Multi-locus phylogenetic analysis reveals the pattern and tempo of bony fish evolution.
Over half of all vertebrates are "fishes", which exhibit enormous diversity in morphology, physiology, behavior, reproductive biology, and ecology. Investigation of fundamental areas of vertebrate biology depend critically on a robust phylogeny of fishes, yet evolutionary relationships among the major actinopterygian and sarcopterygian lineages have not been conclusively resolved. Although a consensus phylogeny of teleosts has been emerging recently, it has been based on analyses of various subsets of actinopterygian taxa, but not on a full sample of all bony fishes. Here we conducted a comprehensive phylogenetic study on a broad taxonomic sample of 61 actinopterygian and sarcopterygian lineages (with a chondrichthyan outgroup) using a molecular data set of 21 independent loci. These data yielded a resolved phylogenetic hypothesis for extant Osteichthyes, including 1) reciprocally monophyletic Sarcopterygii and Actinopterygii, as currently understood, with polypteriforms as the first diverging lineage within Actinopterygii; 2) a monophyletic group containing gars and bowfin (= Holostei) as sister group to teleosts; and 3) the earliest diverging lineage among teleosts being Elopomorpha, rather than Osteoglossomorpha. Relaxed-clock dating analysis employing a set of 24 newly applied fossil calibrations reveals divergence times that are more consistent with paleontological estimates than previous studies. Establishing a new phylogenetic pattern with accurate divergence dates for bony fishes illustrates several areas where the fossil record is incomplete and provides critical new insights on diversification of this important vertebrate group.


[Lymphedema secondary to breast cancer treatment: possibility of diagnostic and therapeutic prevention].
We performed a prospective randomized study upon 50 patients who had undergone a breast cancer treatment, considering particularly the possibility of appearance of arm secondary lymphedema. The patients were divided in two groups of 25 patients each. In the 1st group, we performed only a clinical follow-up, whilst in the 2nd one, we used also lymphoscintigraphy. The aim of the study was to compare the incidence of arm secondary lymphedema in the two groups, and relate the data with those of the international literature, in order to identify diagnostic procedures indicative of the risk of development of lymphedema and find proper therapeutic preventive measures. It is certainty complex to foresee the appearance of arm lymphedema due to breast cancer treatment. No specific preventive therapeutic methods based upon particular diagnostic investigations were ever reported. Patients had undergone surgery and radiation for breast cancer in the period between April 1992 and June 1994, and controlled at over 5 years after operation. Upper limb lymphoscintigraphy was performed only in one of the two groups of 25 patients, before operation and, furthermore, after 1-3-6 months and 1-3 years from the treatment. Patients who presented lymphoscintigraphic alterations (dermal back flow, diffused or delayed transit of the tracer, etc.), before edema appeared clinically, underwent physical and rehabilitative therapy (bandages, manual lymphatic drainage, mechanical lymph drainage, elastic garments, etc.) and microsurgery (lymphatic-venous anastomoses at the arm), performed early (stages Ib and II) in patients not responsive to physical therapy. In the first group followed only clinically, secondary arm lymphedema occurred in 9 cases (36%), and appeared after a period variable from 1 week to 2 years (3-6 months averagely). In the second group, lymphoscintigraphy, performed preoperatively, permitted to find lymphatic impairment (absence of deltoid way, reduced axillary lymph nodal tracer uptake, delayed transit of the tracer) at the upper limb in 4 patients (15%). After breast cancer surgery, lymphoscintigraphy pointed out alterations of lymphatic circulation in 5 patients (20%) after 1 month, in other 6 cases (56%) at 6 months, other 5 (76%) after 1 year and 3 (88%) at 3 and 5 years. Physical preventive therapy performed in patients with positive lymphoscintigraphy, even before the clinical appearance of edema, allowed to find a clinically evident lymphedema only in 2 cases (8%). The last two patients underwent early (at stage Ib and II) microsurgical operation of lymphatic-venous anastomoses, with complete regression of edema and improved lymphatic drainage of the arm controlled by lymphoscintigraphy (appearance of preferential lymphatic pathways, absence of dermal back flow). Secondary arm lymphedema due to breast cancer treatment appears in 20-25% of cases till 35% when surgery is associated with radiotherapy. Lymphoscintigraphy allows to pointout alterations of lymphatic drainage before the clinical appearance of edema. Preventive physical and rehabilitative measures allows to reduce the clinical appearance of lymphedema significantly. Microsurgical operation performed precociously, at the early stages of the disease, permits to obtain the complete regression of the pathology thanks to the repair of preferential lymphatic pathways before of fibrosclerotic tissural alterations occur, which cause progressive worsening of clinical conditions, together with recurrent attacks of acute lymphangitis.


A comparative study of plasma high-density lipoprotein cholesterol in two groups of Nigerians of different socio-economic status.
Blood samples were obtained from two groups of Nigerians of different income and educational status. Group I subjects consisted of 178 males and females with high income and post-secondary-school education; and in group II were 332 males and females with low income and no secondary-school education. Plasma total cholesterol and high-density lipoprotein (HDL) cholesterol were determined in all samples. There was no significant increase in the mean plasma total cholesterol levels in group II subjects after the age of 20 years but the increase in the group I subjects was only significant in the males. The mean HDL cholesterol levels did not increase with age in both groups who were more than 20 years old. Group I males and females had significantly higher mean levels of plasma total and HDL cholesterol than the group II subjects. The female subjects in both groups had significantly higher mean plasma HDL cholesterol than their male counterparts. The mean ratios of HDL: total cholesterol for group I females were significantly higher than the mean for group I males only and not significantly different from values for group II subjects.


Multiscale modelling of relationships between protein classes and drug behavior across all diseases using the CANDO platform.
We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery.


Bevacizumab eye drop treatment stimulates tear secretion in rats through changes in VEGF and NGF lacrimal gland levels.
VEGF and NGF are known to modulate corneal healing, neovascularisation and tear secretion. While a VEGF-NGF cross talk has been recently shown to modulate corneal healing in rats, it is not known whether it also plays a role in the regulation of lacrimal function. In this study we aim to investigate the effects of anti-VEGF eye drop treatment on lacrimal gland function and on the local expression of VEGF and NGF in rats. Tear function was measured in 3 months old rats by modified Schirmer test at baseline and after 3 weeks of topical anti-VEGF eye drop treatment. Whole lacrimal glands from rats were removed after treatment and analysed by ELISA for VEGF and NGF levels. To investigate if the effects of anti-VEGF were mediated by changes in the NGF-pathway, we repeated the experiments in RCS rats, a strain with NGF-pathway impairment associated with decreased tear flow. After topical treatment with anti-VEGF eye drops, an increase in tear secretion was observed in both wild-type and RCS rats. A significant decrease of VEGF levels was also observed in lacrimal glands of both RCS and SD rats, accompanied by a significant increase in NGF levels. Inhibition of VEGF at the ocular surface in rats results in changes of tear function and lacrimal gland levels of VEGF and NGF. Further studies on the VEGF/NGF cross-talk at the ocular surface may expand our knowledge on the pathogenesis of several diseases characterized by tear dysfunction.


Cardiac Magnetic Resonance Tissue Characterization in Ischemic Cardiomyopathy.
Ischemic cardiomyopathy (ICM) is one of the most common causes of congestive heart failure. In patients with ICM, tissue characterization with cardiac magnetic resonance imaging (CMR) allows for evaluation of myocardial abnormalities in acute and chronic settings. Myocardial edema, microvascular obstruction (MVO), intracardiac thrombus, intramyocardial hemorrhage, and late gadolinium enhancement of the myocardium are easily depicted using standard CMR sequences. In the acute setting, tissue characterization is mainly focused on assessment of ventricular thrombus and MVO, which are associated with poor prognosis. Conversely, in chronic ICM, it is important to depict late gadolinium enhancement and myocardial ischemia using stress perfusion sequences. Overall, with CMR's ability to accurately characterize myocardial tissue in acute and chronic ICM, it represents a valuable diagnostic and prognostic imaging method for treatment planning. In particular, tissue characterization abnormalities in the acute setting can provide information regarding the patients that may develop major adverse cardiac event and show the presence of ventricular thrombus; in the chronic setting, evaluation of viable myocardium can be fundamental for planning myocardial revascularization. In this review, the main findings on tissue characterization are illustrated in acute and chronic settings using qualitative and quantitative tissue characterization.


Sealing furcation perforations with silver glass ionomer cement: an in vitro evaluation.
Furcation perforations sealed with silver glass ionomer cement (Chelon Silver) were evaluated in vitro compared with amalgam. Access cavities were prepared in 25 extracted human molar teeth. The coronal orifices of the root canals were sealed with amalgam and varnish. Naturally occurring coronal leakage through the intact pulp chamber floor was determined quantitatively for each tooth, using a modified fluid transport model, under pressure of 1.2 Atm. Each tooth was then disconnected from the system, perforated at the furcation, and the perforation sealed with either Chelon Silver (10 teeth) or amalgam (10 teeth); five remaining teeth served as a negative control. After incubation for 24 h at 37 degrees C in 100% humidity, teeth were reconnected to the modified fluid transport system, and coronal leakage under pressure was evaluated at 1, 2, 6, 15, and 24 h. Leakage through each tooth was compared with that of its own intact pulp chamber floor before perforation and the groups compared with each other. No significant difference was found between the mean leakage of the intact pulp chamber floors of the two groups. Chelon Silver had a significantly better sealing ability than amalgam (p < 0.01): leakage rate of 0.007 and 0.017 microliter/min, respectively. It is concluded that Chelon Silver could be an adequate sealer for furcation perforations.


Improvement in insulin absorption into gastrointestinal epithelial cells by using molecularly imprinted polymer nanoparticles: Microscopic evaluation and ultrastructure.
A molecularly imprinted polymer nanoparticle (MIP) was prepared by integrating a mixed functional monomer into a highly cross-linked polymer. The nanosized insulin as a template transferred into the binding cavities, anchored functional monomer(s) that the insulin structure formed within free space of the molecular size region by MIP nanoparticles. The oral administration with the insulin-loaded MIP resulted in higher fluorescence intensity of rhodamine-labeled insulin into the epithelial cells. We observed the correlation between the lipophilic domains of dye over the affected areas of sites with the interplay of the intestinal epithelial layer on the different intestinal sections. And, the detection with guinea pig anti-insulin antibody followed by goat anti-guinea pig antibody clearly elicited the efficient insulin function in the necessary biological milieu. The root mean square roughness of the MIP indicated difference of the surface density, significantly lower compared with the polymer attributed to the protein-mucin uptake that efficiently promoted the insulin penetration. Eventually electron microscopy data of the conjugated biotin-gold nanoparticles showed the transport of insulin across the intestinal epithelium via transcellular pathway, and the development of the pancreatic β cell in the streptozocin-induced diabetic rats. Histopathological observation exhibited no obvious toxic effect after orally treated with MIP loaded insulin (100mg/kg) daily for 14days compared to control group. The use of an insulin-loaded MIP was proven to be an effective therapeutic protein delivery through transmucosal oral route.


Supporting public health priorities: recommendations for physical education and physical activity promotion in schools.
Physical activity (PA) provides numerous physiological and psychosocial benefits. However, lifestyle changes, including reduced PA opportunities in multiple settings, have resulted in an escalation of overweight and obesity and related health problems. Poor physical and mental health, including metabolic and cardiovascular problems is seen in progressively younger ages, and the systematic decline in school PA has contributed to this trend. Of note, the crowded school curriculum with an intense focus on academic achievement, lack of school leadership support, funding and resources, plus poor quality teaching are barriers to PA promotion in schools. The school setting and physical educators in particular, must embrace their role in public health by adopting a comprehensive school PA program. We provide an overview of key issues and challenges in the area plus best bets and recommendations for physical education and PA promotion in the school system moving forward.


Retrospective analysis of anthropometric and fitness characteristics associated with long-term career progression in Rugby League.
The current study retrospectively investigated the differences in anthropometric and fitness characteristics of junior rugby league players selected onto a talent identification and development (TID) programme between long-term career progression levels (i.e., amateur, academy, professional). Retrospective design. Former junior rugby league players (N=580) selected to a TID programme were grouped according to their career progression level. Anthropometric (height, sitting height, body mass and sum of four skinfolds), maturational and fitness (power, speed, change of direction speed and estimated V̇O2max) assessments were conducted at 13-15 years. Multivariate analysis of covariance (MANCOVA) analyzed differences between career progression levels controlling for chronological age. 57.1% and 12.1% of players selected to the TID programme progressed to academy and professional levels in rugby league, respectively. Sum of four skinfolds (η(2)=0.03), vertical jump (η(2)=0.02), 10 m (η(2)=0.02), 20 m (η(2)=0.02), 30 m (η(2)=0.02), and 60 m (η(2)=0.03) speed, agility 505 left (η(2)=0.06), agility 505 right (η(2)=0.05) and estimated V̇O2max (η(2)=0.03) were superior within junior players who progressed to professional compared to amateur levels. No significant differences were identified between future academy and professional players for any measure. Findings suggest that lower sum of four skinfolds and advanced fitness characteristics within junior (13-15 years) rugby league players may partially contribute to long-term career progression. Therefore, TID programmes within rugby league should aim to assess and develop body composition and fitness characteristics, especially change of direction speed. However, TID programmes should also consider technical, tactical and psycho-social characteristics of junior rugby league players that may be important for long-term career progression.


Neutrophil- and glutathione-mediated hepatotoxicity of alpha-naphthylisothiocyanate.
In summary, both glutathione and blood neutrophils contribute to ANIT hepatotoxicity. Glutathione contributes by virtue of its ability to form a reversible S-conjugate with ANIT that is critical in shuttling ANIT into bile. Where it is released in large and probably toxic concentrations. The possibility remains that this conjugate may be bioactivated by secondary mechanisms, but no evidence for a toxic glutathionyl conjugate of ANIT currently exists. Neutrophils and platelets both appear to play important roles in ANIT hepatotoxicity. The role of platelets is currently unknown, but studies in vitro raise the possibility that neutrophils may be activated during ANIT exposure to release cytotoxic proteases that cause injury to target cells. Although ANIT activates neutrophils in vitro, the mechanisms by which neutrophils are recruited into the periportal region and activated in vivo remain unknown.


Shipping of therapeutic somatic cell products.
Shipment of therapeutic somatic cells between a current good manufacturing practice (cGMP) facility and a clinic or between different cGMP facilities requires validated standard operating procedures (SOP). Under National Heart Lung & Blood Institute (NHLBI) sponsorship, the Production Assistance for Cellular Therapies (PACT) group conducted a validation study for the shipping SOP it has created, including shipments of cryopreserved somatic cells, fresh peripheral blood specimens and apheresis products. Comparisons of pre- and post-shipped cells and cell products at the three participating facilities included measurements of viability, phenotypic profiles and cellular functions. The data were analyzed at the University of Pittsburgh Biostatistics Facility. No consistent shipping effects on cell viability, phenotype or functions were detected for cryopreserved and shipped peripheral blood mononuclear cells (PBMC), monocytes, immature dendritic cells (iDC), NK-92 or cytotoxic T cells (CTL). Cryopreserved mesenchymal stromal cells (MSC) had a significantly decreased viability after shipment, but this effect was in part because of inter-laboratory variability in the viable cell counts. Shipments of fresh peripheral blood and apheresis products for the generation of CTL and dendritic cells (DC), respectively, had no significant effects on cell product quality. MSC were successfully generated from fresh bone marrow samples shipped overnight. This validation study provides a useful set of data for guiding shipments of therapeutic somatic cells in multi-institutional clinical trials.


Mice lacking the Na+/H+ exchanger 2 have impaired recovery of intestinal barrier function.
Ischemic injury induces breakdown of the intestinal barrier. Recent studies in porcine postischemic tissues indicate that inhibition of NHE2 results in enhanced recovery of barrier function in vitro via a process involving interepithelial tight junctions. To further study this process, recovery of barrier function was assessed in wild-type (NHE2(+/+)) and NHE2(-/-) mice in vivo and wild-type mice in vitro. Mice were subjected to complete mesenteric ischemia in vivo, after which barrier function was measured by blood-to-lumen mannitol clearance over a 3-h recovery period or measurement of transepithelial electrical resistance (TER) in Ussing chambers immediately following ischemia. Tissues were assessed for expression of select junctional proteins. Compared with NHE2(+/+) mice, NHE2(-/-) mice had greater intestinal permeability during the postischemic recovery process. In contrast to prior porcine studies, pharmacological inhibition of NHE2 in postischemic tissues from wild-type mice also resulted in significant reductions in TER. Mucosa from NHE2(-/-) mice displayed a shift of occludin and claudin-1 expression to the Triton-X-soluble membrane fractions and showed disruption of occludin and claudin-1 localization patterns following injury. This was qualitatively and quantitatively recovered in NHE2(+/+) mice compared with NHE2(-/-) mice by the end of the 3-h recovery period. Serine phosphorylation of occludin and claudin-1 was downregulated in NHE2(-/-) postischemia compared with wild-type mice. These data indicate an important role for NHE2 in recovery of barrier function in mice via a mechanism involving tight junctions.


A comparison of three dosage regimens of sodium stibogluconate in the treatment of visceral leishmaniasis in Kenya.
A prospective randomized trial of three dosage regimens of sodium stibogluconate (Pentostam; Wellcome Foundation, London) to treat visceral leishmaniasis was conducted. Previously untreated patients were randomized to receive 31 doses of sodium stibogluconate (10 mg Sb/kg of body weight per dose) administered once daily for 31 days (group A), every 12 hr for 15 days (group B), or every 8 hr for 10 days (group C). Of the 29 patients who completed treatment, seven of 10 in group B and all of the patients in groups A and C responded to treatment and remained well for one year. One patient in group B failed to respond to treatment, and two others in group B initially responded to treatment but relapsed six weeks after discharge. None of the treatment regimens was toxic. Parasites disappeared from splenic aspirates most quickly and hemoglobin levels rose most rapidly in patients receiving sodium stibogluconate every 8 hr. Treatment of visceral leishmaniasis in Kenya with sodium stibogluconate at a dose of 10 mg Sb/kg every 8 hr for 10 days appears to be a safe alternative to conventional treatment. Its efficacy should be confirmed in a larger number of patients.


Gypensapogenin H from hydrolyzate of total Gynostemma pentaphyllum saponins induces apoptosis in human breast carcinoma cells.
Gypensapogenin H (Gyp H) is a novel dammarane-type triterpene, isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. Our previous work demonstrated that Gyp H exhibited potent growth inhibitory effects on tumor cells. It significantly inhibited the growth of human breast cancer cells (MDA-MB-231), while having low toxicity to normal human breast epithelial cells, MCF-10a. Further mechanistic study demonstrated that Gyp H decreased survival, inhibited proliferation, migration, induced apoptosis and led to cell cycle arrest. For the MDA-MB-231 cell lines, Gyp H increased expression of P21, Bax and cytochrome c, induced PARP cleavage and activated caspases. Gyp H also reduced expression of CDK2/4, CyclinD1, E2F1 and Bcl2, which associated with the cell cycle arrest. Thus, our finding may be useful for understanding the mechanism of action of Gyp H on breast cancer cells and suggest that Gyp H would be a leading agent for the treatment of breast cancer.


An Adaptive Array Excitation Scheme for the Unidirectional Enhancement of Guided Waves.
Control over the direction of wave propagation allows an engineer to spatially locate defects. When imaging with longitudinal waves, time delays can be applied to each element of a phased array transducer to steer a beam. Because of the highly dispersive nature of guided waves (GWs), this beamsteering approach is suboptimal. More appropriate time delays can be chosen to direct a GW if the dispersion relation of the material is known. Existing techniques, however, need a priori knowledge of material thickness and acoustic velocity, which change as a function of temperature and strain. The scheme presented here does not require prior knowledge of the dispersion relation or properties of the specimen to direct a GW. Initially, a GW is generated using a single element of an array transducer. The acquired waveforms from the remaining elements are then processed and retransmitted, constructively interfering with the wave as it travels across the spatial influence of the transducer. The scheme intrinsically compensates for the dispersion of the waves, and thus can adapt to changes in material thickness and acoustic velocity. The proposed technique is demonstrated in simulation and experimentally. Dispersion curves from either side of the array are acquired to demonstrate the scheme's ability to direct a GW in an aluminum plate. The results show that unidirectional enhancement is possible without a priori knowledge of the specimen using an arbitrary pitch array transducer. The experimental results show a 34-dB enhancement in one direction compared with the other.


Efficacy and safety of erdosteine in the treatment of chronic rhinosinusitis with nasal polyposis - a pilot study.
Erdosteine was originally developed as a mucolytic agent. It is a multimechanism substance with anti-bacterial, anti-oxidant, and most importantly anti-inflammatory effects. Given similar mechanisms of action (suppression of cytokines, including tumor necrosis factor α), it could become a reasonable alternative to currently used treatments with macrolides or steroids. To assess efficacy and safety of erdosteine in the treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP). A prospective non-interventional post-authorisation study comparing patients treated with erdosteine only or the combination of erdosteine and nasal corticosteroid spray for CRSwNP. The end-points were pre- and post-treatment changes in endoscopic score and subjective evaluation of CRSwNP related symptoms using a 22-item Sinonasal Outcome Test questionnaire. Patients underwent nasal endoscopy and filled the questionnaire before and after the treatment. No patient experienced any adverse effect during the study. A comparison of pre- and post-treatment endoscopic findings and questionnaire values revealed significant reduction in both patient groups, with a significantly better response in the erdosteine only group. Based on this pilot study, erdosteine seems effective in the treatment of CRSwNP and might become a reasonable alternative to currently used medication. The therapeutical role of erdosteine needs to be further assessed.


Activation of neutrophil superoxide production by concanavalin A can occur at low levels of intracellular ionized calcium.
The effect of concanavalin A (Con A) on the concentration of ionized intracellular calcium [( Cai++]) in human granulocytes (PMN) was monitored using the fluorescent calcium indicator and chelator, Quin2. The addition of Con A to PMN resulted in a rise in [Cai++] that was markedly enhanced by the presence of Ca++ in the external buffer. The onset of the increment in [Cai++] preceded the onset of O2- production. The rise in [Cai++] induced by Con A is not transient, with a new, higher steady-state level of [Cai++] being attained within five minutes. The addition of alpha-methylmannoside (alpha-MM) one minute after Con A resulted in the return of [Cai++] to the original baseline level and the cessation of O2- production. The addition of a second stimulus (such as arachidonic acid) to these cells resulted in a second increment in [Cai++] and the return of O2- production. Thus the rise in [Cai++] induced by Con A is tightly coupled to the activation, inactivation, and reactivation of the O2- generating system by Con A. Further experiments were undertaken to assess the possible requirement for the rise in [Cai++] in the activation of PMN by Con A. PMN could be depleted of Cai++ by loading with Quin2 in the absence of extracellular Ca++. These Ca++- depleted PMN can be induced to produce O2- after treatment with PMA but not with Con A. The addition of Ca++ to Ca++ -depleted PMN results in a return of [Cai++] to the normal resting level of Ca++ -replete PMN. The time required to return to baseline is a function of the concentration of intracellular Quin2. The addition of Ca++ to Ca++ -depleted, Con A-treated PMN results in the elevation of [Cai++] and the production of O2-. Over a tenfold range of intracellular Quin2 concentration, the onset of O2- production always occurred at [Cai++] that were less than the normal resting level. Thus, activation of the O2- generating system by Con A can occur at [Cai++] which are much lower than the incremental level induced by Con A in Ca++ -replete PMN. Supporting this is the observation that only a very small increment in [Cai++] is induced by Con A in PMN cytoplasts, even though Con A could induce O2- production in the Quin2-loaded cytoplasts.(ABSTRACT TRUNCATED AT 400 WORDS)


Tetrodotoxin-sensitive uptake of ions and water byslices of rat brain in vitro.
1. Under certain conditions the processes that bring about increased Na(+) influx and water uptake into rat brain slices have a tetrodotoxin-sensitive component. 2. Incubation of slices in the absence of glucose, or in the presence of ouabain (0.1mm), protoveratrine (10mum) or electrical stimuli, leads to increased uptakes of water and Na(+) that are partially suppressed by tetrodotoxin (3mum). 3. The increased water uptake and Na(+) influx due to the presence of 30mum-2,4-dinitrophenol or of 100mm-potassium chloride are unaffected by tetrodotoxin. 4. The additional presence of 27mm-potassium chloride diminishes, or abolishes, the inhibitory effects of tetrodotoxin on the increased uptakes of water and Na(+) found on incubation in the absence of glucose or in the presence of protoveratrine. 5. Ouabain increases Na(+) influx into caudate nuclei from rat brain and this process is suppressed by tetrodotoxin. Ouabain does not increase water uptake in the caudate nuclei. 6. Diminution of Na(+) influx in slices due to tetrodotoxin is not accompanied by an equal efflux of K(+). 7. It is concluded that glial-cell membranes are permeable to K(+) and Cl(-) and, as a consequence, when K(+) is released from neurons in association with action potentials it, together with water, moves into the glial cells. The major consequence of K(+) (and Cl(-)) permeability of the glial cell is therefore a buffering of the extracellular K(+) concentration. 8. l-Glutamate presents an anomalous feature that may indicate that its effects are not restricted to neurons. 9. Calculations are made of the increase of K(+) flux into the glia in the presence of ouabain or of protoveratrine or in the absence of glucose or on application of electrical impulses.


Breaking Therapeutic Inertia in Type 2 Diabetes: Active Detection of In-Patient Cases Allows Improvement of Metabolic Control at Midterm.
Type 2 diabetes (T2D) exists in 25-40% of hospitalized patients. Therapeutic inertia is the delay in the intensification of a treatment and it is frequent in T2D. The objectives of this study were to detect patients admitted to surgical wards with hyperglycaemia (HH; fasting glycaemia > 140 mg/dL) as well as those with T2D and suboptimal chronic glycaemic control (SCGC) and to assess the midterm impact of treatment modifications indicated at discharge. A total of 412 HH patients were detected in a period of 18 months; 86.6% (357) had a diagnosed T2D. Their preadmittance HbA1c was 7.7 ± 1.5%; 47% (189) had HbA1c ≥ 7.4% (SCGC) and were moved to the upper step in the therapeutic algorithm at discharge. Another 15 subjects (3.6% of the cohort) had T2D according to their current HbA1c. Ninety-four of the 189 SCGC patients were evaluated 3-6 months later. Their HbA1c before in-hospital-intervention was 8.6 ± 1.2% and 7.5 ± 1.2% at follow-up (P < 0.004). Active detection of hyperglycaemia in patients admitted in conventional surgical beds permits the identification of T2D patients with SCGC as well as previously unknown cases. A shift to the upper step in the therapeutic algorithm at discharge improves this control. Hospitalization is an opportunity to break therapeutic inertia.


Acute dosing of vortioxetine strengthens event-related brain activity associated with engagement of attention and cognitive functioning in rats.
Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10mg/kg) in rats performing an auditory oddball (deviant target) task. We investigated neuronal activity in target vs non-target tone responses in vehicle-treated animals using electroencephalographic (EEG) recordings. Furthermore, we characterized task performance and EEG changes in target tone responses of vortioxetine vs controls. Quantification of event-related potentials (ERPs) was supplemented by analyses of spectral power and inter-trial phase-locking. The assessed brain regions included prelimbic cortex, the hippocampus, and thalamus. As compared to correct rejection of non-target tones, correct target tone responses elicited increased EEG power in all regions. Additionally, neuronal synchronization was increased in vehicle-treated rats during both early and late ERP responses to target tones. This indicates a significant consistency of local phases across trials during high attentional load. During early sensory processing, vortioxetine increased both thalamic and frontal synchronized gamma band activity and EEG power in all brain regions measured. Finally, vortioxetine increased the amplitude of late hippocampal P3-like ERPs, the rodent correlate of the human P300 ERP. These findings suggest differential effects of vortioxetine during early sensory registration and late endogenous processing of auditory discrimination. Strengthened P3-like ERP response may relate to the pro-cognitive profile of vortioxetine in rodents. Further investigations are warranted to explore the mechanism by which vortioxetine increases network synchronization during attentive and cognitive processing.


Endovascular treatment of ophthalmic segment aneurysms with Guglielmi detachable coils.
To evaluate the safety and efficacy of endovascular treatment of ophthalmic segment aneurysms with Guglielmi detachable coils (GDCs), as well as the primary indications for such treatment. We conducted a prospective study of 26 patients with 28 aneurysms of the ophthalmic segment in whom treatment with GDCs was attempted. Anatomic results were measured by statistical analysis of variance for such factors as age, sex, presence of subarachnoid hemorrhage, anatomic type (ophthalmic or superior hypophyseal), size of aneurysmal sac, and width of aneurysmal neck. Clinical evaluation and control angiography were performed at 6 and 18 months. Overall, complete occlusion was obtained in 14 aneurysms (50%) and small residual necks were left in 11 aneurysms (39%). Three treatment attempts failed (11%). Complete occlusion was obtained in 76% of small-necked aneurysms as opposed to 9% of aneurysms with a large neck. The best predictor of anatomic result was the size of the aneurysmal neck. Complete occlusion was obtained in 85% of superior hypophyseal aneurysms of the paraclinoid variant. One permanent complication was related to treatment. Endovascular treatment with GDCs appears to be a safe and efficient alternative approach for ophthalmic segment aneurysms, especially for paraclinoid variants of superior hypophyseal aneurysms, which tend to have a small neck.


Clinical pattern of recurrent herpes simplex keratitis.
To document the clinical pattern in recurrent herpes simplex disease. Eyes with clinically documented pattern of corneal manifestation on more than one occasion were analysed. For each eye recruited, the clinical pattern of the disease at each recurrence of herpes simplex corneal disease, age, disease-free intervals, triggering factors, laterality and steroid abuse were noted and evaluated. For an average follow up of 6.9 years, a recurrence rate of 0.6 episodes per year was observed. Disease-free intervals of 75.7 months for epithelial herpes simplex disease was considerably longer than the 21.3 months observed for stromal disease. Clinical pattern of recurrence was of the same type following first episode of disciform keratitis, epithelial keratitis and endothelitis in 84%, 72.7%, and 75% of the eyes respectively. Herpes simplex disease often recurs in the same manifest clinical pattern as the first episode. This clinical evidence provides additional support for the potential role of herpes simplex biotypes in determining manifestation of clinical disease pattern.


ERP evidence for the influence of scene context on the recognition of ambiguous and unambiguous objects.
We are used to seeing objects in specific settings, and in association with other related objects. This contextual information allows for fast and efficient object recognition and influences brain-related processes. The influence of scene context has been studied using event-related potentials (ERPs) in order to further our understanding of the underlying brain mechanisms. Current ERP studies have focused on effects related to the incongruity between unambiguous objects and their scenes, rather than the specific influence of a congruent scene. The present study sought to examine ERPs associated with the beneficial influence of scene context on object recognition. This influence was examined using ambiguous objects that required a congruent scene in order to be recognized, as well as unambiguous objects, to determine whether scene processing occurs even when it is unnecessary for recognizing the object. Twenty healthy subjects were instructed to indicate whether they recognized, had a vague idea, or did not recognize target objects that appeared within congruent and neutral scenes. ERPs from 250 to 1000 ms, including the N300 and N400, were more positive at anterior sites and more negative at posterior sites, when objects appeared in congruent scenes as opposed to when they appeared in neutral scenes, with a larger effect seen for ambiguous objects. Upon further examination, the results showed that the ERPs to ambiguous objects became similar to those of unambiguous objects when they appeared in congruent contexts. These findings indicated that a congruent context exerted its influence by reducing the ambiguity of objects.


Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics.
Peripartum cardiomyopathy is defined as left ventricular dilation and failure, first developing during the third trimester of pregnancy or in the first 6 months postpartum. In an effort to characterize this syndrome in a middle class population, 14 consecutive patients with peripartum cardiomyopathy underwent a detailed history and physical examination, right heart catheterization, M-mode and two-dimensional echocardiography, radionuclide ventriculography and right ventricular endomyocardial biopsy. These patients were then observed with sequential noninvasive studies to determine prognostic indicators. Eight (57%) of these 14 patients were primiparous and an equal number first presented with heart failure concomitant with or immediately before the onset of labor. When these women were compared with 55 patients with idiopathic dilated cardiomyopathy, only mean age at onset of symptoms (28.7 +/- 5.7 versus 48.2 +/- 13.6 years, p less than 0.001) and symptom duration (4.1 +/- 7.7 versus 19.0 +/- 18.4 months, p less than 0.001) differed between the groups. There was no difference in ventricular arrhythmia, left ventricular chamber size, ejection fraction or hemodynamics. Myocyte histologic findings were similar; however, myocarditis was identified in 29% of patients with peripartum cardiomyopathy and in only 9% of those with idiopathic dilated cardiomyopathy. In all patients with peripartum cardiomyopathy and myocarditis, the myocardial biopsy was performed within 1 week of onset of symptoms. Seven (50%) of the patients with peripartum cardiomyopathy had dramatic improvement within 6 weeks of follow-up, and 6 (43%) died.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of Potassium Fertilizer Rates on Soybean Looper (Lepidoptera: Noctuidae) Development.
Potassium (K) has an important impact on physiological and biochemical processes in plants. Soybean, Glycine max (L.) Merrill, requires high K availability for optimal yield. However, changes in nutrient availability in plants may also affect herbivore population size and/or development. Soybean looper, Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae), is one of the most destructive pests of soybean in the southern United States. In this study, we evaluated the effects of different K fertilization rates on soybean looper development, soybean seed weight, and soybean seed nutritional quality. Soybean plants were supplied with six different rates of K fertilizer (0, 33.6, 67.3, 100.9, 134.5, and 168.1 kg/ha as K2O). Soybean leaves were sampled at R1, R3, R5, and R6 stages and fed to soybean looper in laboratory bioassays. Soybean looper mortality, fecundity, and fertility were not significantly affected by feeding on leaf tissues of soybean treated with different potassium fertilizer rates. However, soybean looper consumed more leaf tissue and spent less time completing larval development when fed on foliage from treatments of 134.5 and 168.1 kg/ha. Pupal weight significantly increased at 134.5 and 168.1 kg/ha. There was no significant difference in percentage of protein, oil, and fiber in soybean seeds among six K fertilizer rates. Percentage of K in soybean seeds and 100 seed weight were significantly enhanced at 168.1 kg/ha. Nitrogen (N) content of foliage was not affected by applying K fertilizer at different rates. Our results indicate that higher K fertilizer rates can enhance soybean seed weight but also facilitate soybean looper development.


Sedated suture adjustment in children undergoing adjustable suture strabismus surgery.
To study methods and adverse events of postoperative, sedated suture adjustment after strabismus surgery in the post-anesthesia care unit (PACU). We reviewed the postoperative experience of all children ≤18 years of age undergoing adjustable suture strabismus surgery at Boston Children's Hospital over a 3-year period. Time in the hospital, adverse events, and surgical outcomes were reviewed to evaluate safety and healthcare resource utilization. Of 356 patients, 113 required suture adjustment in the PACU, including 24 adjusted while awake and 89 adjusted under sedation. For sedation, sequential boluses of propofol were administered until adjustment was complete. Complete data from the sedated adjustment was available in 76 patients. The median initial bolus was 30 mg; the median total propofol rate was 273 mcg/kg/min. Twelve patients (16%) required only a single bolus of propofol. Of remaining 64 patients, median time from initial to final propofol dose was 7 minutes. Median anesthesiologist time in the PACU was 13 minutes. In the sedated adjustment group, there were no clinically significant adverse events, and the pain score never exceeded 6 (of a possible 10). Median duration of PACU stay was shortest in the group not requiring adjustment. Sedated suture adjustment allows for fine-tuning of postoperative binocular alignment in children and uncooperative adults. No adverse events were observed in our study group, but the procedure does increase the time patients spend in the hospital. This work will inform disclosure of risks and benefits of sedated adjustment while allowing for more accurate assessment of the cost and quality of adjustable sutures in children.


A Dynamic Optical Signal in a Nocturnal Moth.
The wings of butterflies and moths generate some of the most spectacular visual displays observed in nature [1-3]. Particularly striking effects are seen when light interferes with nanostructure materials in the wing scales, generating bright, directional colors that often serve as dynamic visual signals [4]. Structural coloration is not known in night-flying Lepidoptera, yet here we show a highly unusual form of wing coloration in a nocturnal, sexually dimorphic moth, Eudocima materna (Noctuidae). Males feature three dark wing patches on the dorsal forewings, and the apparent size of these patches strongly varies depending on the angle of the wing to the viewer. These optical special effects are generated using specialized wing scales that are tilted on the wing and behave like mirrors. At near-normal incidence of light, these "mirror scales" act as thin-film reflectors to produce a sparkly effect, but when light is incident at ∼20°-30° from normal, the reflectance spectrum is dominated by the diffuse scattering of the underlying, black melanin-containing scales, causing a shape-shifting effect. The strong sexual dimorphism in the arrangement and architecture of the scale nanostructures suggests that these patterns might function for sexual signaling. Flickering of the male's wings would yield a flashing, supernormal visual stimulus [5] to a viewer located 20°-30° away from the vertical, while being invisible to a viewer directly above the animal. Our findings reveal a novel use of structural coloration in nature that yields a dynamic, time-dependent achromatic optical signal that may be optimized for visual signaling in dim light.


Intact active bone transplantation synergizes with anti-CD40 ligand therapy to induce B cell tolerance.
Blockade of T cell costimulatory pathways can result in the prolongation of allograft survival through the suppression of Th1 responses; however, late allograft rejection is usually accompanied by an emerging allograft-specific humoral response. We have recently determined that intact active bone (IAB) fragments transplanted under the kidney capsule can synergize with transient anti-CD40 ligand (CD40L) treatment to induce robust donor-specific allograft tolerance and suppress the alloantibody response. In this study, we take advantage of the ability of galactosyltransferase-deficient knockout (GT-Ko) mice to respond to the carbohydrate epitope, galactose-alpha1,3-galactose (Gal), to investigate whether IAB plus transient anti-CD40L therapy directly tolerize B cell responses. GT-Ko mice tolerized to Gal-expressing C3H hearts and IAB plus transient anti-CD40L therapy were challenged with pig kidney membranes that express high levels of Gal. The anti-Gal IgM and IgG responses were significantly suppressed in IAB-tolerant mice compared with controls, while the non-Gal anti-pig Ab responses were comparable. The anti-pig T cell cytokine response (IFN-gamma and IL-4) was comparable in IAB-tolerant and control mice. The tolerant state for the anti-Gal IgM response could be reversed with repeated immunization, whereas the tolerant state for the IgG response was robust and resisted repeated immunization. These observations provide an important proof-of-concept that adjunct therapies can synergize with anti-CD40L Abs to tolerize B cell responses independent of their effects on T cells. This model, which does not require mixed chimerism, provides a unique opportunity for investigating the mechanism of peripheral tolerance in a clinically relevant population of carbohydrate-specific B cells.


Inhibition of in vitro growth of enteropathogens by new Lactobacillus isolates of human intestinal origin.
Three human Lactobacillus strains, coded B21060, B21070 and B21190, have recently been isolated. The strains show a series of features (acid and bile resistance, adhesion to various types of mucosal cell) which make them particularly promising for the preparation of probiotic products. In the present study, the ability of the strains to inhibit the growth of pathogens in coculture was investigated. Lactobacilli were incubated simultaneously or after one overnight growth with enterotoxigenic Escherichia coli, Salmonella enteritidis or Vibrio cholerae. After 24 and 48 h, bacterial counts of the pathogens and of the lactobacilli were performed. The results showed that these Lactobacillus strains inhibited the in vitro growth of E. coli and S. enteritidis under both conditions. Moreover, a cumulative effect was observed for mixtures of lactobacilli. In contrast, no significant inhibition of Vibrio cholerae growth was observed, provided that the pH of the medium was kept constant. The presence of the pathogens did not affect the growth of the Lactobacillus strains. Moreover, each of the Lactobacillus strains showed coaggregation ability with two pathogenic E. coli strains, namely ATCC 25922 and ATCC 35401.


Automated total kidney volume measurements in pre-clinical magnetic resonance imaging for resourcing imaging data, annotations, and source code.
The objective of this study was to validate a fully automated total kidney volume measurement method for pre-clinical rodent trials that is fast, accurate, reproducible, and to provide these resources to the research community. Rodent studies that involve imaging are crucial for monitoring treatment efficacy in diseases such as polycystic kidney disease. Previous studies utilize manual or semi-automated segmentations, which are time consuming and potentially biased. To develop our automated system, a total of 150 axial magnetic resonance images (MRI) from a variety of mouse models were manually segmented and used to train/validate an automated algorithm. To test the longitudinal application of the model, four mutant and four wild-type mice were imaged sequentially over three to twelve weeks via MRI. Segmentations of the kidneys (excluding the renal pelvis) were generated by the automated method and two different readers, with one reader repeating the measurements. Similarity metrics and longitudinal analysis were calculated to assess the performance of the automated compared to the manual methods. The automated approach required no user input, besides a final visual quality control step. Similarity metrics of the automated method versus the manual segmentations were on par with inter- and intra-reader comparisons. Thus, our fully automated approach described here can be safely used in longitudinal, pre-clinical trials that involve the segmentation of rodent kidneys in T2-weighted MRIs.


Liver cell dysplasia and hepatocellular carcinoma in non-A, non-B hepatitis.
Liver cell dysplasia (LCD) is a premalignant cytologic change of hepatocytes that has been statistically linked to cirrhosis, hepatocellular carcinoma (HCC), and chronic liver disease related to hepatitis B virus. The relationship of LCD to non-A, non-B (NANB) hepatitis is currently unknown. We studied liver biopsy and surgical resection specimens from 36 patients with NANB hepatitis, and identified LCD in 17 (42.5%) of 40 specimens, most often associated with cirrhosis. Dysplasia was present in individual hepatocytes, in clusters, and in a distinctive "spreading" pattern of hepatocytes about central veins. Three patients had HCC with a predominant giant cell pattern, as well as LCD. These findings suggest that LCD and HCC should be included among the potential pathologic sequelae of NANB hepatitis.


[Disorders of eating behavior: recent research and controversial results].
The aim of this review is to provide a comprehensive profile of research developments in the field of eating disorders. Eating disorders may be defined as a multidisciplinary field, not only because diverse specialist disciplines are required for treatment, but also because the need to establish ad hoc Eating Disorders Units comprised of psychiatrists, internists, dietologists and endocrinologists has become evident. New research data, collected by use of informatics-based systems, are presented.


Allele-specific RNA imaging shows that allelic imbalances can arise in tissues through transcriptional bursting.
Extensive cell-to-cell variation exists even among putatively identical cells, and there is great interest in understanding how the properties of transcription relate to this heterogeneity. Differential expression from the two gene copies in diploid cells could potentially contribute, yet our ability to measure from which gene copy individual RNAs originated remains limited, particularly in the context of tissues. Here, we demonstrate quantitative, single molecule allele-specific RNA FISH adapted for use on tissue sections, allowing us to determine the chromosome of origin of individual RNA molecules in formaldehyde-fixed tissues. We used this method to visualize the allele-specific expression of Xist and multiple autosomal genes in mouse kidney. By combining these data with mathematical modeling, we evaluated models for allele-specific heterogeneity, in particular demonstrating that apparent expression from only one of the alleles in single cells can arise as a consequence of low-level mRNA abundance and transcriptional bursting.


Effects of dimethylaminoethanol upon life-span and behavior of aged Japanese quail.
The lysosome hypothesis of aging predicts that membrane stabilizers will extend life-span. Stabilizers containing the dimethylaminoethanol moiety (DMAE) have been reported to extend the life-span of drosophila and mice. We tested the prediction in Japanese quail (N = 15) by administering DMAE bitartrate (18.4 mg/kg/day) in the drinking water for 69 weeks, starting at 195 weeks of age. A matched control group (N = 14) received tartaric acid (4.0 mg/kg/day) in the water. Contrary to the prediction, the DMAE-treated group has a shorter life-span after start of treatment (49 weeks) than the controls (69 weeks). No significant differences between the groups were observed in body weight or daily fluid intake. Three behavioral studies were carried out on survivors at 243-249 weeks of age, namely; activity response to light-flash; sexual mounting response to a female quail; and classical conditioning of the heart rate. Aged quail differed from young-adults in changes in motor activity in response to light flashes. Aged quail appeared less responsive initially to reinforced conditioning trials and demonstrated extinction when light flash was not followed by electric shock. There were no detectable differences in latency to mount or in basal heart rate, either as a function of age or as a function of DMAE treatment.


Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions.
Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. inter-response times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.


Oxytocin receptor binding in female prairie voles: endogenous and exogenous oestradiol stimulation.
Abstract Previous studies have demonstrated that oxytocin receptors in specific nuclei of rat forebrain are regulated by gonadal steroids. The current study used in vitro receptor autoradiography to investigate the distribution and regulation of oxytocin receptors in the forebrain of the female prairie vole (Microtus ochrogaster). In contrast to rats, in female prairie voles gonadal steroid secretion and oestrus behaviour result from male chemosignal stimulation and ovulation is induced by mating. Thus, the prairie vole brain provides an opportunity for investigating links between environmental stimuli, gonadal steroids and oxytocin receptors. Using a selective oxytocin receptor ligand [(125)l]d(CH(2))(5)[Tyr(Me)(2),Tyr-NH(2) (9)]ornithine vasotocin ([(125)I]OTA), specific binding was found in several regions including the anterior olfactory nucleus, the ventromedial nucleus of the hypothalamus, the bed nucleus of the stria terminalis, the amygdala and several cortical areas. Following ovariectomy, oestradiol benzoate (10 mug) administration increased oxytocin receptor binding 100% in the anterior olfactory nucleus, but did not affect receptors in other regions. Gonadallyintact females, exposed to male chemosignals, had significant increases in both endogenous oestradiol levels and anterior olfactory nucleus oxytocin receptor binding relative to gonadally-intact females unexposed to male chemosignals. Following prolonged exposure to males with ad libitum mating, [(125)I]OTA receptor binding decreased to the levels found in unstimulated females. These results demonstrate that increases in oestrogen levels, of either exogenous or endogenous origin, can modulate oxytocin receptors in the brains of female prairie voles. In contrast to rats, oestrogen in female prairie voles appears to affect receptors in the anterior olfactory nucleus rather than the hypothalamus. We suggest that the species differences in oxytocin receptor distribution and gonadal steroid responsiveness reflect variations in reproductive physiology and possibly behaviour.


Effect of calligraphy training on hyperarousal symptoms for childhood survivors of the 2008 China earthquakes.
This study investigated the treatment effects of calligraphy therapy on childhood survivors of the 2008 Sichuan earthquakes in the People's Republic of China. In experiment 1, 129 children participated in a 30-day calligraphic training, and 81 children were controls. The Children's Revised Impact of Event Scale was adopted to assess behavioral effects. Experiment 2 involved 41 treatment subjects and 39 controls, with the same procedure as in experiment 1 except that salivary cortisol level was also measured as a physiological indicator. After 30 days of calligraphy treatment, the arousal symptoms and salivary cortisol levels in the experimental group decreased from 5.72±0.31 and 13.34±2.88 to 4.98±0.31 and 9.99±2.81, respectively. In the control group, there was not a significant decrease from pretest to post-test. In addition, the arousal scores in posttest (4.98±4.39) were significantly lower than midtest (5.71±4.14) for girls; in contrast, for boys, posttest (4.90±4.24) showed little change compared with midtest (5.04±4.36), but both were significantly lower than pretest (6.42±4.59). Calligraphy therapy was effective in reducing hyperarousal symptoms among child survivors.


An ecological approach to measuring synchronization abilities across the animal kingdom.
In this perspective paper, we focus on the study of synchronization abilities across the animal kingdom. We propose an ecological approach to studying nonhuman animal synchronization that begins from observations about when, how and why an animal might synchronize spontaneously with natural environmental rhythms. We discuss what we consider to be the most important, but thus far largely understudied, temporal, physical, perceptual and motivational constraints that must be taken into account when designing experiments to test synchronization in nonhuman animals. First and foremost, different species are likely to be sensitive to and therefore capable of synchronizing at different timescales. We also argue that it is fruitful to consider the latent flexibility of animal synchronization. Finally, we discuss the importance of an animal's motivational state for showcasing synchronization abilities. We demonstrate that the likelihood that an animal can successfully synchronize with an environmental rhythm is context-dependent and suggest that the list of species capable of synchronization is likely to grow when tested with ecologically honest, species-tuned experiments. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.


Lack of an effect of drugs acting at histamine receptors on norepinephrine-induced relaxation of porcine coronary arteries.
The effects of selective histamine receptor stimulation on relaxation to norepinephrine (NE) were determined in four sizes of spirally cut porcine coronary arteries. The four sizes of porcine coronary artery were designated very large (greater than 4.0 mm o.d.), large (1.5-2.5 mm o.d.), medium (0.8-1.2 mm o.d.), and small (less than or equal to 0.5 mm o.d.). Histamine, dimaprit, 2-pyridylethylamine, and histamine plus either mepyramine or metiamide did not alter the concentration-response curve to NE. Thus histamine receptor stimulation does not change relaxations of porcine coronary arteries to NE.


Editorial for the IJMS Special Issue on Sglt2 Inhibitors (Volume 2).
The goal of the second volume of this Special Issue was to build upon the success of the first one and to continue to highlight the ever-expanding list of pharmacological properties of the sodium/glucose co-transporter (SGLT) type 2 (SGLT2) inhibitor (SGLT2i) drug class (also known as gliflozins) [...].


Microincisional vitrectomy for retinal detachment in I-125 brachytherapy-treated patients with posterior uveal malignant melanoma.
To analyze functional and anatomical outcomes following 23/25(+) gauge microincisional pars plana vitrectomy surgery (MIVS) in patients with radiation-related retinal detachment after successful 125-iodine (I-125) brachytherapy treatment for malignant uveal melanoma. Retrospective case series of 102 consecutive eyes of 102 patients with history of uveal melanoma treated with I-125 brachytherapy that underwent MIVS at the Bascom Palmer Eye Institute. All cases were evaluated for surgical complications and local tumor control. Extended follow-up included Snellen's best-corrected visual acuity, intraocular pressure evaluation, quantitative echography, indirect ophthalmoscopy, and fundus imaging with optical coherence tomography/wide-field photography. All patients had radiation-related complications, including retinal detachment (102 eyes), vasculopathy (91 eyes), optic neuropathy (32 eyes), and/or vitreous hemorrhage (8 eyes). Sixty-seven patients had vitreoretinal traction. Average follow-up after MIVS was 19.5 months, and from plaque removal was 57.7 months. Interval from plaque to MIVS was 38.1 months. Initial visual acuity was 20/258, which improved to 20/101 at 1 month, 20/110 at 3 months, 20/116 at 6 months, and 20/113 at 12 months (P < 0.05). No eyes required enucleation. Melanoma-related mortality was 0.9% (1/102). There was no intra- or extraocular tumor dissemination, and no tumor recurrence. MIVS was effective in improving visual function and anatomy in patients with radiation-related retinal detachment. Tumors decreased in size and there was no evidence of recurrence or tumor dissemination. This combined procedure addresses the modifiable causes of visual loss in patients with previously treated malignant uveal melanoma and has the potential to enhance their visual function.


Graph-based active learning of agglomeration (GALA): a Python library to segment 2D and 3D neuroimages.
The aim in high-resolution connectomics is to reconstruct complete neuronal connectivity in a tissue. Currently, the only technology capable of resolving the smallest neuronal processes is electron microscopy (EM). Thus, a common approach to network reconstruction is to perform (error-prone) automatic segmentation of EM images, followed by manual proofreading by experts to fix errors. We have developed an algorithm and software library to not only improve the accuracy of the initial automatic segmentation, but also point out the image coordinates where it is likely to have made errors. Our software, called gala (graph-based active learning of agglomeration), improves the state of the art in agglomerative image segmentation. It is implemented in Python and makes extensive use of the scientific Python stack (numpy, scipy, networkx, scikit-learn, scikit-image, and others). We present here the software architecture of the gala library, and discuss several designs that we consider would be generally useful for other segmentation packages. We also discuss the current limitations of the gala library and how we intend to address them.


A preliminary study of bottom care effects on premature infants' heart rate and oxygen saturation.
The purposes of this study were to explore (1) the effect of buttock care (BC) on premature infant heart rate (HR) and oxygen saturation (SpO(2)), and (2) the effect of buttock lifting angle during BCs on HR and SpO(2). The study used a repeated measure design. A convenience sample of 11 premature infants in the neonatal intensive care unit (NICU) of a medical center were studied during 30 BC events. The subjects were of a gestational age of less than and 37 weeks, and postnatal age of less than one month, without known congenital abnormalities and without having been treated with sedatives during the study. Infant HR and SpO(2) were measured at a 30-second interval 10 minutes before and during, and 15 minutes after BC. Maximal lifting angles of BCs during the procedure were recorded. Based on the infant's individual responses to BC, 63.3% of BCs induced an increase in HR and a decrease in SpO(2), defined as the change in HR and SpO(2) greater than two standard deviations from the baseline. In addition, 30% of BCs resulted in cardiac decelerations. The extent of the difference found in these change patterns in HR or SpO(2) were all significant (p <.01) and their mean recovery times were longer than 10 minutes. More HR acceleration events occurred as the BC lifting angle exceeded </= 30 degrees, and more HR deceleration events were found as the angle > 30 degrees (p =.035). Buttock care can have a significant impact on premature infant physiological stability. The BC lifting angle may play an important role in HR acceleration or deceleration. Careful observation before and after BC for premature infants is recommended.


Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway.
The development of novel treatments that selectively inhibit the RAS-RAF-MAPK pathway represents a milestone in the history of melanoma treatment. BRAF mutations occur in approximately 45% of cutaneous melanomas, while mutations in NRAS occur in 15-25%. Vemurafenib was the first BRAF inhibitor to be approved in 2011, based on the results of a phase III trial (BRIM-3) that showed higher progression-free survival and overall survival compared with dacarbazine chemotherapy in metastatic BRAF-mutated melanoma. Dabrafenib, another BRAF inhibitor, has shown similar results and was approved in 2013. Preclinical studies suggested that another novel group of agents, the MEK inhibitors, showed stronger inhibition of both mutated BRAF and NRAS cell cultures than vemurafenib. Trametinib was the first MEK inhibitor approved in 2014, both as a single agent and in combination with dabrafenib for the treatment of advanced BRAF-mutated melanoma. Other MEK inhibitors are also in development. Concomitant inhibition of both MEK and BRAF has shown more durable and greater tumor response than BRAF monotherapy, by overcoming the multiple genetic mechanisms of escape. Combined therapy prevents the development of acquired resistance as well as decreasing cutaneous toxicity secondary to paradoxical activation of the MAPK pathway induced by BRAF inhibitors. Various combinations of BRAF and MEK inhibitors have shown promising results. Moreover, triple combination therapies involved other agents with novel mechanisms of action are also being evaluated. These and other combination strategies involving immunotherapies and targeted therapies offer the hope of improving outcomes beyond those already achieved with anti-BRAF treatments.


Anti-HLA antibodies and pulmonary valve allograft function after the Ross procedure.
Rejection is a plausible cause of failure of allograft valves, but has not been demonstrated unequivocally in humans. A cross-sectional study has been conducted on the frequency of anti-human leukocyte antigen (HLA) antibodies in order to identify any correlation with allograft function in adult patients, following the Ross procedure. Anti-HLA antibodies were determined during regular follow up (median 1.1 years postoperatively) in a random sample of 197 patients (151 males, 46 females; mean age 46 +/- 13 years). Panel-reactive antibodies (PRA) were determined by cytotoxicity testing; anti-HLA class 2 antibodies (HLA2AB) were determined by ELISA in a subgroup of 94 patients. Echocardiographic examinations were performed during the first visit and at a median of 6.8 years postoperatively. The prevalence of positive antibody tests was 47% for PRA and 52% for HLA2AB. A slight deterioration of allograft valve function occurred between the two examinations (median maximal pressure gradient increased from 9 mmHg to 13 mmHg, p < 0.001; median degree of regurgitation increased from zero to trivial, p = 0.020). The degree of regurgitation was slightly, but significantly, higher in PRA-positive patients at both examinations (p = 0.008 and p = 0.038). No relationship was observed between PRA status and pressure gradients, nor between HLA2AB status and allograft valve function. Neither were any other risk factors for allograft valve deterioration identified. Subtle, clinically irrelevant and temporally stable differences with regard to regurgitation across the allograft were observed between PRA-positive and -negative patients. These findings neither proved nor disproved rejection, but rather suggested that a slow deterioration of allograft valve function was complex, and most likely multifactorial.


Immunoglobulin for preventing respiratory syncytial virus infection.
Respiratory Syncytial virus, the most important cause of lower respiratory tract infections in infants and young children in industrialized countries, is associated with increased morbidity in premature infants with or without bronchopulmonary dysplasia as well as those with congenital heart disease. Because of observations that lower rates of disease occur immediately after birth, presumably due to vertical transmission of maternal antibody, and animal studies where protection from pneumonia was observed through administration of immune globulin, the efficacy of passive prophylaxis in premature infants has been studied. This meta-analysis was performed to assess the effects of polyclonal respiratory syncytial virus hyperimmune globulin or monoclonal antibody in preventing RSV hospitalization, receipt of intensive care, mechanical ventilation, and mortality in those with underlying prematurity, bronchopulmonary dysplasia, or congenital heart disease. We searched the Cochrane Acute Respiratory Infections trials register and MEDLINE in March, 1999. In addition, abstracts on these topics were sought from the Pediatric Academies Meetings and the Intersciences Conference on Antimicrobial Agents and Chemotherapy for the years 1994 to 1997, inclusive. Randomized, controlled trials of prevention of RSV using immune globulin, respiratory syncytial virus immune globulin, or monoclonal RSV antibody in children with prematurity, bronchopulmonary dysplasia or congenital heart disease. Two authors independently abstracted data and assessed study quality. Only incidences could be pooled because data for durations was summarized in a manner that did not allow combining results across the studies. Four studies with a total of 2598 subjects were included in the main analysis. All were randomized controlled trials. Two trials were not blinded. Three studies examined RSV hyperimmune globulin and one examined monoclonal RSV antibody. A study of a different monoclonal RSV antibody could not be included because it has not been presented or published. The pooled Peto Odds Ratios favoring prophylaxis were 0.48 (95% CI 0.37, 0.64), 0.47 (0.29, 0. 77), and 0.99 (0.48, 2.07) for incidence of hospitalization, incidence of ICU admission, and incidence of mechanical ventilation, respectively. The numbers needed to prevent one hospitalization and one ICU admission are 17 and 50 respectively. RSVIG is effective in preventing RSV hospitalizations and admission to the intensive care unit, but not in preventing mechanical ventilation. There was a non-significant trend towards a higher mortality in children given RSVIG.


Short-latency inhibition mitigates the relationship between conscious movement processing and overly cautious gait.
Overly cautious gait is common in older adults. This is characterised by excessively slow gait, shortened steps, broadened base of support and increased double limb support. The current study sought to (1) evaluate if overly cautious gait is associated with attempts to consciously process walking movements, and (2) explore whether an individual's ability to rapidly inhibit a dominant motor response serves to mitigate this relationship. A total of 50 older adults walked at a self-selected pace on an instrumented walkway containing two raised wooden obstacles (height = 23 cm). Trait conscious movement processing was measured with the Movement-Specific Reinvestment Scale. Short-latency inhibitory function was assessed using a validated electronic go/no-go ruler catch protocol. We used linear regressions to explore the relationship between these variables and gait parameters indicative of overly cautious gait. When controlling for general cognitive function (MoCA), and functional balance (Berg Balance Scale), the interaction between trait conscious movement processing and short-latency inhibition capacity significantly predicted gait velocity, step length and double limb support. Specifically, older adults with higher trait conscious movement processing and poorer inhibition were more likely to exhibit gait characteristics indicative of cautious gait (i.e. reduced velocity, shorter step lengths and increased double limb support). Neither conscious movement processing nor inhibition independently predicted gait performance. The combination of excessive movement processing tendencies and poor short-latency inhibitory capacity was associated with dysfunctional or 'overly cautious' gait. It is therefore plausible that improvement in either factor may lead to improved gait and reduced fall risk.


Eastern equine encephalomyelitis virus infection in a horse from California.
A yearling quarter horse, which was raised in southern California, received routine vaccinations for prevention of infection by Eastern equine encephalomyelitis virus (EEEV). One week later, severe neurologic signs developed, and the horse was humanely destroyed. A vaccine-related encephalomyelitis was later suspected. A final diagnosis of EEEV infection was established on the basis of acute onset of the neurologic signs, histopathologic and serologic testing, and isolation and molecular characterization of EEEV from brain tissue. The vaccine was extensively tested for viral inactivation. Nucleotide sequences from the vaccine and the virus isolated in the affected horse were also compared. In California, arboviral encephalomyelitides are rarely reported, and EEEV infection has not previously been documented. This report describes the occurrence of EEEV infection in the horse and the investigation to determine the source of infection, which was not definitively identified.


The role of childhood trauma in cognitive performance in schizophrenia and bipolar disorder - A systematic review.
Childhood trauma (CT) has repeatedly been associated with cognitive deficits in patients with psychosis but many inconsistencies have been reported so that the nature of the relationship remains unclear. The purpose of this review was to better characterize the contribution of CT to cognitive deficits by considering the type, severity and frequency of childhood traumatic events and their relationships with psychosis at all stages. Relevant studies were identified via electronic and manual literature searches and included original studies that investigated the relationship between CT and higher cognitive performance or social cognitive performance in patients with schizophrenia, bipolar disorder and psychosis at all stages of the illness stages (i.e. ultra-high risk, first episode or chronic phase). Overall, a majority of studies reported that patients who experienced CT displayed deficits in general cognitive ability compared to patients with psychosis without such a history. Associations between CT and other cognitive function were more mixed. When comparing patient groups, the association between CT and cognitive function was more inconsistent in patients with chronic schizophrenia than in healthy participants, ultra-high risk individuals, first-episode patients and patients with chronic bipolar disorder. In understanding the variability in the reported relationships between CT and cognition across study populations, we highlight the variety of questionnaires used and discuss the likelihood of there being differences in cognitive function based on specific stressors, severity and frequency. Finally, we consider future research steps that may shed light on psychobiological mechanisms underlying CT and cognitive performance in patients with psychosis.


The Investigation of the Antitumor Agent Toxicity and Capsaicin Effect on the Electron Transport Chain Enzymes, Catalase Activities and Lipid Peroxidation Levels in Lung, Heart and Brain Tissues of Rats.
Cisplatin is one of the most active cytotoxic agents in cancer treatment. To clarify the interaction with mitochondria, we hypothesize that the activities of mitochondrial electron transport chain (ETC) enzymes succinate dehydrogenase (SDH) and cytochrome c oxidase (COX), nucleotide levels, as well as levels of catalase (CAT) enzyme and membrane lipid peroxidation (LPO) can be affected by cisplatin. There was a significant decrease of both SDH and COX activities in the lung, heart, and brain tissues at the 1st day after cisplatin exposure, and the observed decreased levels of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) in comparison with the control could be because of cisplatin-induced mitochondrial dysfunction. The investigations suggested that cisplatin inhibits SDH, COX, and ATP synthase. The higher LPO level in the studied tissues after 1 and 4 days post-exposure to cisplatin compared to control can be inferred to be a result of elevated electron leakage from the ETC, and reactive oxygen species (ROS) can lead to wide-ranging tissue damage such as membrane lipid damage. Consequently, it was observed that capsaicin may have a possible protective effect on ETC impairment caused by cisplatin. The activities of SDH and COX were higher in heart and brain exposed to cisplatin + capsaicin compared to cisplatin groups, while LPO levels were lower. The investigated results in the cisplatin + capsaicin groups suggested that the antioxidant capacity of capsaicin scavenges ROS and prevents membrane destruction.


An Integrated Framework for Parameter-based Optimization of Scientific Workflows.
Data analysis processes in scientific applications can be expressed as coarse-grain workflows of complex data processing operations with data flow dependencies between them. Performance optimization of these workflows can be viewed as a search for a set of optimal values in a multi-dimensional parameter space. While some performance parameters such as grouping of workflow components and their mapping to machines do not a ect the accuracy of the output, others may dictate trading the output quality of individual components (and of the whole workflow) for performance. This paper describes an integrated framework which is capable of supporting performance optimizations along multiple dimensions of the parameter space. Using two real-world applications in the spatial data analysis domain, we present an experimental evaluation of the proposed framework.


Dopamine deficiency in the weaver mutant mouse.
The dopamine system in weaver mutant mice (B6CBA-Aw-J/A background) was studied. Dopamine was 27% lower in the olfactory tubercle, 77% lower in the frontal cortex, and 75% lower in the striatum of 6-month-old weaver mice compared to control mice of the same age. Norepinephrine and serotonin were not lower in these brain areas. Tyrosine hydroxylase activity in the striatum was measured with a radiometric assay and was 70% lower in weaver mice. Examination of mice from 11 to 180 days of age revealed that the dopamine system failed to develop in weaver mice. Motor activity in individual animals was assessed using circular photocell activity cages with minimal illumination. Apomorphine and pergolide, direct dopamine agonists, increased activity more in weaver mice than in normal littermates. Amphetamine, which releases endogenous stores of dopamine, was less active in mutant mice. These findings provide suggestive evidence that postsynaptic dopamine receptors in weaver mutants might have become supersensitive as a result of lower levels of dopamine in motor areas of the brain. Anatomical evidence of dopamine system abnormalities was found in weaver mice by examination of serial sections cut from the midbrain of mutant and normal mice. The pars compacta of the substantia nigra in weaver mice appeared hypocellular when compared with the corresponding sections from controls. Fewer large neurons were seen in the affected animals. This study illustrates that weaver mice have specific deficiencies in the dopamine system. The weaver mouse might provide a way of examining the biochemical and behavioral effects of long term dopamine deficiency and a way to examine drugs to treat dopamine-deficient states in vivo.


Defining a core set of actin cytoskeletal proteins critical for actin-based motility of Rickettsia.
Many Rickettsia species are intracellular bacterial pathogens that use actin-based motility for spread during infection. However, while other bacteria assemble actin tails consisting of branched networks, Rickettsia assemble long parallel actin bundles, suggesting the use of a distinct mechanism for exploiting actin. To identify the underlying mechanisms and host factors involved in Rickettsia parkeri actin-based motility, we performed an RNAi screen targeting 115 actin cytoskeletal genes in Drosophila cells. The screen delineated a set of four core proteins-profilin, fimbrin/T-plastin, capping protein, and cofilin--as crucial for determining actin tail length, organizing filament architecture, and enabling motility. In mammalian cells, these proteins were localized throughout R. parkeri tails, consistent with a role in motility. Profilin and fimbrin/T-plastin were critical for the motility of R. parkeri but not Listeria monocytogenes. Our results highlight key distinctions between the evolutionary strategies and molecular mechanisms employed by bacterial pathogens to assemble and organize actin.


Transcytosis of ferritin and increased production of subendothelial matrix components by aortic endothelial cells during the development of hypertension.
The aortic intima of the Spontaneously Hypertensive Rat underwent dramatic structural alterations with respect to the subendothelial space coincident with the rise in arterial pressure. This space became increasingly widened from four to 24 weeks, and exhibited a dense accumulation of granular material, resembling a complex reticular basement membrane. To determine if this alteration was due to an abnormality in endothelial transcytosis, rats of four, ten and 24 weeks of age were studied using ferritin as a tracer. In the SHR, vesicular transport of injected ferritin was significantly increased at all ages studied compared to the WKY, but decreased to prehypertensive levels by 24 weeks of age. This occurred without a change in the density of vesicles and caveolae within the cells. Despite the decrease in transcytosis from 10 to 24 weeks the alterations of the subendothelial space continued indicating that the endothelium may play a role in the synthesis and deposition of the dense extracellular matrix.


Intersecting stigma and HIV testing practices among urban refugee adolescents and youth in Kampala, Uganda: qualitative findings.
HIV-related risks may be exacerbated in humanitarian contexts. Uganda hosts 1.3 million refugees, of which 60% are aged under 18. There are knowledge gaps regarding HIV testing facilitators and barriers, including HIV and intersecting stigmas, among urban refugee youth. In response, we explored experiences and perspectives towards HIV testing strategies, including HIV self-testing, with urban refugee youth in Kampala, Uganda. We implemented a qualitative study with refugee cisgender youth aged 16 to 24 living in Kampala's informal settlements from February-April 2019. We conducted five focus groups with refugee youth, including two with adolescent boys and young men, two with adolescent girls and young women and one with female sex workers. We also conducted five key informant (KI) interviews with government, non-government and community refugee agencies and HIV service providers. We conducted thematic analyses to understand HIV testing experiences, perspectives and recommendations. Participants (n = 49) included young men (n = 17) and young women (n = 27) originally from the Democratic Republic of Congo [DRC] (n = 29), Rwanda (n = 11), Burundi (n = 3) and Sudan (n = 1), in addition to five KI (gender: n = 3 women, n = 2 men; country of origin: n = 2 Rwanda, n = 2 Uganda, n = 1 DRC). Participant narratives revealed stigma drivers included fear of HIV infection; misinformation that HIV is a "Ugandan disease"; and blame and shame for sexual activity. Stigma facilitators included legal precarity regarding sex work, same-sex practices and immigration status, alongside healthcare mistreatment and confidentiality concerns. Stigma experiences were attributed to the social devaluation of intersecting identities (sex work, youth, refugees, sexual minorities, people living with HIV, women). Participants expressed high interest in HIV self-testing. They recommended HIV self-testing implementation strategies to be peer supported and expressed concerns regarding sexual- and gender-based violence with partner testing. Intersecting stigma rooted in fear, misinformation, blame and shame, legal precarity and healthcare mistreatment constrain current HIV testing strategies with urban refugee youth. Findings align with the Health Stigma and Discrimination Framework that conceptualizes stigma drivers and facilitators that devalue intersecting health conditions and social identities. Findings can inform multi-level strategies to foster enabling HIV testing environments with urban refugee youth, including tackling intersecting stigma and leveraging refugee youth peer support.


Association Between Admission Systolic Blood Pressure and Cardiovascular Events in Acute Myocardial Infarction Patients with Different Left Ventricular Ejection Fractions.
Among patients with acute heart failure, left ventricular ejection fraction (LVEF) is closely related with admission blood pressure. However, it is unclear whether the systolic blood pressure is associated with the LVEF in acute myocardial infarction (AMI) patients. we evaluated the predictive value of admission SBP in AMI patients with different LVEF status. Data were from our hospital database bank. 4114 patients were included in this analysis. Patients were divided into 2 groups according to their LVEF in the first echocardiography record after admission. Patients were categorized into 4 groups (SBP 90-99 mm Hg, SBP 100-119 mm Hg, SBP 120-139 mm Hg, and SBP ≥140 mm Hg) based on SBP level at admission. The mean age was 64.9 ± 12.5 years and 28% were female. For patients of LVEF < 50% in the lowest SBP group (SBP 90-99 mm Hg), the incidence of in-hospital cardiovascular death was significantly higher than other SBP groups (reference: SBP 90-99 mm Hg) (adjusted OR = 0.267, 95% CI: 0.113-0.728 for SBP 120-139 mm Hg, P =.004 and OR = 0.241, 95% CI: 0.089-0.651 for SBP ≥ 140 mm Hg, P =.005). Patients of LVEF ≥50% in the highest SBP group (SBP ≥ 140 mm Hg) were at higher risk of cardiogenic mortality during long-term follow-up (reference: SBP ≥140 mm Hg) (adjusted HR = 0.313, 95% CI: 0.489-0.962 for SBP 100-119 mm Hg, P <.001, HR = 0.701, 95% CI: 0.488-0.987 for SBP 120-139 mm Hg, P =.003, and HR = 0.554, 95% CI: 0.198-0.837 for SBP 90-99 mm Hg, P =.001). SBP 90-99 mm Hg were associated with increased in-hospital cardiovascular death in AMI population with LVEF < 50%, and SBP > 140 mm Hg were associated with increased long-term cardiovascular death in AMI subjects with LVEF >50%.


A genetic engineering approach to genetic algorithms.
We present an extension to the standard genetic algorithm (GA), which is based on concepts of genetic engineering. The motivation is to discover useful and harmful genetic materials and then execute an evolutionary process in such a way that the population becomes increasingly composed of useful genetic material and increasingly free of the harmful genetic material. Compared to the standard GA, it provides some computational advantages as well as a tool for automatic generation of hierarchical genetic representations specifically tailored to suit certain classes of problems.


Prior Arrest, Substance Use, Mental Disorder, and Intent-Specific Firearm Injury.
Substance use, mental disorders, and arrest are markers of increased firearm injury risk. It is unclear how these markers vary by intent. Examining these interrelated factors together can clarify their associations with assault-related, self-inflicted, unintentional, and legal intervention firearm injuries, informing intent-specific interventions. In 2017-2018, 2-year diagnosis and arrest histories of intent-specific firearm injury cases were compared with those of unintentionally injured motor vehicle collision passenger controls. Fatal and nonfatal firearm and motor vehicle collision injury records in Seattle (2010-2014) were linked to statewide hospitalization and arrest records. Multinomial logistic regression models compared odds of prior arrest, substance use, and mental disorder diagnoses among intent-specific firearm injury cases relative to controls, adjusting for age, race, and gender. A total of 763 cases and 335 controls were identified. Unintentional and self-inflicted cases did not differ significantly from controls in arrest history. Legal intervention cases resembled assault-related cases in their arrest history, and self-inflicted cases in their hospitalization history. The legal intervention cases were more likely than controls to have a prior felony arrest (OR=7.72, 95% CI=2.63, 20.97), and diagnoses involving alcohol (OR=4.06, 95% CI=1.04, 15.84); cannabis (OR=11.00, 95% CI=1.01, 119.36); depression/anxiety (OR=7.22, 95% CI=1.89, 27.67); psychosis (OR=6.99, 95% CI=1.35, 36.24); or conduct disorder (OR=22.01, 95% CI=1.44, 335.93). Individuals with intent-specific firearm injuries have distinct patterns of prior substance use, mental disorder, and arrest. Many injuries occur after a series of encounters with institutions meant to help individuals during crises that can fail to provide longer-term solutions.


Statewide implementation of the 4 Rs and 2 Ss for strengthening families.
Embedding evidence-informed practices for children with mental health needs into "real-world" community settings has proven challenging. In this article, we discuss how the Practical, Robust, Implementation, and Sustainability Model (PRISM) guided statewide (New York) implementation of an evidence-informed intervention targeting families and youth with oppositional defiant and conduct disorders, collectively referred to as disruptive behavior disorders. Additionally, we present qualitative findings based on provider reports of integrating a novel, evidence-informed intervention within their respective community mental health settings. Finally, we discuss a process of modifying the intervention to address agency-level factors, as well as inform more widespread implementation efforts.


Neural Mechanism to Simulate a Scale-Invariant Future.
Predicting the timing and order of future events is an essential feature of cognition in higher life forms. We propose a neural mechanism to nondestructively translate the current state of spatiotemporal memory into the future, so as to construct an ordered set of future predictions almost instantaneously. We hypothesize that within each cycle of hippocampal theta oscillations, the memory state is swept through a range of translations to yield an ordered set of future predictions through modulations in synaptic connections. Theoretically, we operationalize critical neurobiological findings from hippocampal physiology in terms of neural network equations representing spatiotemporal memory. Combined with constraints based on physical principles requiring scale invariance and coherence in translation across memory nodes, the proposition results in Weber-Fechner spacing for the representation of both past (memory) and future (prediction) timelines. We show that the phenomenon of phase precession of neurons in the hippocampus and ventral striatum correspond to the cognitive act of future prediction.


Toxicity of nalidixic acid on candida albicans, Saccharomyces cerevisiae, and Kluyveromyces lactis.
The antibacterial drug nalidixic acid (Nal) can suppress the growth of Candida albicans at levels of the drug normally found in urine. Growth suppression increases as drug levels are increased, and Nal also causes a similar proportional inhibition of the synthesis of all cellular macromolecules. However, growth temperature (25 versus 37 C) and the divalent cations Mg(2+) and Mn(2+) can increase C. albicans resistance to Nal. Also, nitrogen depletion of Candida shows that Nal-treated and untreated cells exhibit no difference in leucine uptake during readaptation to nitrogen. In Nal-treated, nitrogen-starved cells, ribonucleic acid and deoxyribonucleic acid (DNA) biosynthesis are less affected than in unstarved Nal-treated cells, but of the two nucleic acids DNA synthesis is the most affected. Nal-resistant strains of C. albicans exhibit a slight toxicity for macromolecular synthesis. Nal treatment of a synchronized population of Saccharomyces cerevisiae results in an increase in the culture mean doubling time of, at most, 20%, but Nal causes the loss of synchronous cell division. With a synchronized population of Kluyveromyces lactis, Nal causes an increase in the mean doubling time of upwards of 300%, with synchrony of cell division being maintained. It is known that S. cerevisiae asynchronously synthesizes mitochondrial DNA during the cell cycle, whereas with K. lactis it is synchronous. Thus, with C. albicans Nal toxicity is dependent both on the dose and the physiological state of the cell. Furthermore, Nal inhibits growth of yeast with synchronous mitochondrial DNA synthesis more adversely than yeast with asynchronous mitochondrial DNA synthesis.


Adherence and acceptability of community-based distribution of micronutrient powders in Southern Mali.
Home fortification with micronutrient powders (MNP) has been shown to reduce anaemia, with high overall acceptability and adherence, but there is limited evidence from West Africa. Around 80% of children younger than 5 years are anaemic in Mali, and new interventions are needed. This paper reports on the adherence and acceptability of a community-led MNP intervention targeting children aged 6-59 months in Southern Mali. The MNP were delivered by a multidisciplinary group of community volunteers using community-based preschools, cooking demonstrations, and traditional communication networks to promote MNP, nutrition, hygiene, and child stimulation. The MNP were delivered alongside early childhood development interventions and seasonal malaria chemoprevention. Adherence and acceptability were evaluated through two cross-sectional surveys in 2014 and 2016 and a qualitative evaluation in 2015. Over 80% of parents reported ever having given MNP to their child, with 65% having given MNP for four or more days in the last week. Likely contributors to uptake include: perceived positive changes in the children following MNP use, the selection of a food vehicle that was already commonly given to children (morning porridge or bouillie) and the community driven, decentralized and integrated delivery approach. These findings support recommendations from recent reviews of MNP implementation to use community-based delivery approaches and behaviour change components.