinical data of women between 40 and 45 years of age, who have undergone ART at a tertiary referral ART clinic. The percentage of patients in this age group was analysed over time, in order to determine follicle recruitment, % oocyte yield, embryonic quality, positive hCG (pregnancy rate), clinical pregnancy rate and rate of preclinical pregnancy loss. Results from our clinic show that women greater than 43 years of age have a significantly reduced reproductive potential compared to women in the 40 to 42 years age group. Woman in the 43-45 age group showed reduced fertilization rates (53.73% versus 58.82%), reduced positive hCG rates (11.51%0/ versus 19.03%) and clinical pregnancy rates (5.04% versus 12.52%) and increased rates of preclinical pregnancy loss (56.23% versus 34.23%), compared to women in the 40-42 age group. With the age at which couples are choosing to have children constantly increasing, novel ART treatment strategies need to be developed.


Involvement of extracellular vesicles in aging process and their beneficial effects in alleviating aging-associated symptoms.
Aging is a gradual and unavoidable physiological phenomenon that manifests in the natural maturation process and continues to progress from infanthood to adulthood. Many elderly people suffer from aging-associated hematological and nonhematological disorders. Recent advances in regenerative medicine have shown new revolutionary paths of treating such diseases using stem cells; however, aging also affects the quality and competence of stem and progenitor cells themselves and ultimately directs their death or apoptosis and senescence, leading to a decline in their regenerative potential. Recent research works show that extracellular vesicles (EVs) isolated from different types of stem cells may provide a safe treatment for aging-associated disorders. The cargo of EVs comprises packets of information in the form of various macromolecules that can modify the fate of the target cells. To harness the true potential of EVs in regenerative medicine, it is necessary to understand how this cargo contributes to the rejuvenation of aged stem and progenitor populations and to identify the aging-associated changes in the macromolecular profile of the EVs themselves. In this review, we endeavor to summarize the current knowledge of the involvement of EVs in the aging process and delineate the role of EVs in the reversal of aging-associated phenotypes. We have also analyzed the involvement of the molecular cargo of EVs in the generation of aging-associated disorders. This knowledge could not only help us in understanding the mechanism of the aging process but could also facilitate the development of new cell-free biologics to treat aging-related disorders in the future.


A comparison between the larval eyes of the dimly luminescent Keroplatus nipponicus and the brightly luminescent Arachnocampa luminosa (Diptera; Keroplatidae).
Larvae of the weakly blue-luminescent fungus gnat Keroplatus nipponicus possess on either side of their heads a small black stemmatal eye with a plano-convex lens approximately 25 μm in diameter. In total, 12-14 retinula cells give rise to a centrally fused rhabdom of up to 8 μm in diameter. The rhabdom's constituent microvilli, approximately 70 nm in width, are roughly orthogonally oriented, a requirement for polarization sensitivity. Screening pigment granules are abundant in the retinula cells and measure at least 1 μm in diameter. In comparison with the stemmatal eye of the brightly luminescent Arachnocampa luminosa, that of K. nipponicus is considerably smaller with a poorer developed lens and a rhabdom that is less voluminous, but possesses wider microvilli. Although the larval eye of K. nipponicus can be expected to be functional, as the larvae react to light with a behavioural response, the eyes are probably mainly involved in the detection of ambient light levels and not, as in A. luminosa, also in responding to the luminescence of nearby conspecifics.


Impact of Hypothermia on Oxygenation Variables and Metabolism in Survivors of Out-of-Hospital Cardiac Arrest Undergoing Targeted Temperature Management at 33°C Versus 36°C.
Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2 according to the principle of Fick (VO2 = cardiac output*arteriovenous oxygen content difference). DO2 was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2 was 169 ± 59 mL O2 per minute in TTM33 and 217 ± 53 mL O2 per minute in TTM36 (p < 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2 minute (95% confidence interval [CI]: 31-74, pgroup < 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2 between the groups. DO2 was overall 277 mL O2 per minute (95% CI: 175-379, pgroup < 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: -0.1 to 5, pgroup = 0.09]). VO2 during the first 36 hours after OHCA correlated significantly with temperature, and VO2 was 19 mL O2 per minute lower per degree reduction in temperature (95% CI: 15-22), p < 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2 and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2 fell by 19 mL O2 per minute.


Pd-on-Au Supra-nanostructures Decorated Graphene Oxide: An Advanced Electrocatalyst for Fuel Cell Application.
We report a very easy and effective approach for synthesizing unique palladium-on-gold supra-nanostructure (Au@Pd-SprNS)-decorated graphene oxide (GO) nanosheets. The SprNSs comprising Au nanorods as core and a unique close-packed assembly of tiny anisotropic Pd nanoparticles (NPs) as shell were homogeneously distributed on the GO surface via electrostatic self-assembly. Compared with the traditional one-pot method for synthesis of metal NPs on GO sheets, the size and shape of core-shell Au@Pd SprNSs can be finely controlled and uniformly distributed on the GO carrier. Interestingly, this Au@Pd-SprNSs/GO nanocomposite displayed high electrocatalytic activities toward the oxidation of methanol, ethanol, and formic acid, which can be attributed to the abundance of intrinsic active sites including high density of atomic steps, ledges and kinks, Au-Pd heterojunctions and cooperative action of the two metals of the SprNSs. Additionally, uniform dispersion of the SprNSs over the GO nanosheets prevent agglomeration between the SprNSs, which is of great significance to enhance the long-term stability of catalyst. This work will introduce a highly efficient Pd-based nanoelectrocatalyst to be used in fuel cell application.


Blood pressure target for hypertension in chronic kidney disease: One size does not fit all.
There is disagreement between the American and the European guidelines for hypertension management in regard to the optimal blood pressure target in patients with chronic kidney disease (CKD). Randomized clinical trials and meta-analyses of individual patient data pooled from these trials do not clearly support an intensive blood pressure target for the entire population of CKD patients with hypertension. However, some evidence suggests that in CKD patients with proteinuria strict blood pressure control might confer benefit in terms of renal outcome. Tailored treatment strategy based on the individual's proteinuric profile and tolerability along with standardization of blood pressure measurement methodology including out-of-office evaluation are of paramount importance in patients with CKD.


Chromosome-Level Genome Assembly for the Angiosperm Silene conica.
The angiosperm genus Silene has been the subject of extensive study in the field of ecology and evolution, but the availability of high-quality reference genome sequences has been limited for this group. Here, we report a chromosome-level assembly for the genome of Silene conica based on Pacific Bioscience HiFi, Hi-C, and Bionano technologies. The assembly produced 10 scaffolds (1 per chromosome) with a total length of 862 Mb and only ∼1% gap content. These results confirm previous observations that S. conica and its relatives have a reduced base chromosome number relative to the genus's ancestral state of 12. Silene conica has an exceptionally large mitochondrial genome (>11 Mb), predominantly consisting of sequence of unknown origins. Analysis of shared sequence content suggests that it is unlikely that transfer of nuclear DNA is the primary driver of this mitochondrial genome expansion. More generally, this assembly should provide a valuable resource for future genomic studies in Silene, including comparative analyses with related species that recently evolved sex chromosomes.


Feedback delay attenuates implicit but facilitates explicit adjustments to a visuomotor rotation.
We examined the effects of delaying terminal visual feedback on the relative contribution of explicit and implicit components of adaptation to a visuomotor rotation. Participants practiced a 30° rotation while receiving terminal visual feedback with either a short (0ms), medium (200ms), or long (1500ms) delay. Explicit and implicit adjustments were dissociated by a series of posttests. While overall adaptation did not differ significantly between groups, aftereffects progressively decreased with increasing feedback delay. Moreover, explicit knowledge of the rotation increased in both the medium and high delay groups relative to the short delay group, but did not differ between the former two. This finding of feedback delay differentially affecting implicit adjustments as indexed by aftereffects and conscious strategic corrections based on explicit knowledge of the transformation substantiates the importance of distinguishing implicit and explicit components of adaptation even with rotations of smaller size and emphasizes the need to consider time delays in the interpretation of adaptation experiments and potentially in the design of training environments.


Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation: The Indiana University FIRM Registry.
Mounting evidence shows that localized sources maintain atrial fibrillation (AF). However, it is unclear in unselected "real-world" patients if sources drive persistent atrial fibrillation (PeAF), long-standing persistent atrial fibrillation (LPeAF), or paroxysmal atrial fibrillation (PAF); if right atrial sites are important; and what the long-term success of source ablation is. The aim of this study was to analyze the role of rotors and focal sources in a large academic registry of consecutive patients undergoing source mapping for AF. One hundred seventy consecutive patients (mean age 59 ± 12 years, 79% men) with PAF (37%), PeAF (31%), or LPeAF (32%). Of these, 73 (43%) had undergone at least 1 prior ablation attempt (mean 1.9 ± 0.8; range: 1 to 4). Focal impulse and rotor modulation (FIRM) with an endocardial basket catheter was used in all cases. FIRM analysis revealed sources in the right atrium in 85% of patients (1.8 ± 1.3) and in the left atrium in 90% of patients (2.0 ± 1.3). FIRM ablation terminated AF to sinus rhythm or atrial flutter or tachycardia in 59% (PAF), 37% (PeAF), and 19% (LPeAF) of patients, with 15 of 67 terminations due to right atrial ablation. On follow-up, freedom from AF after a single FIRM procedure for the entire series was 95% (PAF), 83% (PeAF), and 82% (LPeAF) at 1 year and freedom from all atrial arrhythmias was 77% (PAF), 75% (PeAF), and 57% (LPeAF). In the Indiana University FIRM registry, FIRM-guided ablation produced high single-procedure success, mostly in patients with nonparoxysmal AF. Data from mapping, acute terminations, and outcomes strongly support the mechanistic role of biatrial rotors and focal sources in maintaining AF in diverse populations. Randomized trials of FIRM-guided ablation and mechanistic studies to determine how rotors form, progress, and regress are needed.


Autosomal recessive osteopetrosis as an unusual cause of hydrocephalus, extensive calcification of tentorium cerebelli, and calvarial hyperostosis.
Osteopetrosis is an uncommon congenital disorder characterized by defective osteoclastic resorption of bone that results in increased bone density. Clinical symptoms include anemia, hepatosplenomegaly, and cranial nerve and/or brainstem compression and hydrocephalus due to foraminal narrowing in the skull. The authors present an unusual case of a patient with autosomal recessive osteopetrosis associated with extensive calcification of the dura mater covering the brain as well as obstructive hydrocephalus. Ventriculoperitoneal shunt treatment was complicated by persistent overdrainage. It is suggested that chronic progressive triventricular hydrocephalus developed as a result of acquired aqueductal stenosis caused by extensive calcification of the tentorium cerebelli and calvarial hyperostosis. To the best of the authors' knowledge, this has not been described in the literature.


Imaging of treatment response to the combination of carboplatin and paclitaxel in human ovarian cancer xenograft tumors in mice using FDG and FLT PET.
A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responders. In this study we describe the non-invasive PET imaging of glucose uptake and cell proliferation using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) for early assessment of treatment response in a pre-clinical mouse model of human ovarian cancer treated with carboplatin and paclitaxel. In vivo uptake of FLT and FDG in human ovarian cancer xenografts in mice (A2780) was determined before treatment with carboplatin and paclitaxel (CaP) and repeated day 1, 4 and 8 after treatment start. Tracer uptake was quantified using small animal PET/CT. Tracer uptake was compared with gene expression of Ki67, TK1, GLUT1, HK1 and HK2. Tumors in the CaP group was significantly smaller than in the control group (p=0.03) on day 8. On day 4 FDG SUVmax ratio was significantly lower in the CaP group compared to the control group (105 ± 4% vs 138 ± 9%; p=0.002) and on day 8 the FDG SUVmax ratio was lower in the CaP compared to the control group (125 ± 13% vs 167 ± 13%; p=0.05). On day 1 the uptake of FLT SUVmax ratio was 89 ± 9% in the CaP group and 109 ± 6% in the control group; however the difference was not statistically significant (p=0.08). Our data suggest that both FDG and FLT PET may be used for the assessment of anti-tumor effects of a combination of carboplatin and paclitaxel in the treatment of ovarian cancer. FLT provides an early and transient signal and FDG a later and more prolonged response. This underscores the importance of optimal timing between treatment and FLT or FDG imaging since treatment response may otherwise be overlooked.


[Desquamative interstitial pneumonia (apropos of one case)].
Suspected to be a syndrome rather than an authentic clinical entity, the "desquamative interstitial pneumonia" (DIP) exhibits typical anatomo-pathological aspects of intra-alveolar proliferation of granular pneumocytes, type II pneumocytes, leaving the alveolar interstitium unaffected. In absence of superinfection, it remains almost free of fibrous or inflammatory manifestations. The association of DIP to 4 other fundamental histological varieties of diseases of the pulmonary interstitium (UIP, BIP, LIP, GIP) is at the origin of Liebow's classification. The clinical individualization of these entities is still questioned.


Electron currents generated by the human phagocyte NADPH oxidase.
Electron transport across biological membranes is a well-known feature of bacteria, mitochondria and chloroplasts, where it provides motive forces for vectorial transport processes. In contrast, electron transport is generally not found in the plasma membrane of eukaryotic cells, possibly because it would interfere with electric processes at the plasma membrane. An exception is provided by the phagocyte NADPH oxidase, which generates superoxide (O2.-) through electron transfer from cytosolic NADPH to extracellular oxygen. The enzyme is essential for host defence, and patients with chronic granulomatous disease, who lack the functional enzyme, suffer from severe infections. It has been suggested that electron transfer by the NADPH oxidase might be electrogenic. Here we demonstrate, using the whole-cell patch-clamp technique, the generation of electron currents by the NADPH oxidase in human eosinophil granulocytes. The currents were absent in granulocytes of sufferers of chronic granulomatous disease and under conditions of low oxygen. Generation of electron currents across the plasma membrane of eukaryotic cells has not been observed previously and might be-independently of the generation of superoxide-a physiologically relevant function of the phagocyte NADPH oxidase.


Ru(ii)-Pheox-catalyzed Si-H insertion reaction: construction of enantioenriched carbon and silicon centers.
We established a highly enantioselective Si-H insertion reaction to construct chiral centers at the carbon and silicon atoms, using a Ru(ii)-pheox catalyst. The catalytic asymmetric Si-H insertion reaction of α-methyl-α-diazoesters proceeded smoothly with excellent stereoinduction at both the neighboring carbon and silicon atoms (up to 99% yield and 99% ee).


Repeated Warm Water Immersion Induces Similar Cerebrovascular Adaptations to 8 Weeks of Moderate-Intensity Exercise Training in Females.
Exercise training has the potential to enhance cerebrovascular function. Warm water immersion has recently been shown to enhance vascular function including the cerebrovascular response to heating. We suggest that passive heating can be used alternatively to exercise. Our aim was to compare the effects of exercise with warm-water immersion training on cerebrovascular and thermoregulatory function. 18 females (25±5 y) performed 8 weeks of cycling (70% HRmax) or warm water immersion (42°C) for 30 min 3 times per week. Brachial artery flow-mediated dilation (FMD) and peak cardiorespiratory fitness (VO2peak) were measured prior to and following both interventions. A passive heat stress was employed to obtain temperature thresholds (Tb) and sensitivities for sweat rate (SR) and cutaneous vasodilation (CVC). Middle cerebral artery velocity (MCAv) was measured throughout. FMD and VO2peak improved following both interventions (p<0.05). MCAv and cerebrovascular conductance were higher at rest and during passive heating (p<0.001 and <0.001, respectively) following both interventions. SR occurred at a lower Tb following both interventions and SR sensitivity also increased, with a larger increase at the chest (p<0.001) following water immersion. CVC occurred at a lower Tb (p<0.001) following both interventions. Warm water immersion elicits similar cerebrovascular, conduit, and thermoregulatory adaptations compared to a period of moderate-intensity exercise training.


Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide.
1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20 mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software. 3. The predicted in vivo clearance of CP at concentrations of 5, 10 and 20 mM was 11.36, 10.12 and 10.68 mL/min/kg, respectively, within two-fold differences compared with the reported 11.1 mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced. 4. This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.