The Frontal Behavioral Battery: A Measure of Frontal Lobe Symptoms in Brain Aging and Neurodegenerative Disease.
Approximately 90%of persons living with dementia experience behavioral symptoms, including frontal lobe features involving motivation, planning, social behavior, language, personality, mood, swallowing, and gait. We conducted a two-stage study with a development sample (n = 586) and validation sample (n = 274) to evaluate a brief informant-rated measure of non-cognitive features of frontal lobe dysfunction: the Frontal Behavioral Battery (FBB). In the development sample, internal consistency, principal factor analysis, and correlations between the FBB and outcomes were evaluated. In the validation sample, we examined (a) FBB scores by diagnosis, (b) known-group validity by demographics, subjective complaints, and dementia staging, and (c) correlation between FBB and MRI volumes. Receiver operator characteristic curves assessed the ability of the FBB to discriminate individuals with frontal lobe features due to a neurodegenerative disease. The FBB characterized 11 distinct frontal lobe features. Individuals with dementia with Lewy bodies and frontotemporal degeneration had the greatest number of frontal lobe features. Premorbid personality traits of extroversion, agreeableness, and openness were associated with fewer frontal lobe behavioral symptoms, while subjective cognitive complaints were associated with greater symptoms. The FBB provided very good discrimination between individuals with and without cognitive impairment (diagnostic odds ratio: 13.1) and between individuals with and without prominent frontal lobe symptoms (diagnostic odds ratio: 84.8). The FBB may serve as an effective and efficient method to assess the presence of non-cognitive symptoms associated with frontal lobe dysfunction, but in a brief fashion that could facilitate its use in clinical care and research.


Health challenges in Kazakhstan and Central Asia.
The Central Asian region, which encompasses Kazakhstan, Uzbekistan, Tajikistan, Turkmenistan and Kyrgyzstan, is an interesting geographic region with a rich history dating back to the Silk Road, Mongol conquests and expansion of the Russian Empire. However, from a public health viewpoint, the Central Asian region is under-investigated, and many public health challenges exist, as countries of Central Asia inherited the centralised medical systems practiced in the Soviet Union, and are currently undergoing rapid transitions. A large number of low and middle-income countries around the world, including countries of Central Asia, face a double burden of chronic and infectious disease. This essay focuses on the exploration of the most important public health challenges in the Central Asian region, including limited scientific productivity, the double burden of chronic and infectious disease, the need for healthcare reform and the reduction in care variation. Central Asia has a large number of medical schools, medical centres, and emerging research institutes that can be used to foster a change in medical and public health practice in the region.


Linking local retention, self-recruitment, and persistence in marine metapopulations.
Three indices of larval retention have been used in the literature to assess the tendency for self-maintenance of local marine populations: local retention (LR), self-recruitment (SR), and relative local retention (RLR). Only one of these, LR, defined as the ratio of locally produced settlement to local egg production, has a clear relationship to self-persistence of individual sites. However, SR, the ratio of locally produced settlement to settlement of all origins at a site, is generally easier to measure experimentally. We use theoretical, simulation, and empirical approaches to bridge the gap between these different indices, and demonstrate that there is a proportional relationship between SR and LR, for metapopulations close to a stable state and with lifetime egg production (LEP) approximately uniform over space. Similarly, for systems where larval mortality rates are a relatively uniform function of release site, RLR (defined as the ratio of locally produced settlement to all settlement of local origin) and LR will also be proportional. Therefore, SR and RLR provide information on relative rates of LR for systems satisfying these conditions. Furthermore, the ratio between LR and SR can be used to evaluate global persistence of metapopulations, and therefore provides valuable information not necessarily available if only LR is considered.


The distribution of free calcium in transected spinal axons and its modulation by applied electrical fields.
Intracellular free-calcium concentration ([Ca2+]i) was measured in lamprey spinal axons using the fluorescent calcium indicator fura 2. We used both a photomultiplier tube and a video-image processing system to measure the temporal and spatial distributions of [Ca2+]i in the proximal segments of transected axons. Within 3 min following transection, a spatially graded increase in the [Ca2+]i was apparent in the last few millimeters of the axons. Superimposed on the initial gradient was a moving front of calcium that progressed up the axon, reaching 1.6 mm from the cut end in 3 hr. The [Ca2+]i behind the moving front exceeded 10 microM. This movement of Ca2+ was greatly reduced by an externally applied electrical field with the cathode distal to the lesion and was increased by an applied field of the opposite polarity. When axons were transected in Ca2(+)-free medium, no increases in [Ca2+]i occurred. One d after transection, [Ca2+]i was at or below the precut levels, except in the distal 250 microns, where it remained slightly elevated. Therefore, axons can survive the high levels of [Ca2+]i that occur after transection and can reestablish normal [Ca2+]i levels within 24 hr. Measurements of both the diffusion coefficient and the fluorescence polarization of fura 2 indicate that the dye is not significantly bound to axoplasmic components.


Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models.
KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5) reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., three times a week) and MK-2206 (60 mg/kg, orally, three times a week) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP-approved multicenter phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened.


Host-parasitoid spatial ecology: a plea for a landscape-level synthesis.
A growing body of literature points to a large-scale research approach as essential for understanding population and community ecology. Many of our advances regarding the spatial ecology of predators and prey can be attributed to research with insect parasitoids and their hosts. In this review, we focus on the progress that has been made in the study of the movement and population dynamics of hosts and their parasitoids in heterogeneous landscapes, and how this research approach may be beneficial to pest management programs. To date, few studies have quantified prey and predator rates and ranges of dispersal and population dynamics at the patch level--the minimum of information needed to characterize population structure. From host-parasitoid studies with sufficient data, it is clear that the spatial scale of dispersal can differ significantly between a prey and its predators, local prey extinctions can be attributed to predators and predator extinction risk at the patch level often exceeds that of the prey. It is also evident that populations can be organized as a single, highly connected (patchy) population or as semi-independent extinction-prone local populations that collectively form a persistent metapopulation. A prey and its predators can also differ in population structure. At the landscape level, agricultural studies indicate that predator effects on its prey often spill over between the crop and surrounding area (matrix) and can depend strongly on landscape structure (e.g. the proportion of suitable habitat) at scales extending well beyond the crop margins. In light of existing empirical data, predator-prey models are typically spatially unrealistic, lacking important details on boundary responses and movement behaviour within and among patches. The tools exist for conducting empirical and theoretical research at the landscape level and we hope that this review calls attention to fertile areas for future exploration.


Testing devices for the prevention and treatment of stroke and its complications.
We are entering a challenging but exciting period when many new interventions may appear for stroke based on the use of devices. Hopefully these will lead to improved outcomes at a cost that can be afforded in most parts of the world. Nevertheless, it is vital that lessons are learnt from failures in the development of pharmacological interventions (and from some early device studies), including inadequate preclinical testing, suboptimal trial design and analysis, and underpowered studies. The device industry is far more disparate than that seen for pharmaceuticals; companies are very variable in size and experience in stroke, and are developing interventions across a wide range of stroke treatment and prevention. It is vital that companies work together where sales and marketing are not involved, including in understanding basic stroke mechanisms, prospective systematic reviews, and education of physicians. Where possible, industry and academics should also work closely together to ensure trials are designed to be relevant to patient care and outcomes. Additionally, regulation of the device industry lags behind that for pharmaceuticals, and it is critical that new interventions are shown to be safe and effective rather than just feasible. Phase IV postmarketing surveillance studies will also be needed to ensure that devices are safe when used in the 'real-world' and to pick up uncommon adverse events.


Ultrasound-Guided Erector Spinae Plane Block Compared to Modified Pectoral Plane Block for Modified Radical Mastectomy Operations.
Modified radical mastectomy (MRM) is the most common surgery for cancer breast that is associated with marked postoperative pain. Effective control of this pain suppresses the surgical stress response and decreases the opioids and general anesthetics' needs. This study compared the erector spinae plane (ESP) block and the pectoral plane (PECS) block effects on the opioid consumption postoperatively, stress response, fentanyl needs intraoperatively, pain scores, and incidence of complications in female patients subjected to MRM surgery. Fifty patients were allocated randomly and divided into two groups. Forty-seven patients were included in the final analysis after exclusion. ESP block group (E group, n = 24) received 20 mL of 0.25% levobupivacaine plus 0.5 μ/kg dexmedetomidine that was injected in-between erector spinae muscle and transverse process. PECS block group (P group, n = 23) received 30 mL of 0.25% levobupivacaine plus 0.5 μg/kg dexmedetomidine divided into 10 mL that was injected between the two pectoralis muscles in the interfascial plane and the other was 20 mL injected between the serratus anterior and the pectoralis minor. Postoperative morphine consumption and stress hormone level in P group were significantly lower than E group. The pain scores and number of patients requested analgesic postoperatively showed significantly higher values in E group. Hemodynamic parameters, fentanyl needed intraoperatively and the incidence of postoperative complications recorded no significant difference between the two groups. The current study demonstrated that PECS block provides better quality of analgesia than ESP block in patients subjected to MRM operations.


Psychiatric and substance-use comorbidities associated with lifetime crack cocaine use in young adults in the general population.
To assess the association between lifetime crack cocaine use and psychiatric (post-traumatic stress disorder, current depression, current dysthymia, generalized anxiety disorder, panic disorder with agoraphobia, social phobia, as well as SRQ scores and suicide risk) and substance-use disorders (tobacco, alcohol, cannabis, cocaine, amphetamine, inhalants, sedatives, hallucinogens and opioids) in youth in the general population of the city of Pelotas, RS. This was a cross-sectional population-based study, involving 1560 participants between 18 and 24 ears old. Lifetime substance use and abuse were investigated using the ASSIST inventory. Psychiatric comorbidities were assessed using the Mini-International Neuropsychiatric Interview and symptoms of common mental disorders were evaluated with the Self-Reported Questionnaire (SRQ). The prevalence of lifetime crack cocaine use in the sample was 2.5%. Its use was associated with total SRW scores and the presence of post-traumatic stress disorder, antisocial personality disorder and suicide risk in the final regression model. Tobacco, alcohol, cannabis, cocaine, amphetamine and cocaine dependence were also associated with lifetime use of crack cocaine. Youth with a history of crack cocaine use had a higher prevalence of psychiatric conditions such as post-traumatic stress disorder, as well as an increased risk of tobacco, alcohol, cannabis, cocaine, amphetamine and inhalant use and dependence.


Anti-tubercular activity of eleven aromatic and medicinal plants occurring in Colombia.
Human tuberculosis is a contagious-infectious disease mainly caused by Mycobacterium tuberculosis. Although regimens exist for treating tuberculosis, they are far from ideal. Development of effective strategies for treatment of human tuberculosis has posed a challenge, considering the increase in infections associated with the human immunodeficiency virus and immunocompromised patients. Essential oils--volatile, aromatic oil extracts from plants--have been used in traditional treatment of many diseases; however careful investigation of these oils has not been undertaken with respect to treatments of tuberculosis. The in vitro antitubercular activity of essential oils from 11 medicinal plants grown in Colombia were assessed for efficacy as new medications (phytomedicines) for treatment of M. tuberculosis H37Rv. Essential oil extraction and analysis were performed as described Stashenko et al. (2004). Minimal inhibitory concentrations were determined by a colorimetric macrodilution method, following the protocol described by Abate et al. (1998). Isoniazide and rifampin were used as control treatments. Bactericidal and bacteriostatic activity was measured using the method developed by the Clinical and Laboratory Standards Institute consigned in the M26-A protocol. Essential oils from Achyrocline alata and Swinglea glutinosa were the most active with minimal inhibitory concentrations of 62.5 +/- 0.1 and 100 +/- 36 microg ml(-1), respectively. Carvacrol, thymol, p-cymene, 1,8-cineole, limonene, and beta-pinene were the major components, most often identified in the 11 plant extracts of essential oils. Time-kill curve assays demonstrated the bacteriostatic activity of these essential oils. The essential oils from A. alata and S. glutinosa plants, and the components identified therein, are candidates as potential phytotherapeutic agents for human tuberculosis control.


A Plasmodium falciparum homologue of Plasmodium vivax reticulocyte binding protein (PvRBP1) defines a trypsin-resistant erythrocyte invasion pathway.
Invasion of erythrocytes by Plasmodium merozoites is an intricate process involving multiple receptor-ligand interactions. The glycophorins and an unknown trypsin sensitive factor are all erythrocyte receptors used during invasion by the major human pathogen Plasmodium falciparum. However, only one erythrocyte receptor, Glycophorin A, has a well-established cognate parasite ligand, the merozoite protein erythrocyte binding antigen-175 (EBA-175). The involvement of several other parasite proteins during invasion have been proposed, but no direct evidence links them with a specific invasion pathway. Here we report the identification and characterization of P. falciparum normocyte binding protein 1 (PfNBP1), an ortholog of Plasmodium vivax reticulocyte binding protein-1. PfNBP1 binds to a sialic acid dependent trypsin-resistant receptor on the erythrocyte surface that appears to be distinct from known invasion receptors. Antibodies against PfNBP1 can inhibit invasion of trypsinized erythrocytes and two P. falciparum strains that express truncated PfNBP1 are unable to invade trypsinized erythrocytes. One of these strain, 7G8, also does not invade Glycophorin B-negative erythrocytes. PfNBP1 therefore defines a novel trypsin-resistant invasion pathway and adds a level of complexity to current models for P. falciparum erythrocyte invasion.


Photo-responsive properties of azobenzene small molecules in sol-gel hybrid TiO(2)/ormosil organic-inorganic matrices.
Azodye-doped TiO(2)/ormosil hybrid materials for photonic applications were prepared by a low temperature sol-gel process from an organic-inorganic hybrid system. Acid-catalyzed solutions of gamma-glycidoxypropyltrimethoxysilane and methyltrimethoxysilane mixed with tetrapropyl orthotitanate were used as hybrid matrix precursors. The trans-cis-trans photoisomerization of azobenzene small molecules in sol-gel hybrid organic-inorganic matrices was induced by a photoirradiation with UV light and subsequent visible light. It was found that the hybrid film doped with azodyes and heated at a lower temperature was much better for applications in optical storage or optical switch. The planar waveguide properties of the hybrid films were also investigated by using a prism coupling technique. These results indicates that it is possible for the as prepared hybrid films to allow directly integrating on the same chip the optical storage or optical switch devices with the pump source.


Evidence against preserved syntactic comprehension in healthy aging.
We investigated age-related differences in syntactic comprehension in young and older adults. Most previous research found no evidence of age-related decline in syntactic processing. We investigated elementary syntactic comprehension of minimal sentences (e.g., I cook), minimizing the influence of working memory. We also investigated the contribution of semantic processing by comparing sentences containing real verbs (e.g., I cook) versus pseudoverbs (e.g., I spuff). We measured the speed and accuracy of detecting syntactic agreement errors (e.g., I cooks, I spuffs). We found that older adults were slower and less accurate than younger adults in detecting syntactic agreement errors for both real and pseudoverb sentences, suggesting there is age-related decline in syntactic comprehension. The age-related decline in accuracy was smaller for the pseudoverb sentences, and the decline in speed was larger for the pseudoverb sentences, compared to real verb sentences. We suggest that syntactic comprehension decline is stronger in the absence of semantic information, which causes older adults to produce slower responses to make more accurate decisions. In line with these findings, performance for older adults was positively related to a measure of processing speed capacity. Taken together, we found evidence that elementary syntactic processing abilities decline in healthy aging. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Concern and risk perception of osteoporosis and fracture among post-menopausal Australian women: results from the Global Longitudinal Study of Osteoporosis in Women (GLOW) cohort.
The purpose of this study is to identify factors associated with concern and perception of risks of osteoporosis and osteoporotic fractures and determine whether bone mineral density (BMD) testing influenced concern and risk perception. Study subjects (n = 1,082, age 55-94 years) were female Australian participants of the Global Longitudinal Study of Osteoporosis in Women (GLOW). Self-administered questionnaires were sent annually from 2007 to 2010. Study outcomes included 'concern about osteoporosis', 'perception of getting osteoporosis' and 'perception of fracture risk' compared to similar aged women. The closest post-BMD testing or baseline questionnaires were used for women with and without BMD testing, respectively. Multinomial logistic regression was used for the analysis. BMD testing, prior fracture after age 45, younger age and lower self-reported general health were significantly associated with being 'very' or 'somewhat concerned' about osteoporosis and having a 'much higher' or 'little higher' risk perception of osteoporosis and fractures. A poorer BMD result was associated with higher concern and higher risk perceptions. The presence of comorbidities, having ≥2 falls in the preceding year and maternal osteoporosis were associated with higher concern. Maternal osteoporosis, presence of comorbidities, weight loss of ≥5 kg in the preceding year and low body mass index were associated with higher perceptions of osteoporosis risk. Women's concern and risk perception of osteoporosis and osteoporotic fractures were reasonably well founded. However, increasing age, height loss, smoking and drinking were not associated with concern and perception despite being known osteoporosis risk factors. These factors should be considered in planning for education and awareness raising programmes.


Influence of chain topology on polymer crystallization: poly(ethylene oxide) (PEO) rings vs. linear chains.
The absence of entanglements, the more compact structure and the faster diffusion in melts of cyclic poly(ethylene oxide) (PEO) chains have consequences on their crystallization behavior at the lamellar and spherulitic length scales. Rings with molecular weight below the entanglement molecular weight (M < Me), attain the equilibrium configuration composed from twice-folded chains with a lamellar periodicity that is half of the corresponding linear chains. Rings with M > Me undergo distinct step-like conformational changes to a crystalline lamellar with the equilibrium configuration. Rings melt from this configuration in the absence of crystal thickening in sharp contrast to linear chains. In general, rings more easily attain their extended equilibrium configuration due to strained segments and the absence of entanglements. In addition, rings have a higher equilibrium melting temperature. At the level of the spherulitic superstructure, growth rates are much faster for rings reflecting the faster diffusion and more compact structure. With respect to the segmental dynamics in their semi-crystalline state, ring PEOs with a steepness index of ∼34 form some of the "strongest" glasses.


FMRI of working memory impairment after recovery from subarachnoid hemorrhage.
Recovery from aneurysmal subarachnoid hemorrhage (SAH) is often incomplete and accompanied by subtle but persistent cognitive deficits. Previous neuropsychological reports indicate these deficits include most prominently memory impairment, with working memory particularly affected. The neural basis of these memory deficits remains unknown and unexplored by functional magnetic resonance imaging (fMRI). In the present study, patients who experienced (SAH) underwent fMRI during the performance of a verbal working memory paradigm. Behavioral results indicated a subtle but statistically significant impairment relative to healthy subjects in working memory performance accuracy, which was accompanied by relatively increased blood-oxygen level dependent signal in widespread left and right hemisphere cortical areas during periods of encoding, maintenance, and retrieval. Activity increases remained after factoring out inter-individual differences in age and task performance, and included most notably left hemisphere regions associated with phonological loop processing, bilateral sensorimotor regions, and right hemisphere dorsolateral prefrontal cortex. We conclude that deficits in verbal working memory following recovery from (SAH) are accompanied by widespread differences in hemodynamic correlates of neural activity. These differences are discussed with respect to the immediate and delayed focal and global brain damage that can occur following (SAH), and the possibility that this damage induces subcortical disconnection and subsequent decreased efficiency in neural processing.


Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model.
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection.


Regulation of globin gene expression during induced erythroid cell differentiation.
We can provide increasing insight, albeit still incomplete, into the changes in MELC that accompany induced globin gene expression. It is suggested that these transformed CFU-E-like erythroid precursor cells exhibit in their uninduced state a DNA methylation pattern and globin gene chromatin configuration (DNase I sensitivity) that is compatible with actual or potential gene transcription. Such features may reflect alterations in chromatin configuration that occurred earlier, during the differentiation of erythroid precursor cells, which is associated with the restriction in developmental potential that is characteristic of progression to the CFU-E (or MELC) stage of erythropoiesis. Uninduced MELC display a low level of globin gene transcription, producing globin mRNA or mRNA precursors whose processing or stabilization is the site of action of hemin. The major increase in MELC globin gene transcription that is initiated by HMBA or butyric acid is accompanied by an increase in DNase I hypersensitivity in the regions 5' to the active globin genes. This suggests that reorganization of chromatin structure in the globin gene domains is associated with accelerated globin gene transcription and may be characteristic of a developmental stage transition during terminal differentiation in the erythroid cell lineage.


The Relationship between Isometric Force-Time Characteristics and Dynamic Performance: A Systematic Review.
The purpose of this article was to review the data on the relationship between multi-joint isometric strength test (IsoTest) force-time characteristics (peak force, rate of force development and impulse) and dynamic performance that is available in the current literature. Four electronic databases were searched using search terms related to IsoTest. Studies were considered eligible if they were original research studies that investigated the relationships between multi-joint IsoTest and performance of dynamic movements; published in peer-reviewed journals; had participants who were athletes or active individuals who participate in recreational sports or resistance training, with no restriction on sex; and had full text available. A total of 47 studies were selected. These studies showed significant small to large correlations between isometric bench press (IBP) force-time variables and upper body dynamic performances (r2 = 0.221 to 0.608, p < 0.05) and significant small to very large correlation between isometric squat (ISqT) (r2 = 0.085 to 0.746, p < 0.05) and isometric mid-thigh pull (IMTP) (r2 = 0.120 to 0.941, p < 0.05) force-time variables with lower body dynamic performances. IsoTest force-time characteristics were shown to have small to very large correlations with dynamic performances of the upper and lower limbs as well as performance of sporting movements (r2 = 0.118 to 0.700, p < 0.05). These data suggest that IsoTest force-time characteristics provide insights into the force production capability of athletes which give insight into dynamic performance capabilities.


The evolution of the placenta drives a shift in sexual selection in livebearing fish.
The evolution of the placenta from a non-placental ancestor causes a shift of maternal investment from pre- to post-fertilization, creating a venue for parent-offspring conflicts during pregnancy. Theory predicts that the rise of these conflicts should drive a shift from a reliance on pre-copulatory female mate choice to polyandry in conjunction with post-zygotic mechanisms of sexual selection. This hypothesis has not yet been empirically tested. Here we apply comparative methods to test a key prediction of this hypothesis, which is that the evolution of placentation is associated with reduced pre-copulatory female mate choice. We exploit a unique quality of the livebearing fish family Poeciliidae: placentas have repeatedly evolved or been lost, creating diversity among closely related lineages in the presence or absence of placentation. We show that post-zygotic maternal provisioning by means of a placenta is associated with the absence of bright coloration, courtship behaviour and exaggerated ornamental display traits in males. Furthermore, we found that males of placental species have smaller bodies and longer genitalia, which facilitate sneak or coercive mating and, hence, circumvents female choice. Moreover, we demonstrate that post-zygotic maternal provisioning correlates with superfetation, a female reproductive adaptation that may result in polyandry through the formation of temporally overlapping, mixed-paternity litters. Our results suggest that the emergence of prenatal conflict during the evolution of the placenta correlates with a suite of phenotypic and behavioural male traits that is associated with a reduced reliance on pre-copulatory female mate choice.


A new form of access for endo-organ surgery. The initial experience with percutaneous endoscopic gastrostomy.
Intraluminal gastric surgery provides a new treatment option for various disease processes. This study assesses the safety of a new large-diameter percutaneous endoscopic gastrostomy (PEG) for intraluminal surgery. Investigators at six institutions were asked to complete a standard questionnaire to assess the difficulties associated with the assembly and introduction of the PEG, plus intraoperative and postoperative problems related to placement of the device. In terms of assembly; 1.9% of respondents reported difficulty obtaining complete vacuum of the balloon tip, and 3.8% had difficulty fitting the graduated dilator to the balloon-tipped cannula. Difficulties associated with introduction of the PEG included disengagement of the dilator from the balloon-tipped cannula (0%), extraction of the dilator-port assembly (0%), difficult PEG pullout (1.9%), abdominal wall bleeding (0%), and difficult PEG dilator separation (7.5%). Intraoperatively, 7.5% of respondents reported inadequate skin bolster fitting, 1.9% had CO(2) leakage into the peritoneal cavity, 0% had inadvertent PEG extraction, and 0% reported injury to the esophagus, colon, or small intestine. Postoperatively, there was a 9.4% rate of wound infection, a 1.9% rate of gastrocutaneous fistula, and a 1.9% rate of esophageal, colon, or small intestine injury. The large-diameter PEG is safe and effective for endo-organ surgery. Additional preventive measures for PEG site infection should be investigated.


CHILE: an evidence-based preschool intervention for obesity prevention in Head Start.
Obesity is a major concern among American Indians and Hispanics. The Child Health Initiative for Lifelong Eating and Exercise (CHILE) is an evidence-based intervention to prevent obesity in children enrolled in 16 Head Start (HS) Centers in rural communities. The design and implementation of CHILE are described. CHILE uses a socioecological approach to improve dietary intake and increase physical activity. The intervention includes: a classroom curriculum; teacher and food service training; family engagement; grocery store participation; and health care provider support. Lessons learned from CHILE include the need to consider availability of recommended foods; the necessity of multiple training sessions for teachers and food service; the need to tailor the family events to local needs; consideration of the profit needs of grocery stores; and sensitivity to the time constraints of health care providers. HS can play an important role in preventing obesity in children. CHILE is an example of a feasible intervention that addresses nutrition and physical activity for preschool children that can be incorporated into HS curricula and aligns with HS national performance standards.


Carbon nanospikes grown on metal wires as microelectrode sensors for dopamine.
Carbon nanomaterials are advantageous as electrodes for neurotransmitter detection, but the difficulty of nanomaterials deposition on electrode substrates limits the reproducibility and future applications. In this study, we used plasma enhanced chemical vapor deposition (PECVD) to directly grow a thin layer of carbon nanospikes (CNS) on cylindrical metal substrates. No catalyst is required and the CNS surface coverage is uniform over the cylindrical metal substrate. The CNS growth was characterized on several metallic substrates including tantalum, niobium, palladium, and nickel wires. Using fast-scan cyclic voltammetry (FSCV), bare metal wires could not detect 1 μM dopamine while carbon nanospike coated wires could. The highest sensitivity and optimized S/N ratio was recorded from carbon nanospike-tantalum (CNS-Ta) microwires grown for 7.5 minutes, which had a LOD of 8 ± 2 nM for dopamine with FSCV. CNS-Ta microelectrodes were more reversible and had a smaller ΔE(p) for dopamine than carbon-fiber microelectrodes, suggesting faster electron transfer kinetics. The kinetics of dopamine redox were adsorption controlled at CNS-Ta microelectrodes and repeated electrochemical measurements displayed stability for up to ten hours in vitro and over a ten day period as well. The oxidation potential was significantly different for ascorbic acid and uric acid compared to dopamine. Growing carbon nanospikes on metal wires is a promising method to produce uniformly-coated, carbon nanostructured cylindrical microelectrodes for sensitive dopamine detection.


Persistent coherent random lasing using resonant scatterers.
We study the frequency behavior of coherent random lasers consisting monodisperse scatterers with single-particle resonances. A three-dimensional photon propagation model is employed to compute the wavelength-sensitive path length distribution of fluorescence photons in this system. We observe that a persistence interval of wavelengths exists for the coherent random lasing modes, corresponding to the Mie resonances of the individual resonant scatterer. Within the interval, characteristic pulse to pulse fluctuations continue to be observed from the system. The gain competition in the random laser suppresses likely coherent modes in other regions of the emission band, thereby reducing the wavelength fluctuations in the random laser. We further illustrate the tunability of this persistence interval by varying the size parameter of the resonant scatterers.


iManageMyHealth and iSupportMyPatients: mobile decision support and health management apps for cancer patients and their doctors.
Clinical decision support systems can play a crucial role in healthcare delivery as they promise to improve health outcomes and patient safety, reduce medical errors and costs and contribute to patient satisfaction. Used in an optimal way, they increase the quality of healthcare by proposing the right information and intervention to the right person at the right time in the healthcare delivery process. This paper reports on a specific approach to integrated clinical decision support and patient guidance in the cancer domain as proposed by the H2020 iManageCancer project. This project aims at facilitating efficient self-management and management of cancer according to the latest available clinical knowledge and the local healthcare delivery model, supporting patients and their healthcare providers in making informed decisions on treatment choices and in managing the side effects of their therapy. The iManageCancer platform is a comprehensive platform of interconnected mobile tools to empower cancer patients and to support them in the management of their disease in collaboration with their doctors. The backbone of the iManageCancer platform comprises a personal health record and the central decision support unit (CDSU). The latter offers dedicated services to the end users in combination with the apps iManageMyHealth and iSupportMyPatients. The CDSU itself is composed of the so-called Care Flow Engine (CFE) and the model repository framework (MRF). The CFE executes personalised and workflow oriented formal disease management diagrams (Care Flows). In decision points of such a Care Flow, rules that operate on actual health information of the patient decide on the treatment path that the system follows. Alternatively, the system can also invoke a predictive model of the MRF to proceed with the best treatment path in the diagram. Care Flow diagrams are designed by clinical experts with a specific graphical tool that also deploys these diagrams as executable workflows in the CFE following the Business Process Model and Notation (BPMN) standard. They are exposed as services that patients or their doctors can use in their apps in order to manage certain aspects of the cancer disease like pain, fatigue or the monitoring of chemotherapies at home. The mHealth platform for cancer patients is currently being assessed in clinical pilots in Italy and Germany and in several end-user workshops.


Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival.
Young women are at increased risk for developing more aggressive subtypes of breast cancer. Although previous studies have shown a higher risk of breast cancer recurrence and death among young women with early-stage breast cancer, they have not adequately addressed the role of tumor subtype in outcomes. We examined data from women with newly diagnosed stage I to III breast cancer presenting to one of eight National Comprehensive Cancer Network centers between January 2000 and December 2007. Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer-specific survival. A total of 17,575 women with stage I to III breast cancer were eligible for analysis, among whom 1,916 were ≤ 40 years of age at diagnosis. Median follow-up time was 6.4 years. In a multivariable Cox proportional hazards model controlling for sociodemographic, disease, and treatment characteristics, women ≤ 40 years of age at diagnosis had greater breast cancer mortality (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.7). In stratified analyses, age ≤ 40 years was associated with statistically significant increases in risk of breast cancer death among women with luminal A (HR, 2.1; 95% CI, 1.4 to 3.2) and luminal B (HR 1.4; 95% CI, 1.1 to 1.9) tumors, with borderline significance among women with triple-negative tumors (HR, 1.4; 95% CI, 1.0 to 1.8) but not among those with human epidermal growth factor receptor 2 subtypes (HR, 1.2; 95% CI, 0.8 to 1.9). In an additional model controlling for detection method, young age was associated with significantly increased risk of breast cancer death only among women with luminal A tumors. The effect of age on survival of women with early breast cancer seems to vary by breast cancer subtype. Young age seems to be particularly prognostic in women with luminal breast cancers.


Specific ions modulate diffusion dynamics of hydration water on lipid membrane surfaces.
Effects of specific ions on the local translational diffusion of water near large hydrophilic lipid vesicle surfaces were measured by Overhauser dynamic nuclear polarization (ODNP). ODNP relies on an unpaired electron spin-containing probe located at molecular or surface sites to report on the dynamics of water protons within ~10 Å from the spin probe, which give rise to spectral densities for electron-proton cross-relaxation processes in the 10 GHz regime. This pushes nuclear magnetic resonance relaxometry to more than an order of magnitude higher frequencies than conventionally feasible, permitting the measurement of water moving with picosecond to subnanosecond correlation times. Diffusion of water within ~10 Å of, i.e., up to ~3 water layers around the spin probes located on hydrophilic lipid vesicle surfaces is ~5 times retarded compared to the bulk water translational diffusion. This directly reflects on the activation barrier for surface water diffusion, i.e., how tightly water is bound to the hydrophilic surface and surrounding waters. We find this value to be modulated by the presence of specific ions in solution, with its order following the known Hofmeister series. While a molecular description of how ions affect the hydration structure at the hydrophilic surface remains to be answered, the finding that Hofmeister ions directly modulate the surface water diffusivity implies that the strength of the hydrogen bond network of surface hydration water is directly modulated on hydrophilic surfaces.


Closing the translation gap for justice requirements in international research.
Bioethicists have long debated the content of sponsors and researchers' obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and other actors are to successfully translate them into practice because doing so is often a complicated, context-specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial example, the paper shows how information can be gathered from not only international clinical researchers but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research; and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements.


Pregnancy-related hormones, progesterone and human chorionic gonadotrophin, upregulate expression of maternal plasma gelsolin.
Plasma gelsolin (pGSN), a protein primarily involved in clearance of circulating actin filaments, is an upcoming novel biomarker. Its level changes in multiple disease and injury conditions, attributable mainly to its consumption during actin clearance; the endogenous regulation of its expression, however, remains elusive as well as unexplored. Here, we are reporting the first isolation of the promoter region of pGSN gene and investigation of its transcriptional regulation during pregnancy (a natural process associated with a well-programmed injury course of parturition). Interestingly, two of the pregnancy-related hormones, human chorionic gonadotrophin (hCG) and progesterone, significantly upregulated pGSN promoter activity in muscle cells. This action of both hormones was found to mediate through their respective cellular receptors and involved a contribution of multiple signaling pathways including those of protein kinase A, protein kinase C, epidermal growth factor receptor and prostaglandin-endoperoxidase synthase 2 in the case of hCG-mediated upregulation. This novel upregulation was further supported by elevated levels of endogenous pGSN transcripts as well as secreted protein upon hormonal treatments of muscle cells compared with untreated controls. A participation of pGSN promoter cis-elements, capable of interacting with endogenous transcription factors, Ap1, Sp1, and p300, was also observed during this hormonal upregulation. Additionally, the augmented pGSN levels observed in pregnant mice compared with the control animals further supported an upregulation of this protein during pregnancy, implicating vital role(s) played by pGSN during this period in mammals.


Internuclear ophthalmoplegia: MR-anatomic correlation.
Internuclear ophthalmoplegia is a gaze disorder characterized by impaired adduction on the side of a lesion involving the medial longitudinal fasciculus with dissociated nystagmus of the abducting eye. Eleven patients with internuclear ophthalmoplegia (nine with clinical multiple sclerosis, two with clinical infarction) underwent MR imaging with spin-echo techniques on a 1.5-T system. Nine patients also had CT. MR showed focal or nodular areas of high signal intensity on T2-weighted images in the region of the medial longitudinal fasciculus in 10 of 11 patients. In one of four patients with internuclear ophthalmoplegia who had MR after intravenous gadolinium-DTPA, an enhancing ring lesion was seen in the region of the medial longitudinal fasciculus on short TR/TE images, indicating active blood-brain-barrier disruption, which correlated with this patient's recent-onset internuclear ophthalmoplegia. CT failed to show the lesions in all nine patients examined. This report demonstrates the superiority of MR in evaluating gaze disorders attributable to brainstem dysfunction, such as internuclear ophthalmoplegia, and correlates MR findings with the relevant neuroanatomy of the medial longitudinal fasciculus.


Vaccination and immunization strategies to design Aedes aegypti salivary protein based subunit vaccine tackling Flavivirus infection.
Flavivirus causes arthropod-borne severe diseases that sometimes lead to the death. The Flavivirus species including Dengue virus, Zika virus and yellow fever virus are transmitted by the bite of Aedes mosquitoes. All these viral species target the people living in their respective endemic zone causing a high mortality rate. Recent studies show that immune factors present in the Ae. aegypti saliva is the hidden culprit promoting blood meal collection, suppressing host immune molecules and promoting disease establishment. This study was designed to develop a subunit vaccine using Aedes mosquito salivary proteins targeting the aforementioned Flaviviruses. Subunit vaccine was designed very precisely by combining the immunogenic B-cell epitope with CTL and HTL epitopes and also suitable adjuvant and linkers. Immunogenicity, allergenicity and physiochemical characterization were also performed for scientific validation. Molecular docking and molecular dynamics simulations studies were carried out to confirm the stable affinity between the vaccine protein (3D) and TLR3 receptor. At last, in silico cloning was executed to get the subunit vaccine restriction clone into pET28a vectro to express it in microbial expression system. Additionally, this study warrants the experimental evaluation for the validation purposes.


Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype.
The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.


Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary.
In December 2015, the Royal Australian and New Zealand College of Psychiatrists published a comprehensive set of mood disorder clinical practice guidelines for psychiatrists, psychologists and mental health professionals. This guideline summary, directed broadly at primary care physicians, is an abridged version that focuses on bipolar disorder. It is intended as an aid to the management of this complex disorder for primary care physicians working in collaboration with psychiatrists to implement successful long term management. Main recommendations: The guidelines address the main phases of bipolar disorder with a particular emphasis on long term management, and provide specific clinical recommendations. Mania: All physicians should be able to detect its early signs so that treatment can be initiated promptly. At the outset, taper and cease medications with mood-elevating properties and institute measures to reduce stimulation, and transfer the patient to specialist care. Bipolar depression: Treatment is complicated and may require trialling treatment combinations. Monotherapy with mood-stabilising agents or second generation antipsychotics has demonstrated efficacy but using combinations of these agents along with antidepressants is sometimes necessary to achieve remission. Commencing adjunctive structured psychosocial treatments in this phase is benign and likely effective. Long term management: Physicians should adjust treatment to prevent the recurrence of manic and/or depressive symptoms and optimise functional recovery. Closely monitor the efficacy of pharmacological and psychological treatments, adverse effects and compliance. Changes in management as a result of the guidelines: The guidelines position bipolar disorder as part of a spectrum of mood disorders and provide a longitudinal perspective for assessment and treatment. They provide new management algorithms for the maintenance phase of treatment that underscore the importance of ongoing monitoring to achieve prophylaxis. As a first line treatment, lithium remains the most effective medication for the prevention of relapse and potential suicide, but requires nuanced management from both general practitioners and specialists. The guidelines provide clarity and simplicity for the long term management of bipolar disorder, incorporating the use of new medications and therapies alongside established treatments.


Socioenvironmental threats to pastoral livelihoods: risk perceptions in the Altay and Tianshan Mountains of Xinjiang, China.
Subjective risk perceptions give rise to unique policy implications as they reflect both the expectation of risk exposure and the ability to mitigate or cope with the adverse impacts. Based on data collected from semistructured interviews and iterative ranking exercises with 159 households in the Altay and Tianshan Mountains of Xinjiang, China, this study investigates and explains the risks with respect to a seriously understudied population and location. Using both geostatistical and econometric methods, we show that although fear of environmental crisis is prevalent among our respondents, recently implemented pastoral conservation, sedentarization, and development projects are more likely to be ranked as the top concerns among affected households. In order to reduce these concerns, future pastoral policy must be built on the livestock economy, and intervention priority should be given to the geographic areas identified as risk hot spots. In cases where pastoralists have to give up their pastures, the transition to other comparable livelihood strategies must be enabled by creating new opportunities and training pastoralists to acquire the needed skills.


Tests of chameleon gravity.
Theories of modified gravity, where light scalars with non-trivial self-interactions and non-minimal couplings to matter-chameleon and symmetron theories-dynamically suppress deviations from general relativity in the solar system. On other scales, the environmental nature of the screening means that such scalars may be relevant. The highly-nonlinear nature of screening mechanisms means that they evade classical fifth-force searches, and there has been an intense effort towards designing new and novel tests to probe them, both in the laboratory and using astrophysical objects, and by reinterpreting existing datasets. The results of these searches are often presented using different parametrizations, which can make it difficult to compare constraints coming from different probes. The purpose of this review is to summarize the present state-of-the-art searches for screened scalars coupled to matter, and to translate the current bounds into a single parametrization to survey the state of the models. Presently, commonly studied chameleon models are well-constrained but less commonly studied models have large regions of parameter space that are still viable. Symmetron models are constrained well by astrophysical and laboratory tests, but there is a desert separating the two scales where the model is unconstrained. The coupling of chameleons to photons is tightly constrained but the symmetron coupling has yet to be explored. We also summarize the current bounds on f(R) models that exhibit the chameleon mechanism (Hu and Sawicki models). The simplest of these are well constrained by astrophysical probes, but there are currently few reported bounds for theories with higher powers of R. The review ends by discussing the future prospects for constraining screened modified gravity models further using upcoming and planned experiments.


HINGE: long-read assembly achieves optimal repeat resolution.
Long-read sequencing technologies have the potential to produce gold-standard de novo genome assemblies, but fully exploiting error-prone reads to resolve repeats remains a challenge. Aggressive approaches to repeat resolution often produce misassemblies, and conservative approaches lead to unnecessary fragmentation. We present HINGE, an assembler that seeks to achieve optimal repeat resolution by distinguishing repeats that can be resolved given the data from those that cannot. This is accomplished by adding "hinges" to reads for constructing an overlap graph where only unresolvable repeats are merged. As a result, HINGE combines the error resilience of overlap-based assemblers with repeat-resolution capabilities of de Bruijn graph assemblers. HINGE was evaluated on the long-read bacterial data sets from the NCTC project. HINGE produces more finished assemblies than Miniasm and the manual pipeline of NCTC based on the HGAP assembler and Circlator. HINGE also allows us to identify 40 data sets where unresolvable repeats prevent the reliable construction of a unique finished assembly. In these cases, HINGE outputs a visually interpretable assembly graph that encodes all possible finished assemblies consistent with the reads, while other approaches such as the NCTC pipeline and FALCON either fragment the assembly or resolve the ambiguity arbitrarily.


Video-assisted thoracoscopic microthymectomy.
There are many techniques for performing video-assisted thoracoscopic (VATS) thymectomy. This article describes one particular technique that we employ in thymectomies as well as lobectomies. The principles of both operations are as follows, and have been presented in greater detail for lobectomies previously: (I) the use of ports no greater than 5-mm in the intercostal spaces; (II) the use of a 12-mm subxiphoid port; (III) subxiphoid removal of the specimen; (IV) carbon dioxide (CO2) insufflation; (V) vision enabled through a 5-mm camera; (VI) in microlobectomies, the use of a 5-mm stapling device. These principles are particularly suited to thymectomy, as there are no large vascular structures that require stapling and a large number of the instruments required for thymectomy are already 5-mm in diameter, including energy devices, graspers, clip applicators and suction devices. We believe that this technique, which eliminates the need for large incisions in the intercostal spaces, is less painful than other techniques that we have employed, including intercostal uniportal surgery. It also allows the use of CO2 insufflation, which is very useful indeed in endoscopic thymectomies. Furthermore, microthymectomy is technically easier than subxiphoid-only techniques, in that it requires little modification compared to a more conventional VATS thymectomy. We describe this technique in detail in this article.


Mechanism of augmented rate of left ventricular filling during exercise.
At rest, most of left ventricular (LV) filling occurs early in diastole. This LV filling occurs in response to the pressure gradient produced as LV pressure falls below left atrial (LA) pressure. Because mitral valve flow occurs in response to an LA to LV pressure gradient, augmented diastolic mitral valve flow during exercise may be due to an increased mitral valve pressure gradient resulting from a rise in LA pressure and/or a fall in LV early diastolic pressure. Accordingly, we studied 13 conscious dogs, instrumented to measure micromanometer LV and LA pressures, and determined LV volume from three ultrasonic dimensions during exercise. The animals ran on a treadmill for 8-15 minutes at 5-8 miles/hr. With reflexes intact, during exercise, the heart rate increased from 116 +/- 20 to 189 +/- 24 beats per minute (mean +/- SD, p less than 0.01), the maximum rate of change of LV volume (dV/dtmax) increased from 185 +/- 44 to 282 +/- 76 ml/sec (p less than 0.01), the ejection fraction and cardiac output increased, and the duration of diastole decreased from 296 +/- 83 to 162 +/- 71 msec (p less than 0.01). Mitral valve opening pressure, mean LA pressure (10.9 +/- 4.4 versus 10.2 +/- 3.9 mm Hg, p = NS), and LV end-diastolic pressure (12.8 +/- 4.8 versus 13.1 +/- 3.3 mm Hg, p = NS) were all relatively unchanged. The time constant of the fall of isovolumic LV pressure decreased from 28 +/- 3.3 to 21 +/- 4.4 msec (p less than 0.05). The early diastolic portion of the LV pressure-volume loop was shifted downward during exercise, with the minimum LV pressure decreasing from 3.3 +/- 2.8 to -2.8 +/- 3.4 mm Hg (p less than 0.05) and the maximum mitral valve pressure gradient increasing from 5.5 +/- 1.7 to 11.8 +/- 3.5 mm Hg (p less than 0.01). A similar downward shift of the early diastolic portion of the LV pressure-volume loop was produced by infusion of dobutamine (6 micrograms/kg/min i.v.) at rest, as well as by exercise when the heart rate was held constant by right ventricular pacing at 190-210 beats per minute. The downward shift during exercise was prevented by beta-blockade (metoprolol, 0.5 mg/kg i.v.). We conclude that during exercise, sympathetic stimulation and tachycardia produce a downward shift of the early diastolic portion of the LV pressure-volume loop.(ABSTRACT TRUNCATED AT 400 WORDS)


Ionic liquid thin layer-induced memory effects in organic field-effect transistors.
We examined the morphologies and structures of pentacene and C60 thin films grown on thin layers of an ionic liquid, N,N-diethyl-N-methyl-N-(2-methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide (DEME-TFSI), and found that the characteristics of the films depended significantly on the thickness of DEME-TFSI. In addition, we fabricated organic field-effect transistors (OFETs) of pentacene and C60 in which a thin layer of DEME-TFSI was inserted between the organic semiconductor (pentacene or C60) and the gate insulating layer, and measured their performance in situ. We found that 1.5-2 ML (ML: monolayer) DEME-TFSI produced a large hysteresis loop in the transfer characteristics in these OFETs, but 5 ML DEME-TFSI resulted in the formation of normally-on states with far smaller memory effects. The curvatures of the hysteresis loops were caused by the formation of trap states induced by the DEME-TFSI layers. This novel technique provides a simple tool for creating hysteresis behavior and could potentially be applied to transistor memory devices.


Wavelength-compensated Fourier and Fresnel transformers: a unified approach.
We recognize that one can adapt any dispersion-compensated broadband optical Fourier transformer to achieve wavelength compensation in the Fresnel diffraction region just by inserting a diffractive lens at the input plane and vice versa. This unification procedure is employed in a second stage in the design of a novel hybrid (diffractive-refractive) optical setup that provides, in a sequential way, nearly wavelength-independent Fresnel diffraction patterns in the irradiance of the object transmittance.


Protocol for rapid fluorescence in situ hybridization of bacteria in cryosections of microarthropods.
A protocol was developed to detect bacteria inhabiting microarthropods by means of small-subunit rRNA-targeted fluorescence in situ hybridization and microscopy. The protocol is based on cryosections of whole specimens. In contrast to more commonly applied paraffin-embedding techniques, the protocol is quicker and reduces the number of manipulations which might damage the microscopic material. The method allowed the study of the bacterial colonization of Folsomia candida (Collembola) and the detection of bacteria in both the gut and tissue.


Multiple endocrine neoplasias type 2B and RET proto-oncogene.
Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.


Pulmonary arteriovenous malformations: endovascular therapy.
Pulmonary arteriovenous malformations (PAVM) are abnormal direct communications between the branches of pulmonary arteries and veins, and are often seen in patients with hereditary hemorrhagic telangiectasia (HHT). If untreated, the right to left shunt can result in symptoms of hypoxemia, paradoxical emboli to the left side circulation, stroke and intracranial abscess. Endovascular therapy is a minimally invasive outpatient based treatment wherein the feeding artery to the PAVM is occluded with coils or plugs or a combination of both and is associated with minimal morbidity and no mortality. In this manuscript, we will review the indications and contraindications for endovascular therapy, pre-procedural work up, procedure technique and variations, complications, and outcomes.


Mitral valve replacement and tricuspid annuloplasty via right mini-thoracotomy in a patient with tracheostomy.
This report describes our experience in performing mitral valve replacement and tricuspid annuloplasty via a right mini-thoracotomy in a patient with tracheostomy. A 24-year-old woman was admitted with shortness of breath and palpitations. She had subglottic tracheal stenosis and tracheostomy due to tracheal intubation of long duration. Echocardiography revealed chronic severe mitral and tricuspid valve regurgitation. We planned to perform at first the cardiac, and then the tracheal operation, because her left ventricular function was worsening. To eliminate the potential complications of sternotomy in patients with tracheostomy, we used right mini-thoracotomy. We performed mechanical mitral valve replacement for the mitral valve and De Vega annuloplasty for the tricuspid valve. The patient was transferred to the tracheal surgery clinic after the 20th day. Tracheal resection and anastomosis were performed in this department. Three months later, the patient was asymptomatic. We believe that the right mini-thoracotomy approach is a good technique for mitral valve replacement in patients with tracheostomy.


Endoplasmic Reticulum Stress Activates Unfolded Protein Response Signaling and Mediates Inflammation, Obesity, and Cardiac Dysfunction: Therapeutic and Molecular Approach.
Obesity has been implicated as a risk factor for insulin resistance and cardiovascular diseases (CVDs). Although the association between obesity and CVD is a well-established phenomenon, the precise mechanisms remain incompletely understood. This has led to a relative paucity of therapeutic measures for the prevention and treatment of CVD and associated metabolic disorders. Recent studies have shed light on the pivotal role of prolonged endoplasmic reticulum stress (ERS)-initiated activation of the unfolded protein response (UPR), the ensuing chronic low-grade inflammation, and altered insulin signaling in promoting obesity-compromised cardiovascular system (CVS). In this aspect, potential ways of attenuating ERS-initiated UPR signaling seem a promising avenue for therapeutic interventions. We review intersecting role of obesity-induced ERS, chronic inflammation, insulin resistance, and oxidative stress in the discovery of targeted therapy. Moreover, this review highlights the current progress and strategies on therapeutics being explored in preclinical and clinical research to modulate ERS and UPR signaling.


Inhibition of lung fluid clearance and epithelial Na+ channels by chlorine, hypochlorous acid, and chloramines.
We investigated the mechanisms by which chlorine (Cl(2)) and its reactive byproducts inhibit Na(+)-dependent alveolar fluid clearance (AFC) in vivo and the activity of amiloride-sensitive epithelial Na(+) channels (ENaC) by measuring AFC in mice exposed to Cl(2) (0-500 ppm for 30 min) and Na(+) and amiloride-sensitive currents (I(Na) and I(amil), respectively) across Xenopus oocytes expressing human alpha-, beta-, and gamma-ENaC incubated with HOCl (1-2000 microm). Both Cl(2) and HOCl-derived products decreased AFC in mice and whole cell and single channel I(Na) in a dose-dependent manner; these effects were counteracted by serine proteases. Mass spectrometry analysis of the oocyte recording medium identified organic chloramines formed by the interaction of HOCl with HEPES (used as an extracellular buffer). In addition, chloramines formed by the interaction of HOCl with taurine or glycine decreased I(Na) in a similar fashion. Preincubation of oocytes with serine proteases prevented the decrease of I(Na) by HOCl, whereas perfusion of oocytes with a synthetic 51-mer peptide corresponding to the putative furin and plasmin cleaving segment in the gamma-ENaC subunit restored the ability of HOCl to inhibit I(Na). Finally, I(Na) of oocytes expressing wild type alpha- and gamma-ENaC and a mutant form of beta ENaC (S520K), known to result in ENaC channels locked in the open position, were not altered by HOCl. We concluded that HOCl and its reactive intermediates (such as organic chloramines) inhibit ENaC by affecting channel gating, which could be relieved by proteases cleavage.


Sustainable care for children with cancer: a Lancet Oncology Commission.
We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million (44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020-50 would be four times greater than the cumulative treatment costs of $594 billion, producing a net benefit of $1986 billion on the global investment: a net return of $3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths.


Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report.
The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state-of-the-art, clinical diagnostics literature by experts in the field and an open public forum in a face-to-face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design.


Transcriptional activation by STAT6 requires the direct interaction with NCoA-1.
Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that is activated by interleukin-4 (IL-4)-induced tyrosine phosphorylation and mediates most of the IL-4-induced gene expression. Transcriptional activation by STAT6 requires the interaction with coactivators like p300 and the CREB-binding protein (CBP). In this study we have investigated the function of the CBP-associated members of the p160/steroid receptor coactivator family in the transcriptional activation by STAT6. We found that only one of them, NCoA-1, acts as a coactivator for STAT6 and interacts directly with the transactivation domain of STAT6. The N-terminal part of NCoA-1 interacts with the far C-terminal part of the STAT6 transactivation domain but does not interact with the other members of the STAT family. This domain of NCoA-1 has a strong inhibitory effect on STAT6-mediated transactivation when overexpressed in cells, illustrating the importance of NCoA-1 for STAT6-mediated transactivation. In addition, we showed that both coactivators CBP and NCoA-1 bind independently to specific regions within the STAT6 transactivation domain. Our results suggest that multiple contacts between NCoA-1, CBP, and STAT6 are required for transcriptional activation. These findings provide new mechanistic insights into how STAT6 can recruit coactivators required for IL-4-dependent transactivation.


Vaccine Induction of Lymph Node-Resident Simian Immunodeficiency Virus Env-Specific T Follicular Helper Cells in Rhesus Macaques.
Measurement of Ag-specific T follicular helper (TFH) cell activity in rhesus macaques has not previously been reported. Given that rhesus macaques are the animal model of choice for evaluating protective efficacy of HIV/SIV vaccine candidates and that TFH cells play a pivotal role in aiding B cell maturation, quantifying vaccine induction of HIV/SIV-specific TFH cells would greatly benefit vaccine development. In this study, we quantified SIV Env-specific IL-21-producing TFH cells for the first time, to our knowledge, in a nonhuman primate vaccine study. Macaques were primed twice mucosally with adenovirus 5 host range mutant recombinants encoding SIV Env, Rev, Gag, and Nef followed by two i.m. boosts with monomeric SIV gp120 or oligomeric SIV gp140 proteins. At 2 wk after the second protein boost, we obtained lymph node biopsy specimens and quantified the frequency of total and SIV Env-specific IL-21(+) TFH cells and total germinal center B cells, the size and number of germinal centers, and the frequency of SIV-specific Ab-secreting cells in B cell zones. Multiple correlation analyses established the importance of TFH for development of B cell responses in systemic and mucosally localized compartments, including blood, bone marrow, and rectum. Our results suggest that the SIV-specific TFH cells, initially induced by replicating adenovirus-recombinant priming, are long lived. The multiple correlations of SIV Env-specific TFH cells with systemic and mucosal SIV-specific B cell responses indicate that this cell population should be further investigated in HIV vaccine development as a novel correlate of immunity.


Cause of death and presence of respiratory disease at autopsy in an HIV-1 seroconversion cohort of southern African gold miners.
To describe causes of death and respiratory infections in HIV-infected miners in the pre-antiretroviral era, by duration of HIV infection. A retrospective cohort of 1950 gold miners with known dates of HIV seroconversion and 6164 HIV-negative miners was followed from the early 1990s to 2002. Causes of death were available from multiple sources: personnel records, clinical records, death certificates and autopsies of cardiorespiratory organs performed for compensation purposes. Causes of death were known for 279 of 308 HIV-positive (91%) and 234 of 254 HIV-negative (92%) men who died while employed or within 6 months of leaving employment. The mortality rate from unnatural causes was similar in HIV-positive and HIV-negative miners and by duration of HIV infection. Among deaths from natural causes, 87% in HIV-positive and 41% in HIV-negative individuals were caused by infection (P < 0.001); 47% of HIV-positive and 26% of HIV-negative individuals had tuberculosis. The proportion of deaths from natural causes with any infection, or with specific infections (tuberculosis, cryptococcus, pneumocystis), did not vary with the duration of HIV infection. Autopsies were performed on 29% of men who died from natural causes: 83% of HIV-positive and 37% of HIV-negative men had respiratory infections (P < 0.001), half of which were clinically undiagnosed. Tuberculosis was the leading cause of death in HIV-positive and negative men who died from natural causes. Although the mortality rate from natural causes increased greatly with the duration of HIV infection, the pattern of disease hardly changed, suggesting that slow and fast progressors succumb to the same range of diseases.


Oolong, black and pu-erh tea suppresses adiposity in mice via activation of AMP-activated protein kinase.
It is well known that tea has a variety of beneficial impacts on human health, including anti-obesity effects. It is well documented that green tea and its constituent catechins suppress obesity, but the effects of other types of tea on obesity and the potential mechanisms involved are not yet fully understood. In this study, we investigated the suppression of adiposity by oolong, black and pu-erh tea and characterized the underlying molecular mechanism in vivo. We found that the consumption of oolong, black or pu-erh tea for a period of one week significantly decreased visceral fat without affecting body weight in male ICR mice. On a mechanistic level, the consumption of tea enhanced the phosphorylation of AMP-activated protein kinase (AMPK) in white adipose tissue (WAT). This was accompanied by the induction of WAT protein levels of uncoupling protein 1 and insulin-like growth factor binding protein 1. Our results indicate that oolong, black and pu-erh tea, and in particular, black tea, suppresses adiposity via phosphorylation of the key metabolic regulator AMPK and increases browning of WAT.


Microchimerism in autoimmunity and transplantation: potential relevance to multiple sclerosis.
Microchimerism (MC) is the stable presence of small numbers of non-host cells and appears to be commonly present in parous women. There are several methods of detecting microchimerism and each has advantages for different types of studies, but the risk of contamination and the differing levels of sensitivity lead to difficulties in estimating the proportion of individuals that are microchimeric. Recent observations of an increased frequency of microchimerism in women with scleroderma and Hashimoto's thyroiditis suggest that microchimerism may increase the risk of developing autoimmune disease. Inferences regarding autoimmunity are drawn from the immunological effects of organ and bone-marrow transplantation. Potential research questions regarding microchimerism, human leukocyte antigen (HLA) similarity, and autoimmune diseases in the context of multiple sclerosis (MS) are discussed.


Multicenter evaluation of the administration of crotalid antivenom in cats: 115 cases (2000-2011).
To evaluate use of crotalid antivenom, frequency of hypersensitivity reactions, and risk factors for hypersensitivity reactions and death in envenomed cats. Retrospective multicenter case series. 115 envenomed cats treated with antivenom and 177 envenomed cats treated without antivenom. Procedures-Medical records from 5 institutions were searched by means of a multiple-choice survey with standardized answers for patient data including signalment, diagnosis, antivenom administration criteria, premedication, product, dose, administration rate, hypersensitivity reactions, and mortality rate. 95 of 115 (82.6%) cats received whole IgG antivenom, 11 (9.57%) received F(ab')2 antivenom, and 4 (3.48%) received Fab antivenom. The majority (101/115 [878%]) of cats received 1 vial of antivenom. In all cats, the median dilution of antivenom was 1:60 (range, 1:10 to 1:250) administered over a median period of 2.0 hours (range, 0.3 to 9.0 hours). There was no mortality rate difference between cats that did (6.67%) or did not (5.08%) receive antivenom. A type I hypersensitivity reaction was diagnosed in 26 of 115 (22.6%) cats. The use of premedications did not decrease type I hypersensitivity or improve mortality rate. Cats that had a type I hypersensitivity reaction were 10 times as likely to die as were those that did not have such a reaction. The mortality rate of cats treated with antivenom was low. The administration of premedications did not improve mortality rate or prevent hypersensitivity reactions. The only variable associated with mortality rate was development of a type I hypersensitivity reaction. The rate of antivenom administration should be further evaluated as a possible risk factor for type I hypersensitivity reactions.


Alternative splicing and nonsense-mediated decay modulate expression of important regulatory genes in Arabidopsis.
Alternative splicing (AS) coupled to nonsense-mediated decay (NMD) is a post-transcriptional mechanism for regulating gene expression. We have used a high-resolution AS RT-PCR panel to identify endogenous AS isoforms which increase in abundance when NMD is impaired in the Arabidopsis NMD factor mutants, upf1-5 and upf3-1. Of 270 AS genes (950 transcripts) on the panel, 102 transcripts from 97 genes (32%) were identified as NMD targets. Extrapolating from these data around 13% of intron-containing genes in the Arabidopsis genome are potentially regulated by AS/NMD. This cohort of naturally occurring NMD-sensitive AS transcripts also allowed the analysis of the signals for NMD in plants. We show the importance of AS in introns in 5' or 3'UTRs in modulating NMD-sensitivity of mRNA transcripts. In particular, we identified upstream open reading frames overlapping the main start codon as a new trigger for NMD in plants and determined that NMD is induced if 3'-UTRs were >350 nt. Unexpectedly, although many intron retention transcripts possess NMD features, they are not sensitive to NMD. Finally, we have shown that AS/NMD regulates the abundance of transcripts of many genes important for plant development and adaptation including transcription factors, RNA processing factors and stress response genes.


Gene flow and the geographic structure of natural populations.
There is abundant geographic variation in both morphology and gene frequency in most species. The extent of geographic variation results from a balance of forces tending to produce local genetic differentiation and forces tending to produce genetic homogeneity. Mutation, genetic drift due to finite population size, and natural selection favoring adaptations to local environmental conditions will all lead to the genetic differentiation of local populations, and the movement of gametes, individuals, and even entire populations--collectively called gene flow--will oppose that differentiation. Gene flow may either constrain evolution by preventing adaptation to local conditions or promote evolution by spreading new genes and combinations of genes throughout a species' range. Several methods are available for estimating the amount of gene flow. Direct methods monitor ongoing gene flow, and indirect methods use spatial distributions of gene frequencies to infer past gene flow. Applications of these methods show that species differ widely in the gene flow that they experience. Of particular interest are those species for which direct methods indicate little current gene flow but indirect methods indicate much higher levels of gene flow in the recent past. Such species probably have undergone large-scale demographic changes relatively frequently.


Reduced heart rate variability in social anxiety disorder: associations with gender and symptom severity.
Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance. Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures. Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use. The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach-related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains.


Normal distribution of palpebral fissure lengths in Canadian school age children.
Fetal alcohol syndrome (FAS) includes the facial dysmorphic feature of short palpebral fissures (PFs) and short PFs are a key physical marker for identifying children with FAS and some other rarer conditions. There is concern that normative data on PFs now available may not reflect all racial/ethnic groups and might be inaccurate in general. To accomplish a large population based study that would accurately determine normative PF values across the full diversity of the Canadian school age population. A normative sample of school age children was identified in Vancouver, British Columbia and Winnipeg, Manitoba to reflect the diversity of racial and national groups in Canada. The sample included students in grades 2, 4, 6, 8, and 10 from 17 schools in Vancouver and 31 schools in Winnipeg. Schools were selected based on racial diversity obtained from data from the 2001 Statistics Canada census. 1064 students in Vancouver and 1033 students in Winnipeg were photographed in a standardized way. Photographs were analyzed using a computerized method. Analysis demonstrated that PFs do grow with age and there is a slight but meaningful difference between boys and girls in each age group. It is possible to define Canadian standards without reference to racial or ethnic origin. Mean results with norms and standard deviations are presented in figures for clinical use and are clinically smaller than those found in the most commonly used reference book.


Combined motor imagery and SSVEP based BCI control of a 2 DoF artificial upper limb.
A Brain-Computer Interface (BCI) is a device that transforms brain signals, which are intentionally modulated by a user, into control commands. BCIs based on motor imagery (MI) and steady-state visual evoked potentials (SSVEP) can partially restore motor control in spinal cord injured patients. To determine whether these BCIs can be combined for grasp and elbow function control independently, we investigated a control method where the beta rebound after brisk feet MI is used to control the grasp function, and a two-class SSVEP-BCI the elbow function of a 2 degrees-of-freedom artificial upper limb. Subjective preferences for the BCI control were assessed with a questionnaire. The results of the initial evaluation of the system suggests that this is feasible.


Perspectives on pregnancy in women with chronic kidney disease: systematic review of qualitative studies.
Achieving parenthood in women with chronic kidney disease (CKD) is challenging due to reduced fertility and the risk of adverse outcomes. We aimed to describe women's perspectives of pregnancy in CKD. Electronic databases were searched to April 2014. Studies were synthesized thematically. From 15 studies (n = 257) we identified seven themes. 'Pursuing motherhood' was fulfilling an innate or social desire to have a child. 'Failure to fulfill social norms' of being unable to conceive diminished their self-worth. 'Fear of birth defects' was attributed to the potential side effects of immunosuppression. 'Decisional insecurity and conflict' encompassed uncertainties of prioritizing pregnancy as sacrifices had to be made in family life and work to minimize their risk of complications. Transplant recipients were concerned about the increased likelihood of graft loss. The possibility of genetic transmission of kidney disease influenced decisions about childbearing. 'Withholding emotional investment' was a way of protecting against the devastation of inability to conceive, miscarriage or stillbirth. 'Control and determination' reflected their capacity to choose to accept the risks of pregnancy. Some felt traumatized when their physician unduly warned against pregnancy. 'Exacerbating disease' due to pregnancy was also of concern to women. For women with CKD, pregnancy decisions can be emotionally complicated by health risks, family burden and the perceived risk of fetal malformation. Proactive counseling, shared decision-making about family planning and managing pregnancy in CKD that addresses patient preferences, and multidisciplinary care involving nephrologists, reproductive and obstetrics specialists, and psychological support may improve management of pregnancy issues in CKD.


Monitoring focal adhesion kinase phosphorylation dynamics in live cells.
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase essential for a diverse set of cellular functions. Current methods for monitoring FAK activity in response to an extracellular stimulus lack spatiotemporal resolution and/or the ability to perform multiplex detection. Here we report on a novel approach to monitor the real-time kinase phosphorylation activity of FAK in live single cells by fluorescence lifetime imaging.


cAMP metabolism controls caspase-11 inflammasome activation and pyroptosis in sepsis.
The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11-dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or Escherichia coli infection in macrophages. l-adrenaline-induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11-mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of caspase-11 (Casp11-/- ), or Gsdmd inactivation (GsdmdI105N/I105N ) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.


Guide lines for the tuning and the evaluation of decentralized and decoupling controllers for processes with recirculation.
This paper gives guidelines for the pairing, the time response specification, and the tuning for processes with recirculation when decentralized controllers are used. This selection is based on the condition number, which is an indicator of the process directionality, and on the generalized dynamic relative gain (GDRG), which is a measure of the interaction. Simple tuning rules are developed and results are compared to algebraic controllers with decouplers. Performances are evaluated for set-point changes as well as disturbance rejection using the generalized step response (GSR). The GSR gives a 3D graphic of the system response as a function of the input direction.


Improving laboratory test ordering can reduce costs in surgical wards.
Background and Aim Laboratory blood tests for hospitalized patients are often overused. Excessive costs and no proof of benefit suggest re-evaluating the current approach to laboratory test ordering. The aim of the study is to improve the decision-making process of test ordering and to investigate what effect a rational, evidence-based use of laboratory test ordering in surgical wards would have on costs and healthcare resources. Methods Three-phase experimental prospective study carried out at the tertiary referral teaching hospital of Parma. Phase 1 (baseline status). The baseline status of laboratory test ordering was evaluated by recording the number of biochemical tests requested for patients undergoing elective surgery. Laboratory tests were grouped in "recommended" (RT) and "non recommended" (nRT) tests on the basis of pertinent literature. Phase 2 (improvement action): new guidelines were introduced into clinical practice. Phase 3 (feedback): Prospective data collection for first and second feedback was performed with no advance notice. Results A highly significant reduction in test ordering was found on occasion of the phases 2 and 3 of the study. The overall number of tests decreased, largely due to a decrease in the use of nRT. Conclusions Analysis was justified by the fact that most test requests proved not to be supported by clinical evidence. Inappropriate ordering of laboratory tests results in an unnecessarily high number of requests, which do not in turn improve patient management. Moreover, more appropriate, evidence-based laboratory test ordering for patients undergoing elective surgery may produce a significant reduction in costs, particularly in high-cost settings. (www.actabiomedica.it).


The syndrome of unilateral tuberothalamic artery territory infarction.
The study of 3 personal cases and 5 published cases of unilateral infarct limited to the territory of the tuberothalamic artery suggests that this syndrome should be differentiated from the other thalamic syndromes. The onset is usually sudden, with moderate contralateral weakness. Sensory changes may be present but remain mild. The patients are apathetic, show perseveration and may be disoriented. In left-sided infarcts, transcortical aphasia, verbal and visual memory impairment and sometimes acalculia are found. In right-sided infarcts, hemispatial neglect, visual memory impairment and disturbed visuospatial processing are common. A decreased level of consciousness, disturbed ocular movements, severe motor weakness and delayed abnormal movements do not occur. Involvement of the ventral lateral and dorsomedial nucleus with sparing of the intralaminar nuclei, posterolateral formation and upper midbrain may explain this picture. The fact that the tuberothalamic artery arises from the posterior communicating artery, which often receives its supply from the carotid system, further justifies considering unilateral tuberothalamic infarcts as a syndrome.