Being discharged from hospice alive: the lived experience of patients and families.
Approximately 259,000 patients were discharged alive from U.S. hospices in 2010. There is a paucity of research describing the experiences of these individuals and their family members. The study objective was to explore the experiences of adults discharged from a hospice program due to decertification related to ineligibility or extended prognosis, from the perspective of the individual and his or her adult family members. Research questions were, How do participants perceive and describe (1) the experience of being discharged alive from hospice, and (2) their quality of life after a live hospice discharge? A transcendental phenomenological design guided this study. Purposive, snowball sampling was used to recruit 12 volunteers, aged 35-92 years, who had experienced live hospice discharge due to decertification. Data collection included open-ended interviews and journals. Findings included two primary themes: suffering "AS…" and the paradox of hospice discharge. These primary themes were supported by 12 subthemes: abandonment, unanswered questions, loss of security, loneliness, uncertainty, anger and frustration, physical decline, bearing exhaustive witness, having and needing support, mixed feelings, not dying fast enough, and hospice equals life. Understanding this experience may enhance understanding and aid health care providers to anticipate the unique needs of the hospice population.


Novel growth systems.
Most laboratory growth systems are based on homogeneous culture techniques. This review article discusses model systems which incorporate spatial heterogeneity. The latter include linked homogeneous growth vessels such as the multistage chemostat and the bidirectionally connected gradostat, gel stabilized models including one and two dimensional variants, microbial film fermenters, percolating columns and fluidized bed reactors.


[Travel, sports and pregnancy].
This article is an attempt to review and to discuss critically the pros and cons of physical stress to which a pregnant woman is subjected by sports activities or by travel. The review is based on theoretical considerations as communicated in the article as well as on facts derived from casual observations or systematic studies. Besides the subjective feeling of well-being of the pregnant woman associated with sports activities, objective data favour the preservation or enhancement of fitness by training during pregnancy; other factors in favour of physical load, and the capacity to sustain such load, are the positive reports on the course of pregnancy, on birth, and on the influence exercised on the child by the sports activities of the pregnant mother, the often-quoted experiences collected during sports activities of competitive sportswomen who are pregnant, and the behaviour of pregnant animals. Risks consist in an increased danger of traumatization of mother and foetus resulting from certain types of sports requiring maintenance of balance or sudden changes of movement. Hyperthermia should be avoided, for example, excessively long-lasting sauna baths, or physical activity associated with high stress, such as marathon running, because thermoregulation is hampered during pregnancy in such a way that blood flow of the uterus is affected; besides, there is also the risk of teratogenic effects during the early stages of pregnancy. Excess physical stress leading to exhaustion of the pregnant woman (in animal experiments, in circulatory collapse) definitely exercises an adverse effect on the foetus.(ABSTRACT TRUNCATED AT 250 WORDS)


[The diagnosis and course of progressive disseminated pulmonary tuberculosis].
A hundred and forty-six patients with disseminated pulmonary tuberculosis were examined. Hematogenous disseminated tuberculosis at this stage was ascertained to run more frequently as acute and acutely progressive. The proportion of lymphogenous tuberculosis was shown to increase among all the types of disseminated pulmonary tuberculosis. Identification of the lymphobronchogenic type of disseminated pulmonary tuberculosis is recommended.


Effects of Different Relative Loads on Power Performance During the Ballistic Push-up.
Wang, R, Hoffman, JR, Sadres, E, Bartolomei, S, Muddle, TWD, Fukuda, DH, and Stout, JR. Effects of different relative loads on power performance during the ballistic push-up. J Strength Cond Res 31(12): 3411-3416, 2017-The purpose of this investigation was to examine the effect of load on force and power performance during a ballistic push-up. Sixty (24.5 ± 4.3 years, 1.75 ± 0.07 m, and 80.8 ± 13.5 kg) recreationally active men who participated in this investigation completed all testing and were included in the data analysis. All participants were required to perform a 1 repetition maximum bench press, and ballistic push-ups without external load (T1), with 10% (T2) and 20% (T3) of their body mass. Ballistic push-ups during T2 and T3 were performed using a weight loaded vest. Peak and mean force, power, as well as net impulse and flight time were determined for each ballistic push-up. Peak and mean force were both significantly greater (p < 0.01) during T3 (1,062 ± 202 and 901 ± 154 N, respectively), than both T2 (1,017 ± 202 and 842 ± 151 N, respectively) and T1 (960 ± 188 and 792 ± 140 N, respectively). Peak and mean power were significantly greater (p < 0.01) during T1 (950 ± 257 and 521 ± 148 W, respectively), than both T2 (872 ± 246 and 485 ± 143 W, respectively) and T3 (814 ± 275 and 485 ± 162 W, respectively). Peak and mean power were greatest during T1, regardless of participants' strength levels. Significant (p < 0.01) greater net impulse and smaller peak velocity and flight time were also noted from T1 to T3. Results of this investigation indicated that maximal power outputs were achieved without the use of an external load when performing the ballistic push-up, regardless of the participants' level of strength.


Dynamic Angular Stiffness of the Ankle Joint during Running and Sprinting.
The purpose of this study was to compare the moment-angle relationship of the ankle joint during running and sprinting to determine how the dynamic angular stiffness is influenced by different activities. For both running and sprinting, the results indicated that the ankle joint produced an exclusively extensor moment, absorbing energy during the first half of the stance phase and producing energy during the second half. The biphasic nature of the joint absorbing energy followed by the joint producing energy, while continually creating an extensor moment, was similar to a spring being compressed and allowed to extend. The dynamic stiffness of the ankle joint was 5.68 N · m/° for running and 7.38 N · m/° for sprinting. It appeared that the stiffness of the ankle joint was not a specialized characteristic of each individual but rather a specialized characteristic of the activity or demand placed upon it.


Nanoscopic subcellular imaging enabled by ion beam tomography.
Multiplexed ion beam imaging (MIBI) has been previously used to profile multiple parameters in two dimensions in single cells within tissue slices. Here, a mathematical and technical framework for three-dimensional (3D) subcellular MIBI is presented. Ion-beam tomography (IBT) compiles ion beam images that are acquired iteratively across successive, multiple scans, and later assembled into a 3D format without loss of depth resolution. Algorithmic deconvolution, tailored for ion beams, is then applied to the transformed ion image series, yielding 4-fold enhanced ion beam data cubes. To further generate 3D sub-ion-beam-width precision visuals, isolated ion molecules are localized in the raw ion beam images, creating an approach coined as SILM, secondary ion beam localization microscopy, providing sub-25 nm accuracy in original ion images. Using deep learning, a parameter-free reconstruction method for ion beam tomograms with high accuracy is developed for low-density targets. In cultured cancer cells and tissues, IBT enables accessible visualization of 3D volumetric distributions of genomic regions, RNA transcripts, and protein factors with 5 nm axial resolution using isotope-enrichments and label-free elemental analyses. Multiparameter imaging of subcellular features at near macromolecular resolution is implemented by the IBT tools as a general biocomputation pipeline for imaging mass spectrometry.


COPD exacerbations: defining their cause and prevention.
Exacerbations of chronic obstructive pulmonary disease (COPD) are episodes of worsening of symptoms, leading to substantial morbidity and mortality. COPD exacerbations are associated with increased airway and systemic inflammation and physiological changes, especially the development of hyperinflation. They are triggered mainly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. Some patients are particularly susceptible to exacerbations, and show worse health status and faster disease progression than those who have infrequent exacerbations. Several pharmacological interventions are effective for the reduction of exacerbation frequency and severity in COPD such as inhaled steroids, long-acting bronchodilators, and their combinations. Non-pharmacological therapies such as pulmonary rehabilitation, self-management, and home ventilatory support are becoming increasingly important, but still need to be studied in controlled trials. The future of exacerbation prevention is in assessment of optimum combinations of pharmacological and non-pharmacological therapies that will result in improvement of health status, and reduction of hospital admission and mortality associated with COPD.


Use of antipsychotic medications in pediatric populations: what do the data say?
Recent reports of antipsychotic medication use in pediatric populations describe large increases in rates of use. Much interest in the increasing use has focused on potentially inappropriate prescribing for non-Food and Drug Administration-approved uses and use amongst youth with no mental health diagnosis. Different studies of antipsychotic use have used different time periods, geographic and insurance populations of youth, and aggregations of diagnoses. We review recent estimates of use and comment on the similarities and dissimilarities in rates of use. We also report new data obtained on 11 health maintenance organizations that are members of the Mental Health Research Network in order to update and extend the knowledge base on use by diagnostic indication. Results indicate that most use in pediatric populations is for disruptive behaviors and not psychotic disorders. Differences in estimates are likely a function of differences in methodology; however, there is remarkable consistency in estimates of use by diagnosis.


Application of the Caprini risk assessment model in evaluation of non-venous thromboembolism complications in plastic and reconstructive surgery patients.
The Caprini Risk Assessment Model is used to categorize patient risk for venous thromboembolism (VTE) events; its predictive associations have been repeatedly corroborated. Calculating scores involves consideration of systemic factors that may predict other postoperative complications. This study investigates whether Caprini scores can be applied to non-VTE complications. The authors undertook a retrospective chart review of 1598 encounters for a series of complex reconstructive and body contouring operations at an academic medical institution. Input variables included Caprini score components, patient comorbidities, and prophylactic use of antithrombotic drugs. Output variables were postoperative complications. Tests for proportions were performed on percentile data. Nonpercentile data were treated with comparison of means (t test). Odds ratios for complications were calculated for stratified risk groups and compared. The overall complication rate was 28.03%. Deep vein thrombosis (DVT) incidence was 1.50%. Differences in age, body mass index (BMI), operation time, hypertension, diabetes, renal disease, and cancer were statistically significant between patients who experienced complications and those who did not. For DVT versus DVT-free patients, differences in sex, BMI, operation time, smoking status, diabetes, hypertension, and prior DVT were significant. Caprini scores identified 628 encounters as low risk (0-4) and 970 as high risk (>5). Dehiscence, infection, necrosis, seroma, hematoma, and overall complication rate significantly increased the incidence for the high-risk group. Caprini scores can be used as valuable predictors for some non-VTE postoperative complications (dehiscence, infection, seroma, hematoma, and necrosis). In addition to VTE events, clinicians should pay special attention to clinical signs indicative of the complications listed above when dealing with high-risk, high-Caprini score patients.


Twenty-five year review of Pseudomonas aeruginosa bacteremia in a burn center.
The incidence of Pseudomonas aeruginosa bacteremia was examined in 5,882 burn patients consecutively admitted over a 25-year period to one burn center. The population examined had an average burn size of 33.8% of the body surface and an average age of 26.3 years. Pseudomonas aeruginosa bacteremia occurred in 540 patients. These patients had an average burn size of 54.2% and average age of 28 years. Mortality was 77%. Bacteremia with other organisms occurred during hospitalization of all but 128 of the 540 patients. Comparison of predicted mortality based on burn size and age to observed mortality showed Pseudomonas aeruginosa bacteremia to be associated with a 28% increase in mortality. Examination of mortality as a function of time showed no significant change over the 25-year period. The incidence of Pseudomonas aeruginosa colonization and infection was examined in 400 recently admitted burn patients. Colonization occurred in 107 and 34 infections were recorded in 27 of the colonized patients.


Wayside Detection of Wheel Minor Defects in High-Speed Trains by a Bayesian Blind Source Separation Method.
For high-speed trains, out-of-roundness (OOR)/defects on wheel tread with small radius deviation may suffice to give rise to severe damage on both vehicle components and track structure when they run at high speeds. It is thus highly desirable to detect the defects in a timely manner and then conduct wheel re-profiling for the defective wheels. This paper presents a wayside fiber Bragg grating (FBG)-based wheel condition monitoring system which can detect wheel tread defects online during train passage. A defect identification algorithm is developed to identify potential wheel defects with the monitoring data of rail strain response collected by the devised system. In view that minor wheel defects can only generate anomalies with low amplitude compared with the wheel load effect, advanced signal processing methods are needed to extract the defect-sensitive feature from the monitoring data. This paper explores a Bayesian blind source separation (BSS) method to decompose the rail response signal and to obtain the component that contains defect-sensitive features. After that, the potential defects are identified by analyzing anomalies in the time history based on the Chauvenet's criterion. To verify the proposed defect detection method, a blind test is conducted using a new train equipped with defective wheels. The results show that all the defects are identified and they concur well with offline wheel radius deviation measurement results. Minor defects with a radius deviation of only 0.06 mm are successfully detected.


Importance of stimulation paradigm in determining facilitation and effects of neuromodulation.
Evoked synaptic activity within the CNS and at the neuromuscular junction in most in vivo preparations studied occurs not with single isolated stimuli, but with trains, or bursts, of stimuli. Although for ease in studying the mechanisms of vesicular synaptic transmission one often uses single discrete stimuli, the true mechanisms in the animal may be far more complex. When repetitive stimuli are present at a nerve terminal, often a heightened (i.e., facilitated) postsynaptic potential can be as a result. Facilitation is commonly used as an index of synaptic function and plasticity induced by chronic stimulation or by neuromodulation. The mechanisms that give rise to facilitation are thought to be the same that may underlie short-term learning and memory [C.H. Bailey, E.R. Kandel, Structural changes accompanying memory storage. Annu. Rev. Physiol. 55 (1993) 397-426.]. Differences in short term facilitation (STF) are seen depending on the conventional stimulation paradigm (twin pulse, train, or continuous) used to induce facilitation. Thus, a battery of paradigms should be used to characterize synaptic function to obtain a closer understanding of the possible in vivo conditions.


[Molecular nature of the direct mutations induced by 4-nitro-quinoline-N-oxide and 3-methyl-4-nitroquinoline-N-oxide in the ADE2 gene of Saccharomyces cerevisiae].
The lethal and mutagenic effects and the nature of forward mutations in ADE2 gene induced by highly carcinogenic agent 4-nitroquinoline-N-oxide (4NQO) and its noncarcinogenic analogue 3-methyl-4-nitroquinoline-N-oxide (3M4NQO) have been examined in Saccharomyces cerevisiae. It is shown that 3M4NQO is more toxic than 4NQO. Both are very efficient mutagens: the mutagenic efficiency for ADE1 and ADE2 genes was 7.9 X 10(-5) for 4NQO and 10.5 X 10(-5) for 3M4NQO. The base pair substitutions are the main type of induced mutations in ADE2 gene (95 and 89% for 4NQO and 3M4NQO, respectively); among these 40% transversions for 4NQO and 63% for 3M4NQO, GC----AT transitions-32 and 31% for 4NQO and 3M4NQO, respectively, AT----GC transitions-23 and 22% for 4NQO and 3M4NQO, respectively. The results obtained indicate that 4NQO and 3M4NQO induce the same spectrum of mutations in ADE2 gene and that both mutagens are nonspecific in yeast cells.


Interspecific difference in the photosynthesis-nitrogen relationship: patterns, physiological causes, and ecological importance.
The photosynthesis-nitrogen relationship is significantly different among species. Photosynthetic capacity per unit leaf nitrogen, termed as photosynthetic nitrogen-use efficiency (PNUE), has been considered an important leaf trait to characterise species in relation to their leaf economics, physiology, and strategy. In this review, I discuss (1) relations between PNUE and species ecology, (2) physiological causes and (3) ecological implications of the interspecific difference in PNUE. Species with a high PNUE tend to have high growth rates and occur in disturbed or high productivity habitats, while those with a low PNUE occur in stressful or low productivity habitats. PNUE is an important leaf trait that correlates with other leaf traits, such as leaf mass per area (LMA) and leaf life span, irrespective of life form, phylogeny, and biomes. Various factors are involved in the interspecific difference. In particular, nitrogen allocation within leaves and the mesophyll conductance for CO(2) diffusion are important. To produce tough leaves, plants need to allocate more biomass and nitrogen to make thick cell walls, leading to a reduction in the mesophyll conductance and in nitrogen allocation to the photosynthetic apparatus. Allocation of biomass and nitrogen to cell walls may cause the negative relationship between PNUE and LMA. Since plants cannot maximise both PNUE and leaf toughness, there is a trade-off between photosynthesis and persistence, which enables the existence of species with various leaf characteristics on the earth.


Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries.
Achieving sufficient enrichment of ligands from DNA-encoded libraries for detection can be difficult, particularly for low affinity ligands within highly complex libraries. To address this challenge, we present an approach for crosslinking DNA-linked ligands to target proteins using electrophilic or photoreactive groups. The approach involves the teathering of a ssDNA oligonucleotide to a DNA-encoded molecule to enable attachment of a reactive group post-synthetically via DNA hybridization. Crosslinking traps ligand-protein complexes while in solution and allows for stringent washing conditions to be applied in the subsequent purification. Five reactive groups (tosyl, NHS ester, sulfonyl fluoride, phenyl azide, and diazirine) were tested for crosslinking efficiency and specificity with three DNA-linked ligands to their target proteins. In a model selection, crosslinking resulted in improved enrichment of both high and a low affinity ligands in comparison to a selection with a solid-phase immobilized protein.


Detection of amyloid plaques targeted by bifunctional USPIO in Alzheimer's disease transgenic mice using magnetic resonance microimaging.
Amyloid plaques are a key pathological hallmark of Alzheimer's disease (AD). The detection of amyloid plaques in the brain is important for the diagnosis of AD, as well as for following potential amyloid targeting therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (µMRI) in AD transgenic mice, where we used mannitol to enhance blood brain barrier (BBB) permeability. In the present study, we used bifunctional ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Aβ1-42 peptide to image amyloid plaque deposition in the mouse brain. We coupled the nanoparticles to polyethylene glycol (PEG) in order to improve BBB permeability. These USPIO-PEG-Aβ1-42 nanoparticles were injected intravenously in AD model transgenic mice followed by initial in vivo and subsequent ex vivo μMRI. A 3D gradient multi-echo sequence was used for imaging with a 100 µm isotropic resolution. The amyloid plaques detected by T2*-weighted μMRI were confirmed with matched histological sections. The region of interest-based quantitative measurement of T2* values obtained from the in vivo μMRI showed contrast injected AD Tg mice had significantly reduced T2* values compared to wild-type mice. In addition, the ex vivo scans were examined with voxel-based analysis (VBA) using statistical parametric mapping (SPM) for comparison of USPIO-PEG-Aβ1-42 injected AD transgenic and USPIO alone injected AD transgenic mice. The regional differences seen by VBA in the USPIO-PEG-Aβ1-42 injected AD transgenic correlated with the amyloid plaque distribution histologically. Our results indicate that USPIO-PEG-Aβ1-42 can be used for amyloid plaque detection in vivo by intravenous injection without the need to co-inject an agent which increases permeability of the BBB. This technique could aid the development of novel amyloid targeting drugs by allowing therapeutic effects to be followed longitudinally in model AD mice.


Semisupervised Gaussian Process for Automated Enzyme Search.
Synthetic biology is today harnessing the design of novel and greener biosynthesis routes for the production of added-value chemicals and natural products. The design of novel pathways often requires a detailed selection of enzyme sequences to import into the chassis at each of the reaction steps. To address such design requirements in an automated way, we present here a tool for exploring the space of enzymatic reactions. Given a reaction and an enzyme the tool provides a probability estimate that the enzyme catalyzes the reaction. Our tool first considers the similarity of a reaction to known biochemical reactions with respect to signatures around their reaction centers. Signatures are defined based on chemical transformation rules by using extended connectivity fingerprint descriptors. A semisupervised Gaussian process model associated with the similar known reactions then provides the probability estimate. The Gaussian process model uses information about both the reaction and the enzyme in providing the estimate. These estimates were validated experimentally by the application of the Gaussian process model to a newly identified metabolite in Escherichia coli in order to search for the enzymes catalyzing its associated reactions. Furthermore, we show with several pathway design examples how such ability to assign probability estimates to enzymatic reactions provides the potential to assist in bioengineering applications, providing experimental validation to our proposed approach. To the best of our knowledge, the proposed approach is the first application of Gaussian processes dealing with biological sequences and chemicals, the use of a semisupervised Gaussian process framework is also novel in the context of machine learning applied to bioinformatics. However, the ability of an enzyme to catalyze a reaction depends on the affinity between the substrates of the reaction and the enzyme. This affinity is generally quantified by the Michaelis constant KM. Therefore, we also demonstrate using Gaussian process regression to predict KM given a substrate-enzyme pair.


Conserved charged residues in the leucine-rich repeat domain of the Ran GTPase activating protein are required for Ran binding and GTPase activation.
GTPase activating proteins (GAPs) for Ran, a Ras-related GTPase participating in nucleocytoplasmic transport, have been identified in different species ranging from yeast to man. All RanGAPs are characterized by a conserved domain consisting of eight leucine-rich repeats (LRRs) interrupted at two positions by so-called separating regions, the latter being unique for RanGAPs within the family of LRR proteins. The cytosolic RanGAP activity is essential for the Ran GTPase cycle which in turn provides directionality in nucleocytoplasmic transport, but the structural basis for the interaction between Ran and its GAP has not been elucidated. In order to gain a better understanding of this interaction we generated a number of mutant RanGAPs carrying amino acid substitutions in the LRR domain and analysed their complex formation with Ran as well as their ability to stimulate the intrinsic GTPase activity of the G protein. We show that conserved charged residues present in the separating regions of the LRR domain are indispensable for efficient Ran binding and GAP activity. These separating regions contain three conserved arginines which could possibly serve as catalytic residues similar to the arginine fingers identified in GAPs for other small GTPases. However, mutations in two of these arginines do not affect the GAP activity and replacement of the third conserved arginine (Arg91 in human RanGAP) severely interferes not only with GAP activity but also with Ran binding. This indicates that RanGAP-stimulated GTP hydrolysis on Ran does not involve a catalytic arginine residue but requires certain charged residues of the LRR domain of the GAP for mediating the protein-protein interaction.


Ludwig Mauthner (1840-1894): neuroanatomist and noted ophthalmologist in Fin-de-Siècle Vienna.
Ludwig Mauthner was only 19 years old when he published his discovery of the colossal fibers in the spinal cord of fishes which now bear his name. Based on Mauthner's works, archival material, and contemporary sources we provide a summary of his life and work as neuroanatomist and ophthalmologist in imperial Austria. In the years 1859-1863 Mauthner published four papers on the structure of the central nervous system in vertebrates. His first report on fishes contains the original description of a 'colossal myelinated nerve fiber' on each side of the central canal, extending through the entire spinal cord. Another, more general, treatise on 'the morphological elements of the nervous system' (published in 1863) summarizes his neurohistological studies of various vertebrates. It includes a classification of nerve cells based on their (histochemical) reaction to carmine. The main findings were soon shown to be artefactual; the paper had a long-range impact, however, because it provoked fruitful controversy among contemporary neuroanatomists. Mauthner published several monographs and numerous articles in ophthalmology, a newly developing branch of medicine that he chose for his later career. After abruptly resigning from a professorship at Innsbruck University, he opened a private practice in Vienna and continued lecturing in his field. He became a noted eye-surgeon, was elected Assistant Director of the Vienna 'Allgemeine Poliklinik', and in 1894 became Professor and Chair of Ophthalmology at the University of Vienna. Mauthner unexpectedly died on the night following the formal announcement of his appointment.


Ferroelectric control of a Mott insulator.
The electric field control of functional properties is an important goal in oxide-based electronics. To endow devices with memory, ferroelectric gating is interesting, but usually weak compared to volatile electrolyte gating. Here, we report a very large ferroelectric field-effect in perovskite heterostructures combining the Mott insulator CaMnO3 and the ferroelectric BiFeO3 in its "supertetragonal" phase. Upon polarization reversal of the BiFeO3 gate, the CaMnO3 channel resistance shows a fourfold variation around room temperature, and a tenfold change at ~200 K. This is accompanied by a carrier density modulation exceeding one order of magnitude. We have analyzed the results for various CaMnO3 thicknesses and explain them by the electrostatic doping of the CaMnO3 layer and the presence of a fixed dipole at the CaMnO3/BiFeO3 interface. Our results suggest the relevance of ferroelectric gates to control orbital- or spin-ordered phases, ubiquitous in Mott systems, and pave the way toward efficient Mott-tronics devices.


Early cortical atrophy is related to depression in patients with neuropathologically confirmed Parkinson's disease.
Depression is a common comorbidity in Parkinson's disease (PD) and other synucleinopathies. In non-PD geriatric patients, cortical atrophy has previously been connected to depression. Here, we investigated cortical atrophy and vascular white matter hyperintensities (WMHs) in autopsy-confirmed parkinsonism patients with the focus on clinical depression. The sample consisted of 50 patients with a postmortem confirmed neuropathological diagnosis (30 Parkinson's disease [PD], 10 progressive supranuclear palsy [PSP] and 10 multiple system atrophy [MSA]). Each patient had been scanned with brain computerized tomography (CT) antemortem (median motor symptom duration at scanning = 3.0 years), and 19 patients were scanned again after a mean interval of 2.7 years. Medial temporal atrophy (MTA), global cortical atrophy (GCA) and WMHs were evaluated computationally from CT scans using an image quantification tool based on convolutional neural networks. Depression and other clinical parameters were recorded from patient files. Depression was associated with increased MTA after controlling for diagnosis, age, symptom duration, and cognition (p = 0.006). A similar finding was observed with GCA (p = 0.017) but not with WMH (p = 0.47). In PD patients alone, the result was confirmed for MTA (p = 0.021) with the same covariates. In the longitudinal analysis, GCA change per year was more severe in depressed patients than in nondepressed patients (p = 0.029). Early medial temporal and global cortical atrophy, as detected with automated analysis of CT-images using convolutional neural networks, is associated with clinical depression in parkinsonism patients. Global cortical atrophy seems to progress faster in depressed patients.


Motor patterns during walking on a slippery walkway.
Friction and gravity represent two basic physical constraints of terrestrial locomotion that affect both motor patterns and the biomechanics of bipedal gait. To provide insights into the spatiotemporal organization of the motor output in connection with ground contact forces, we studied adaptation of human gait to steady low-friction conditions. Subjects walked along a slippery walkway (7 m long; friction coefficient approximately 0.06) or a normal, nonslippery floor at a natural speed. We recorded gait kinematics, ground reaction forces, and bilateral electromyographic (EMG) activity of 16 leg and trunk muscles and we mapped the recorded EMG patterns onto the spinal cord in approximate rostrocaudal locations of the motoneuron (MN) pools to characterize the spatiotemporal organization of the motor output. The results revealed several idiosyncratic features of walking on the slippery surface. The step length, cycle duration, and horizontal shear forces were significantly smaller, the head orientation tended to be stabilized in space, whereas arm movements, trunk rotations, and lateral trunk inclinations considerably increased and foot motion and gait kinematics resembled those of a nonplantigrade gait. Furthermore, walking on the slippery surface required stabilization of the hip and of the center-of-body mass in the frontal plane, which significantly improved with practice. Motor patterns were characterized by an enhanced (roughly twofold) level of MN activity, substantial decoupling of anatomical synergists, and the absence of systematic displacements of the center of MN activity in the lumbosacral enlargement. Overall, the results show that when subjects are confronted with unsteady surface conditions, like the slippery floor, they adopt a gait mode that tends to keep the COM centered over the supporting limbs and to increase limb stiffness. We suggest that this behavior may represent a distinct gait mode that is particularly suited to uncertain surface conditions in general.


Inverse association of glucosamine use and risk of new-onset kidney stones in UK adults with less sedentary time.
To assess the association of different sedentary behaviors and glucosamine use with the risk of kidney stones and examine the modification of genetic risk of kidney stones on this association. 473,225 participants free of kidney stones at baseline from the UK Biobank were included. Total sedentary time was calculated as the sum of the duration of TV-watching, driving, and non-occupational computer using. The primary outcome was new-onset kidney stones. During a median follow-up of 12.0 years, 5528 cases of kidney stones were documented. All major sedentary behaviors and total sedentary time were significantly positively related to the risk of kidney stones (All P for trend<0.05). Participants with total sedentary time ≥ 3.5 h/day had a significantly higher risk of new-onset kidney stones (vs. <3.5 h/day [tertile 1]; HR, 1.18; 95%CI,1.10-1.27). Compared with non-users, participants who regularly used glucosamine had a significantly lower risk of new-onset kidney stones in those with total sedentary time < 3.5 h/day (HR, 0.72; 95%CI,0.59-0.86), but not in those with total sedentary time ≥ 3.5 h/day (HR, 0.99; 95%CI,0.91-1.08; P-interaction = 0.001). Among participants with total sedentary time < 3.5 h/day, there was a dose-response relationship of glucosamine use with new-onset kidney stones (P for trend<0.001). Genetic risks of kidney stones did not significantly modify the association. TV-watching, driving and non-occupational computer using were all positively associated with the risk of new-onset kidney stones. Glucosamine use was associated with a lower risk of new-onset kidney stones in participants with total sedentary time < 3.5 h/day, following a dose-response relationship.


Analysis of Connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart.
The functional consequences of Connexin43 (Cx43) phosphorylation remain largely unexplored. Using an antibody that specifically recognizes Cx43 phosphorylated at serine residues 325, 328 and/or 330 (pS325/328/330-Cx43), we show that labeling of this form of Cx43 as well as of total Cx43 is restricted to the intercalated disk region of normal ventricular tissue. In ischemic heart, significant relocalization of total Cx43 to the lateral edges of myocytes was evident; however pS325/328/330-Cx43 remained predominately at the intercalated disk. Western blots indicated a eightfold decrease in pS325/328/330-Cx43 in ischemic tissue. Peptide-binding- and competition-experiments indicated that our antibody mainly detected Cx43 phosphorylated at S328 and/or S330 in heart tissue. To evaluate how this change in Cx43 phosphorylation contributes to ischemia-induced downregulation of intercellular communication, we stably transfected Cx43(-/-) cells with a Cx43 construct in which serine residues 325, 328 and 330 had been mutated to alanine (Cx43-TM). Cx43-TM was not efficiently processed to isoforms that have been correlated with gap junction assembly. Nevertheless, Cx43-TM cells were electrically coupled, although development of coupling was delayed. Fully opened channels were only rarely observed in Cx43-TM cells, and Lucifer-Yellow-dye-coupling was significantly reduced compared with wild-type cells. These data suggest that phosphorylation of Cx43 at serine residues 325, 328 and/or 330 influences channel permselectivity and regulates the efficiency of gap junction assembly.


Impact of an Intensive Care Information System on the Length of Stay of Surgical Intensive Care Unit Patients: Observational Study.
The implementation of computerized monitoring and prescription systems in intensive care has proven to be reliable in reducing the rate of medical error and increasing patient care time. They also showed a benefit in reducing the length of stay in the intensive care unit (ICU). However, this benefit has been poorly studied, with conflicting results. This study aimed to show the impact of computerization on the length of stay in ICUs. This was a before-after retrospective observational study. All patients admitted in the surgical ICU at the Rouen University Hospital were included, from June 1, 2015, to June 1, 2016, for the before period and from August 1, 2016, to August 1, 2017, for the after period. The data were extracted from the hospitalization report and included the following: epidemiological data (age, sex, weight, height, and body mass index), reason for ICU admission, severity score at admission, length of stay and mortality in ICU, mortality in hospital, use of life support during the stay, and ICU readmission during the same hospital stay. The consumption of antibiotics, biological analyses, and the number of chest x-rays during the stay were also analyzed. A total of 1600 patients were included: 839 in the before period and 761 in the after period. Only the severity score Simplified Acute Physiology Score II was significantly higher in the postcomputerization period (38 [SD 20] vs 40 [SD 21]; P<.05). There was no significant difference in terms of length of stay in ICU, mortality, or readmission during the stay. There was a significant increase in the volume of prescribed biological analyses (5416 [5192-5956] biological exams prescribed in the period before Intellispace Critical Care and Anesthesia [ICCA] vs 6374 [6013-6986] biological exams prescribed in the period after ICCA; P=.002), with an increase in the total cost of biological analyses, to the detriment of hematological and biochemical blood tests. There was also a trend toward reduction in the average number of chest x-rays, but this was not significant (0.55 [SD 0.39] chest x-rays per day per patient before computerization vs 0.51 [SD 0.37] chest x-rays per day per patient after computerization; P=.05). On the other hand, there was a decrease in antibiotic prescribing in terms of cost per patient after the implementation of computerization (€149.50 [$164 USD] per patient before computerization vs €105.40 [$155 USD] per patient after computerization). Implementation of an intensive care information system at the Rouen University Hospital in June 2016 did not have an impact on reducing the length of stay.


Initial analysis of ocean color data from the ocean color and temperature scanner. I. Imagery analysis.
The ocean color and temperature scanner (OCTS) collected global ocean color data from November 1996 to June 1997. Analyses of OCTS imagery indicate three features that impair scientific research uses: (1) band misalignments, (2) image striping, and (3) image noise. These are due to (1) band offsets in the sensor design, (2) detector radiometric response variability, and (3) primarily cloud contamination, respectively. Methods are analyzed to ameliorate the effects of each that facilitate use of OCTS ocean color data for quantitative scientific analyses.


APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia.
Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes. We assessed plasma lipoprotein profiles and APOA5 S19W and -1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry. We observed significant stepwise relationships between APOA5 minor allele carrier frequencies and plasma triglyceride quartiles. The odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W carriers were 3.11 (95% CI 1.63-5.95), 4.76 (2.25-10.1), 2.89 (1.17-7.18) and 6.16 (3.66-10.3), respectively. For APOA5 -1131T>C carriers, the odds ratios for these hyperlipoproteinemia subtypes were 2.23 (95% CI 1.21-4.08), 3.18 (1.55-6.52), 3.95 (1.85-8.45) and 4.24 (2.64-6.81), respectively. The overall odds ratio for the presence of either allele in lipid clinic patients was 2.58 (95% CI 1.89-3.52). A high proportion of patients with four classic hyperlipoproteinemia phenotypes are carriers of either the APOA5 S19W or -1131T>C variant or both. These two variants are robust genetic biomarkers of a range of clinical hyperlipoproteinemia phenotypes linked by hypertriglyceridemia.


Cryoablation in the management of Barrett's esophagus.
Providing an overview on types of cryotherapy for esophageal application and their role in the management of Barrett's esophagus. Recent studies have involved multiple types of cryotherapy including cryospray techniques that use either liquid nitrogen or carbon dioxide as the cryogenic fluid, and the CryoBalloon focal ablation device that uses nitrous oxide. Overall, studies report cryotherapy to be safe and effective in eradicating Barrett's epithelium. However, substantial variations among these studies in design and outcomes preclude direct comparisons of the results. Moreover, little is known of the long-term outcomes of cryotherapy, with only one report describing 5-year follow-up of patients treated with liquid nitrogen cryospray. The concept of cryotherapy is appealing. By preserving the extracellular matrix and inducing anesthetic effects, cryotherapy has the potential to enable deeper ablations with less pain and a lower rate of stricture formation than radiofrequency ablation. To date, however, these potential benefits remain unproved. Prospective studies with clearly defined endpoints and longer follow-up are necessary to determine the role of cryotherapy in the management of patients with Barrett's esophagus.


Hypochlorite-induced damage to proteins: formation of nitrogen-centred radicals from lysine residues and their role in protein fragmentation.
Stimulated monocytes and neutrophils generate hypochlorite (HOCl) via the release of the enzyme myeloperoxidase and hydrogen peroxide. HOCl damages proteins by reaction with amino acid side-chains or backbone cleavage. Little information is available about the mechanisms and intermediates involved in these reactions. EPR spin trapping has been employed to identify radicals on proteins, peptides and amino acids after treatment with HOCl. Reaction with HOCl gives both high- and low-molecular-mass nitrogen-centred, protein-derived radicals; the yield of the latter increases with both higher HOCl:protein ratios and enzymic digestion. These radicals, which arise from lysine side-chain amino groups, react with ascorbate, glutathione and Trolox. Reaction of HOCl-treated proteins with excess methionine eliminates radical formation, which is consistent with lysine-derived chloramines (via homolysis of N-Cl bonds) being the radical source. Incubation of HOCl-treated proteins, after removal of excess oxidant, gives rise to both nitrogen-centred radicals, over a period of hours, and time-dependent fragmentation of the protein. Treatment with excess methionine or antioxidants (Trolox, ascorbate, glutathione) protects against fragmentation; urate and bilirubin do not. Chloramine formation and nitrogen-centred radicals are therefore key species in HOCl-induced protein fragmentation.


Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment.
Anti-angiogenic and vascular disrupting therapies rely on the dependence of tumors on new blood vessels to sustain tumor growth. We previously reported a potent vascular disrupting agent, a theranostic nanosystem consisting of a tumor vasculature-homing peptide (CGKRK) fused to a pro-apoptotic peptide [D(KLAKLAK)2] coated on iron oxide nanoparticles. This nanosystem showed promising therapeutic efficacy in glioblastoma (GBM) and breast cancer models. However, complete control of the tumors was not achieved, and some tumors became non-responsive to the treatment. Here we examined the non-responder phenomenon in an aggressive MCF10-CA1a breast tumor model. In the treatment-resistant tumors we noted the emergence of CD31-negative patent neovessels and a concomitant loss of tumor homing of the nanosystem. In vivo phage library screening in mice bearing non-responder tumors showed that compared to untreated and treatment-sensitive tumors, treatment sensitive tumors yield a distinct landscape of vascular homing peptides characterized by over-representation of peptides that target αv integrins. Our approach may be generally applicable to the development of targeted therapies for tumors that have failed treatment.


Determining Intraosseous Needle Placement Using Point-of-Care Ultrasound in a Swine (Sus scrofa) Model.
Intraosseous (IO) access is critical in resuscitation, providing rapid access when peripheral vascular attempts fail. Unfortunately, misplacement commonly occurs, leading to possible fluid extravasation and tissue necrosis. Current research exploring the utility of bedside ultrasound in confirming IO line placement is limited by small sample sizes of skeletally immature subjects or geriatric cadaveric models. The objective of this study was to investigate the potential value of ultrasound confirming IO needle placement in a live tissue model with bone densities approximated to the young adult medical or trauma patient. In this randomized, blinded prospective study, IO devices were placed into the bilateral humeri of 36 sedated adult swine (N = 72) with bone densities approximating that of a 20-39-year-old adult. Of the 72 lines, 53 were randomized to the IO space ("correct") and 19 into the subcutaneous tissue ("incorrect"). Four emergency physicians with variable ultrasound experience and blinded to needle location independently assessed correct or incorrect needle placements based on the presence of an intramedullary "flare" on color power Doppler (CPD) during a saline flush. Participants adjusted the ultrasound beam trajectory and recorded assessments up to three times, totaling 204 separate observations. Overall, sensitivity for placement confirmation was 72% (95% CI: 64%-79%). Specificity was 79% (95% CI: 66%-89%). First assessment and final assessment results were similar. More experienced sonographers demonstrated greater success in identifying inaccurate placements with a specificity of 86% (95% CI: 63%-96%). Within the context of this study, point-of-care ultrasound with CPD did not reliably confirm IO line placement. However, more accurate assessments of functional and malpositioned catheters were noted in sonographers with greater than 4 years of experience. Future study into experienced sonographers' use of CPD to confirm IO catheter placement is needed.


Effects of bilateral hypoglossal and glossopharyngeal nerve blocks on epiglottic and soft palate position in exercising horses.
To determine the effect of bilateral hypoglossal and and glossopharyngeal nerve block on epiglottic and soft palate position and tracheal and pharyngeal pressures in exercising horses. 5 Standardbreds. Tracheal and pharyngeal pressures were measured in 5 Standardbreds exercising at the speed at which the horses achieved 50, 75, and 100% of maximal heart rate after bilateral hypoglossal and glossopharyngeal nerve block and without nerve block. Nerve block was achieved by injection of 1 to 2 ml of 2% mepivicaine hydrochloride between the glossopharyngeal and hypoglossal nerves, as they coursed through the medial compartment of the diverticulum of the auditory tube (guttural pouch), using videoendoscopic guidance and an injection apparatus. Compared with control values, peak inspiratory tracheal pressure was significantly (P = 0.02) more negative, and peak pharyngeal inspiratory pressure was less negative (P = 0.004) after bilateral hypoglossal and glossopharyngeal nerve block. Respiratory frequency was significantly (P = 0.024) lower after nerve block, compared with control values. The epiglottis was unstable and retroflexed through the rima glottis during inspiration after bilateral hypoglossal and glossopharyngeal nerve block. Despite loss of contact between the epiglottis and the caudal free margin of the soft palate, dorsal displacement of the soft palate did not occur. Loss of contact of the epiglottis with the soft palate did not affect soft palate position, suggesting that when the soft palate is normal, the epiglottis does not function as a support, holding the soft palate in a ventral position. Therefore, epiglottic dysfunction is not solely responsible for intermittent dorsal displacement of the soft palate in horses, and neuromuscular dysfunction involving the hyoepiglotticus muscle, geniohyoideus muscle, or the hypoglossal nerve may cause epiglottic retroflexion in horses.


Hyperventilation, cerebral perfusion, and syncope.
This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2 the contribution of a low PaCO2 to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced cardiac output brain perfusion becomes jeopardized. Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to TLOC, remains to be established.


Image guidance in prostate cancer - can offline corrections be an effective substitute for daily online imaging?
This aim of this study was to determine if a less resource-intensive and established offline correction protocol - the No Action Level (NAL) protocol was as effective as daily online corrections of setup deviations in curative high-dose radiotherapy of prostate cancer. A total of 683 daily megavoltage CT (MVCT) or kilovoltage CT (kvCBCT) images of 30 patients with localized prostate cancer treated with intensity modulated radiotherapy were evaluated. Daily image-guidance was performed and setup errors in three translational axes recorded. The NAL protocol was simulated by using the mean shift calculated from the first five fractions and implemented on all subsequent treatments. Using the imaging data from the remaining fractions, the daily residual error (RE) was determined. The proportion of fractions where the RE was greater than 3,5 and 7 mm was calculated, and also the actual PTV margin that would be required if the offline protocol was followed. Using the NAL protocol reduced the systematic but not the random errors. Corrections made using the NAL protocol resulted in small and acceptable RE in the mediolateral (ML) and superoinferior (SI) directions with 46/533 (8.1%) and 48/533 (5%) residual shifts above 5 mm. However; residual errors greater than 5mm in the anteroposterior (AP) direction remained in 181/533 (34%) of fractions. The PTV margins calculated based on residual errors were 5mm, 5mm and 13 mm in the ML, SI and AP directions respectively. Offline correction using the NAL protocol resulted in unacceptably high residual errors in the AP direction, due to random uncertainties of rectal and bladder filling. Daily online imaging and corrections remain the standard image guidance policy for highly conformal radiotherapy of prostate cancer.


Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia.
Despite the identification of several baseline prognostic indicators, the outcome of patients with acute myeloid leukemia (AML) is generally heterogeneous. The effects of autologous (AuSCT) or allogeneic stem-cell transplantation (SCT) are still under evaluation. Minimal residual disease (MRD) states may be essential for assigning patients to therapy-dependent risk categories. By multiparametric flow cytometry, we assessed the levels of MRD in 142 patients with AML who achieved complete remission after intensive chemotherapy. A level of 3.5 x 10(-4) residual leukemia cells (RLCs) after consolidation therapy was established to identify MRD-negative and MRD-positive cases, with 5-year relapse-free survival (RFS) rates of 60% and 16%, respectively (P < .0001) and overall survival (OS) rates of 62% and 23%, respectively (P = .0001). Of patients (n = 77) who underwent a transplantation procedure (56 AuSCT and 21 SCT procedures); 42 patients (55%) were MRD positive (28 patients who underwent AuSCT and 14 patients who underwent SCT) and 35 patients (45%) were MRD negative (28 patients who underwent AuSCT and seven who underwent SCT). MRD-negative patients had a favorable prognosis, with only eight (22%) of 35 patients experiencing relapse, whereas 29 (69%) of 42 MRD-positive patients experienced relapse (P < .0001). In this high-risk group of 42 patients, we observed that 23 (82%) of 28 of those who underwent AuSCT experienced relapse, whereas six (43%) of 14 who underwent SCT experienced relapse (P = .014). Patients who underwent SCT also had a higher likelihood of RFS (47% v 14%). A threshold of 3.5 x 10(-4) RLCs postconsolidation is critical for predicting disease outcome. MRD-negative patients have a good outcome regardless of the type of transplant they receive. In the MRD-positive group, AuSCT does not improve prognosis and SCT represents the primary option.


A Regional System of High-Quality Care: Rural Hastings Health Link - A Collaborative Initiative.
The Rural Hastings Health Link coordinates care for the 1-5% of the local population whose complexity represents two-thirds of healthcare spending. Gateway Community Health Centre developed a primary care-led model with local partners in primary care and the broader health and social sector built on four interventions: a structure to support integrated system thinking with partners, system navigators embedded in primary care addressing medical and social needs, a digital care-coordination tool and data management supporting accountability. It has altered how providers respond to clients' needs and, as an integrated system of care, created a shared culture of change driven by trust.


The gender gap in suicide and premature death or: why are men so vulnerable?
Suicide and premature death due to coronary heart disease, violence, accidents, drug or alcohol abuse are strikingly male phenomena, particularly in the young and middle-aged groups. Rates of offending behaviour, conduct disorders, suicide and depression are even rising, and give evidence to a high gender-related vulnerability of young men. In explaining this vulnerability, the gender perspective offers an analytical tool to integrate structural and cultural factors. It is shown that traditional masculinity is a key risk factor for male vulnerability promoting maladaptive coping strategies such as emotional unexpressiveness, reluctance to seek help, or alcohol abuse. This basic male disposition is shown to increase psychosocial stress due to different societal conditions: to changes in male gender-role, to postmodern individualism and to rapid social change in Eastern Europe and Russia. Relying on empirical data and theoretical explanations, a gender model of male vulnerability is proposed. It is concluded that the gender gap in suicide and premature death can most likely be explained by perceived reduction in social role opportunities leading to social exclusion.


Streptococcus crista sp. nov., a viridans streptococcus with tufted fibrils, isolated from the human oral cavity and throat.
We studied strains of an unusual streptococcus that superficially resembles Streptococcus sanguis but has fibrils that are arranged in lateral tufts. These strains were originally isolated from human throats and oral cavities and have been referred to previously as "Streptococcus sanguis I," the "CR group," and the "tufted-fibril group." Until now, insufficient phenotypic data have been available to allow reliable differentiation of these strains from other viridans streptococcal species, particularly the species in the S. sanguis group. Recently, workers have proposed a scheme of phenetic tests that is based on 4-methylumbelliferyl-linked substrates and conventional biochemical tests and allows the tufted-fibril group to be differentiated; these organisms differ from other viridans species in being able to hydrolyze arginine but not esculin and in producing alpha-L-fucosidase but not beta-glucosidase or alkaline phosphatase. These data, together with the results of our DNA-DNA hybridization experiments and the unusual ultrastructure of the tufted-fibril strains as determined by electron microscopy, demonstrate that these organisms represent a new species, for which the name Streptococcus crista is proposed. The DNA base composition is 42.6 to 43.2 mol% G + C. The type strain is strain CR311 (= NCTC 12479).


Factors associated with low school readiness, a linked health and education data study in Wales, UK.
School readiness is a measure of a child's cognitive, social, and emotional readiness to begin formal schooling. Children with low school readiness need additional support from schools for learning, developing required social and academic skills, and catching-up with their school-ready peers. This study aims to identify the most significant risk factors associated with low school readiness using linked routine data for children in Wales. This was a longitudinal cohort study using linked data. The cohort comprises of children who completed the Foundation Phase assessment between 2012 and 2018. Individuals were identified by linking Welsh Demographic Service and Pre16 Education Attainment datasets. School readiness was assessed via the binary outcome of the Foundation Phase assessment (achieved/not achieved). This study used multivariable logistic regression model and a decision tree to identify and weight the most important risk factors associated with low school readiness. In order of importance, logistic regression identified maternal learning difficulties (adjusted odds ratio 5.35(95% confidence interval 3.97-7.22)), childhood epilepsy (2.95(2.39-3.66)), very low birth weight (2.24(1.86-2.70), being a boy (2.11(2.04-2.19)), being on free school meals (1.85(1.78-1.93)), living in the most deprived areas (1.67(1.57-1.77)), maternal death (1.47(1.09-1.98)), and maternal diabetes (1.46(1.23-1.78)) as factors associated with low school readiness. Using a decision tree, eligibility for free school meals, being a boy, absence/low attendance at school, being born late in the academic year, being a low birthweight child, and not being breastfed were factors which were associated with low school readiness. This work suggests that public health interventions focusing on children who are: boys, living in deprived areas, have poor early years attendance, have parents with learning difficulties, have parents with an illness or have illnesses themselves, would make the most difference to school readiness in the population.


The influences of stimulus wavelength and eccentricity on short-wavelength pathway isolation in automated perimetry.
The aim of the study was to determine whether the suggested stimulus and background parameters employed in commercially available short-wavelength sensitive perimetry (SWAP) are clinically appropriate. Threshold versus intensity curves were measured using a modified Humphrey Field Analyser. The reduction in background luminance was achieved using aperture stops in order to avoid changes in the chromaticity of the background. Short-wavelength thresholds were determined for 440, 450 and 460 nm stimuli and were corrected for pre-receptoral absorption. Short-wavelength sensitive pathway isolation was approximately 1.5 log units and decreased with increases in eccentricity and in stimulus wavelength. It would seem that the use of a 450 nm narrowband stimulus filter would offer a compromise between both the physiological requirements and the physical properties of the stimulus. Such an approach would reduce some of the inherent between-subject normal variability associated with SWAP.


Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules.
To investigate whether a predictive estimate can be obtained for a 'tolerance level' of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data. Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1-3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd(1 + d/(alpha/beta) - Ln2(T - T(k))/alpha T(p) (see text for parameters). A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of 'intolerable' or 'tolerable'. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a 'tolerance zone of uncertainty' could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2-10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced by up to roughly 3-5 Gy10 in BED, with a request for further evidence. It is suggested that total BED should be used, as specified above. Parameters of alpha=0.35 Gy-(1), alpha/beta=10 Gy, Tk=7 days and Tp=2.5 days are suggested. The 'acute/ tolerance zone' then turns out to be 59-61 Gy10 for radiation-only treatments. Further information about the decrement caused by concurrent head-and-neck cancer chemoradiotherapy, possibly 3-5 Gy10, is required.


Sickle Cell Disease: Advances in Treatment.
Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease. Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy. These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.


The efficacy of behavioral treatments for hypertension.
Evidence is reviewed for the efficacy of behavioral treatments for hypertension. The format chosen here is a review of reviews given that numerous consensus committee reports and quantitative reviews on the topic have been published. Extensive evidence from over 100 randomized controlled trials indicates that behavioral treatments reduce blood pressure (BP) to a modest degree, and this change is greater than what is seen in wait-list or other inactive controls. Effect sizes are quite variable. The observed BP reductions are much greater when BP levels were high at pre-test, and behavioral studies tend to underestimate possible benefits because of floor effects in their protocols. Blood pressure measured in the office may be confounded with measurement habituation. Multi-component, individualized psychological treatments lead to greater BP changes than do single-component treatments. Among biofeedback treatments, thermal feedback and electrodermal activity feedback fare better than EMG or direct BP feedback, which tend to produce null effects. There continues to be a scarcity of strong protocols that properly control for floor effects and potential measurement confounds.


Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.
Hyaluronan (HA) is an abundant matrix molecule, the function of which in the skin remains to be fully defined. To explore the roles of HA in cutaneous injury responses, double-knockout mice (abbreviated as Has1/3 null) that lack two HA synthase enzymes (Has1 and Has3), but still express functional Has2, were used in two types of experiments: (i) application of 12-O-tetradecanoylphorbol-13-acetate (TPA) and (ii) full-thickness wounding of the skin. Uninjured Has1/3-null mice were phenotypically normal. However, after TPA, the accumulation of HA that normally occurs in wild-type epidermis was blunted in Has1/3-null epidermis. In excisional wound-healing experiments, wound closure was significantly faster in Has1/3 null than in wild-type mice. Coincident with this abnormal wound healing, a marked decrease in epidermal and dermal HA and a marked increase in neutrophil efflux from cutaneous blood vessels were observed in Has1/3-null skin relative to wild-type skin. Has1/3-null wounds displayed an earlier onset of myofibroblast differentiation. In summary, selective loss of Has1 and Has3 leads to a proinflammatory milieu that favors recruitment of neutrophils and other inflammation-related changes in the dermis.


Plasma proteomic profiles differ between European and North American myotid bats colonized by Pseudogymnoascus destructans.
Emerging fungal diseases have become challenges for wildlife health and conservation. North American hibernating bat species are threatened by the psychrophilic fungus Pseudogymnoascus destructans (Pd) causing the disease called white-nose syndrome (WNS) with unprecedented mortality rates. The fungus is widespread in North America and Europe, however, disease is not manifested in European bats. Differences in epidemiology and pathology indicate an evolution of resistance or tolerance mechanisms towards Pd in European bats. We compared the proteomic profile of blood plasma in healthy and Pd-colonized European Myotis myotis and North American Myotis lucifugus in order to identify pathophysiological changes associated with Pd colonization, which might also explain the differences in bat survival. Expression analyses of plasma proteins revealed differences in healthy and Pd-colonized M. lucifugus, but not in M. myotis. We identified differentially expressed proteins for acute phase response, constitutive and adaptive immunity, oxidative stress defence, metabolism and structural proteins of exosomes and desmosomes, suggesting a systemic response against Pd in North American M. lucifugus but not European M. myotis. The differences in plasma proteomic profiles between European and North American bat species colonized by Pd suggest European bats have evolved tolerance mechanisms towards Pd infection.


Interference of a short-chain phospholipid with ion transport pathways in frog skin.
The effects of mucosal application of the short-chain phospholipid didecanoyl-L-alpha-phosphatidylcholine (DDPC; with two saturated 10-carbon acyl chains) on active Na+ transport and transepithelial conductance (G) in the frog skin (Rana temporaria) were investigated. Active Na+ transport was measured as the amiloride-sensitive short-circuit current (ISC) and G was determined from transepithelial voltage-clamp pulses under short-circuit conditions. DDPC dose-dependently inhibited ISC with an ID50 of about 0.05% (w/v) and a maximal effect ( approximately 55%) at >/= 1% DDPC. G increased to steady-state values above control level. Simultaneously, equal increases in unidirectional sucrose permeabilities (PSu; measured from [14C]sucrose fluxes) were observed, and a positive correlation was demonstrated between DDPC-induced changes in PSu and G. Since amiloride did not prevent the increase in G by DDPC, these results suggest that the DDPC-induced increase in G represents an increase in the paracellular shunt conductance. The effects of mucosal DDPC were almost fully reversible within 8 h. The results indicate that DDPC inhibits amiloride-sensitive Na+ channels in the apical membrane of the frog skin epithelium and opens a paracellular tight junction pathway. Both effects may be caused by incorporation of DDPC in the apical cell membrane.


Underrepresented minorities in academic medicine: is Florida better off?
The state of Florida has experienced challenges recruiting and retaining underrepresented minority faculty in academic medicine, as well as maintaining a population-like balance of minority physicians practicing in the state. We sought to quantify the percentage of practicing minority physicians as compared to the general population of Florida and focus specifically on black, Hispanic, and Asian/Pacific Islander physicians in academic medicine. We hypothesized that because of the diversity of the state, the number of underrepresented minority academic physicians in Florida would be higher than the national average. Data were derived and analyzed from a biennial survey initiated in 2007 that all physicians renewing licenses in Florida are required to complete. Fifty percent of the licensing cohort completes the survey annually. We focused on physician practice demographics and academic employment. Blacks make up 15.4% of the state population, 6.4% of practicing physicians, but only 3.9% of academic physicians. Hispanics are 22.8% of the state population, 19.2% of practicing physicians, but only 12.5% of academic physicians. Asians are 2.5% of the state population, 14.4% of practicing physicians, and 12.6% of academic physicians. Whites are 58% of the state population, 52% of practicing physicians, and 65% of academic physicians. There is disparity in clinical practice and academic medicine for blacks and Hispanics. Despite the diversity of the state, the disparity of blacks in academic medicine in Florida only marginally exceeds the national average. Asians and Hispanics make up the same percentage of academic physicians, but there are 10 times more Hispanics in the state. More research and programming are needed to further define and arrive at solutions to this problem.


[Angioneurotic edema secondary to antihypertensive therapy].
Secondary angioneurotic oedema due to antihypertensive drugs of the angiotensin-converting enzyme inhibitors type, is an uncommon entity which must be remembered when dealing with differential diagnosis of this type of oedema. We have reviewed the subject following 2 of our own cases.


Aptamers: selected oligonucleotides for therapy.
In vitro selection constitutes a unique way to explore vast libraries (up to 10(14) to 10(15) different molecules) of randomly synthesized nucleic acids. Selected RNA or DNA sequences (aptamers) may help to understand the molecular interactions and processes of interest for human diseases. Aptamers can be chemically-modified for improved efficiency and use in complex biological media. Moreover, aptamers selected in vitro may retain their activity in vivo and thus offer novel perspectives for gene therapy and the design of new drugs.


Felbamate in vitro metabolism by rat liver microsomes.
Incubation of [14C]felbamate at 37 degrees C for 60 min with liver microsomes from untreated Sprague-Dawley rats converted 10% of the drug to the p-hydroxy (6%) and 2-hydroxy (4%) metabolites. With microsomes from phenobarbital-pretreated rats, 21% of the drug was metabolized to the p-hydroxy (7.5%) and 2-hydroxy (13.5%) metabolites. With microsomes from felbamate-pretreated rats, up to 25% of drug was metabolized to the p-hydroxy (5%) and 2-hydroxy (20%) metabolites. In addition, a small amount of the monocarbamate metabolite was also present, but no other metabolites were formed. Coincubations of [14C]phenytoin with felbamate had no effect on the metabolism of phenytoin, whereas the amount of [14C]felbamate metabolized in the presence of phenytoin decreased by 30-38%.


Polymorphic microsatellite DNA markers in the penduline tit, Remiz pendulinus.
To describe the exceptional mating system of the penduline tit, Remiz pendulinus, we aim to combine field observation records with DNA analysis based on polymorphic microsatellite DNA markers. Here we describe features of nine loci and their corresponding polymerase chain reaction primers. The observed number of alleles varied from four to seven and the observed heterozygosity ranged from 0.419 to 0.802. Neither of the loci is sex-linked and as linkage disequilibrium analysis showed they assort independently. Seven of the nine loci were polymorphic in the Cape penduline tit, Anthoscopus minutus.


Effects of a Phytogenic Supplement Containing Olive By-Product and Green Tea Extracts on Growth Performance, Lipid Metabolism, and Hepatic Antioxidant Capacity in Largemouth Bass (Micropterus salmoides) Fed a High Soybean Meal Diet.
A 10-week growth trial was conducted to investigate the effects of a phytogenic feed additive (PFA) containing olive by-products and green tea extracts supplemented to a reduced fishmeal/high soybean meal diet on the growth performance, hepatic antioxidant capacity, lipid metabolism, and liver health of largemouth bass (Micropterus salmoides). Three experimental diets were tested: (1) a control high fishmeal (40%) and low soybean meal (15.57%) diet (named HFM), (2) a reduced fishmeal (30%) and high soybean meal (30.97%) diet (named HSB), and (3) a HSB diet supplemented with the PFA at 500 mg/kg (named HSB+P). Each diet was assigned to four replicate tanks, each containing 30 largemouth bass (initial body weight, IBW = 48.33 ± 0.01 g). The results showed that increasing the soybean meal content in the diet did not negatively affect growth performance, whereas supplementation with PFA significantly increased weight gain and specific growth rate of largemouth bass compared to both HFM and HSB groups. Reducing fishmeal and increasing soybean meal in the diet caused oxidative stress with a higher content of ROS in the liver. However, the hepatic antioxidant capacity was enhanced, with reduced ROS and increased GSH-Px levels in the HSB+P group. Moreover, the decrease of plasma TG, LDL-C, and LDL-C/TC, and downregulation of lipogenesis and cholesterol synthesis gene expression in liver, indicated that supplementation with the PFA improved fish lipid metabolism. Protein retention efficiency was also significantly increased in largemouth bass fed the diet with PFA supplementation, which regulated (enhanced) AKT-mTOR phosphorylation. These results clearly indicated that a PFA containing olive by-product and green tea extracts can positively improve growth performance, protein retention efficiency, antioxidant capacity, and lipid metabolism of largemouth bass fed a reduced fishmeal/high soybean meal diet.


Importance of functional EGF receptors in recovery from acute nephrotoxic injury.
Previous studies have demonstrated increased renal expression of EGF receptor (EGFR) and EGFR ligands in response to acute toxic or ischemic renal tubular injury and have indicated that exogenous administration of EGF accelerates recovery from such injury. However, no studies to date have proved definitively an essential role for EGFR-mediated responses in regeneration after tubule injury. To this end, waved-2 (wa-2) mice, which contain a point mutation in EGFR that reduces receptor tyrosine kinase activity by >90%, were studied. These mice have a mild phenotype (wavy coat, curly whiskers, and runted stature) and normally developed kidneys. Acute nephrotoxic injury was induced in wa-2 and wild-type mice with HgCl(2). One day after HgCl(2) injection, functional renal compromise was comparable in wild-type and wa-2 mice. However, the rates of recovery of serum blood urea nitrogen and creatinine levels were markedly slower in wa-2 mice. Histologic evidence of tubular injury also was more severe and persisted longer in wa-2 mice. Furthermore, their kidneys demonstrated reduced levels of DNA synthesis and increased TdT-mediated dUTP nick-end labeling staining. These studies indicate that functional EGFR activity is an essential component of the kidney's ability to recover from acute injury and that EGFR may regulate genes involved in growth, repair, and cell survival in the kidney.


Carbon Nanotubes Induced Fibrogenesis on Nanostructured Substrates.
While the rapidly evolving nanotechnology has shown promise in electronics, energy, healthcare and many other fields, there is an increasing concern about the adverse health consequences of engineered nanomaterials. To accurately evaluate the toxicity of nanomaterials, in vitro models incorporated with in vivo microenvironment characteristics are desirable. This study aims to delineate the influence of nanotopography on fibrogenic response of normal human lung fibroblasts to multi-walled carbon nanotubes (MWCNTs). Nanoscale gratings and pillars of various heights were fabricated on polydimethylsiloxane substrates. Cell spreading and biomechanics were measured, and fibrogenic responses including proliferation, collagen production and reactive oxygen species generation of the fibroblasts grown on the nanostructured substrates in response to MWCNTs were assessed. It was observed that the cells could be largely stretched on shallow nanogratings, leading to stiffer cytoskeleton and nucleus, enhanced cell proliferation and collagen production, and consequently, toxic response sensitivity of the fibroblasts was undermined. In contrast, the cell spreading and stiffness could be reduced using tall, isotropic nanopillars, which significantly improved the cell toxic sensitivity to the MWCNTs. In addition to highlighting the significant influence of cell-nanotopography interactions on cell sensing CNTs, this study contributed to development of physiologically relevant in vitro models for nanotoxicology study.


Ayurvedic formulation of Liv-Pro-08 reduces nonalcoholic fatty liver disease in rats fed with high-fat diet.
Nonalcoholic fatty liver disease (NAFLD) has emerged as a serious obesity-related disorder, and it will continue to be a major liver health issue worldwide in the coming decades. We aimed to determine the effect of Liv-Pro-08 (Nigella sativa, Entada pursaetha, and Ficus glomerata) an oral ayurvedic formulation on rats fed with high-fat diet. Rats were given a high-fat diet for a period of 7 days. After this period, Liv-Pro-08 (250, 500, and 750 mg/kg.body weight was given orally for 7 days. We examined the effect of the high-fat diet on various parameters related to obesity and insulin resistance. In the experimental rats who received the extract of Liv-Pro-08, their lipoprotein profiles were significantly improved compared with those that are not receiving the extract. Also, a slight reduction was observed in serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase enzymes. Moreover, Liv-Pro-08 significantly decreased their fasting serum glucose and fasting insulin levels. This experimental study suggests that Liv-Pro-08 can act as a therapeutic tool in preventing NAFLD progression (i.e., reducing hepatic lipid accumulation). Although further investigations and large randomized trials should be conducted, ayurvedic Liv-Pro-08 oral formulation may be a potential natural drug for NAFLD in the future.


Acupuncture for posttraumatic stress disorder: conceptual, clinical, and biological data support further research.
Posttraumatic stress disorder (PTSD) is common, debilitating, and has highly heterogeneous clinical and biological features. With the exception of one published preliminary clinical trial, rationale in support of the efficacy of acupuncture, a modality of Chinese medicine (CM), for PTSD has not been well described. This is a focused review of conceptual and clinical features of PTSD shared by modern western medicine (MWM) and CM, and of biological mechanisms of acupuncture that parallel known PTSD pathology. MWM and CM both recognize individual developmental variables and interactions between external conditions and internal responses in the genesis of PTSD. There is one published and one unpublished clinical trial that preliminarily support the efficacy of acupuncture for PTSD. Although there have been no mechanistic studies of acupuncture in human PTSD, extant research shows that acupuncture has biological effects that are relevant to PTSD pathology. Conceptual, clinical, and biological data support possible efficacy of acupuncture for PTSD. However, further definitive research about simultaneous clinical and biological effects is needed to support the use of acupuncture for PTSD in health care systems.


[Cytochemical study of various stages of the life cycle of Toxoplasma gondii. 4. Dehydrogenases in the endozoa].
Dehydrogenases of glycolysis, Krebs' cycle and pentosephosphate shunt are present in the metabolic machinery of toxoplasma endozoites (strain SS-119), thus suggesting a mixed oxidative metabolism in these. The enzymes are most commonly localized in the perinuclear area of the cytoplasm. Of special interest is the increased activity of some enzymes (especially lactate dehydrogenase) (fig HC) in the infected cells seen as definite layers of the stuff surrounding each parasite. This may correspond to the "overcoating" by mitochondrial material observed by Jones and Hirsch (1972) with the electron microscope. The importance of host-parasite relationships in the existence of the obligate intracellular parasite is discussed.


In Situ Observations during Chemical Vapor Deposition of Hexagonal Boron Nitride on Polycrystalline Copper.
Using a combination of complementary in situ X-ray photoelectron spectroscopy and X-ray diffraction, we study the fundamental mechanisms underlying the chemical vapor deposition (CVD) of hexagonal boron nitride (h-BN) on polycrystalline Cu. The nucleation and growth of h-BN layers is found to occur isothermally, i.e., at constant elevated temperature, on the Cu surface during exposure to borazine. A Cu lattice expansion during borazine exposure and B precipitation from Cu upon cooling highlight that B is incorporated into the Cu bulk, i.e., that growth is not just surface-mediated. On this basis we suggest that B is taken up in the Cu catalyst while N is not (by relative amounts), indicating element-specific feeding mechanisms including the bulk of the catalyst. We further show that oxygen intercalation readily occurs under as-grown h-BN during ambient air exposure, as is common in further processing, and that this negatively affects the stability of h-BN on the catalyst. For extended air exposure Cu oxidation is observed, and upon re-heating in vacuum an oxygen-mediated disintegration of the h-BN film via volatile boron oxides occurs. Importantly, this disintegration is catalyst mediated, i.e., occurs at the catalyst/h-BN interface and depends on the level of oxygen fed to this interface. In turn, however, deliberate feeding of oxygen during h-BN deposition can positively affect control over film morphology. We discuss the implications of these observations in the context of corrosion protection and relate them to challenges in process integration and heterostructure CVD.


[Effect of rheopolyglucin and dialdehyde dextran on thermostability of human haemoglobin molecules].
Structural characteristics and thermostability of human haemoglobin molecules, modified by reopolyglukine and dialdehyddextrane (DAD) have been studied. Haemoglobin mainly preserves its oxyform when including reopolyglukine in mixture (the mol. ratio of protein to dextrane was 1:4), and disordering of polypeptide chains and increasing the volume of haemoproteids molecules are noticed. Assessment of the influence of mixture pH, exposure and temperature of incubation and the rate of dextrane oxidation on the intensity of the process of human haemoglobin conjugation with DAD have been chosen. Formation of the haemoglobin-DAD complex leads to shielding protein chromophoral groups by polysugar matrix and to transforming the part of haemoproteid molecules from lowspin form (HbO2) to highspin forms (Hb, MetHb). It has been detected that temperature of denaturational points for native protein and haemoglobin in the presence of reopoliglukine is 60 degrees C, but it is 80 degrees C for the haemoglobin-DAD conjugate. The latter is probably determined by increasing hydrophobic interactions inside the protein globule under the effect of DAD and by ability of the surface-bound carbohydrate components prevent association of haemoglobin molecules.


Differential expression of galectin-1 and galectin-3 during first trimester human embryogenesis.
Development of complex organisms requires specific temporospatial differentiation and expression of the correct phenotype through activation of a variety of genes. Galectins are mammalian lectins able to interact with various extracellular matrix glycoconjugates and have been implicated in several biological events including cell attachment, differentiation, apoptosis, embryogenesis, and cancer invasion and metastasis. In this study, we have examined the expression of galectin-1 and galectin-3 during human first trimester embryogenesis using immunohistochemistry and Western blotting. Variable amounts of galectin-1 and galectin-3 were detected in all tissue protein extracts. Galectin-1 expression was demonstrated in the connective tissue and derived tissues such as smooth and striated muscle cells, and in some epithelia, such as in the basal layers of the skin after 14 weeks and in the epithelial cells of the gonads. Galectin-3 was detected mainly in epithelia, such as the skin, epithelial lining of the digestive and respiratory tract, and urothelium and excretory tubes of the kidney, but also in the myocardial cells, in the peripheral and preossifying hypertrophic chondrocytes, and in the notochord and in the liver. Our study constitutes the first demonstration of galectin-1 and galectin-3 during human embryogenesis. The differential expression of these two lectins suggests that they could participate in the complex processes of tissue differentiation.


Ultrastructure of the nonciliated bronchiolar epithelial (Clara) cell of mammalian lung. III. A study of man with comparison of 15 mammalian species.
Two morphologic characteristics have been used to define the nonciliated bronchiolar epithelial cell: (1) abundance of agranular endoplasmic reticulum (AER) and (2) numerous membrane-bound ovoid granules. In this study, we examined lobectomy specimens from three nonsmoking humans: one male (9.5 yr) and two females (62 and 43 yr) for comparison with lung specimens from mammalian species used as experimental models in lung research. Following fixation by airway infusion at constant pressure (20 cm), lung tissue was processed by a selective embedding technique and bronchioles of known anatomic location were studied by electron microscopy. Nonciliated bronchiolar epithelial cells of man contained numerous membrane-bound granules (averaging 6 per cell) in the apical cytoplasm and abundant granular endoplasmic reticulum (GER), AER was not observed. Granules averaged 0.3 micrometer in diameter and contained a fine granular matrix and parallel tubular arrays. After comparing these features in man with those of fifteen other species, we concluded that there is a great deal of interspecies variability in the cellular morphology of the nonciliated epithelial cell of distal conducting airways in mammalian lung. Three categories of this cell were observed: (1) with abundant granules and AER, characteristic of rabbit, guinea pig, rat, hamster, mouse, horse, sheep, and pig; (2) with abundant granules of GER, but no AER, characteristic of man and other primates; and (3) with few granules, little AER, and abundant glycogen, characteristic of steer, dog, cat, and ferret.


Deprescribing interventions in primary health care mapped to the Behaviour Change Wheel: A scoping review.
Polypharmacy and inappropriate medication use are an increasing concern. Deprescribing may improve medication use through planned and supervised dose reduction or stopping of medications. As most medication management occurs in primary health care, which is generally described as the first point of access for day-to-day care, deprescribing in primary health care is the focus on this review. This scoping review aimed to identify and characterize strategies for deprescribing in primary health care and map the strategies to the Behaviour Change Wheel (BCW). A scoping review was conducted that involved searches of six databases (2002-2018) and reference lists of relevant systematic reviews and included studies. Studies that described and evaluated deprescribing strategies in primary health care were eligible. Two independent reviewers screened articles and completed data charting with charting verified by a third. Deprescribing strategies were mapped to the intervention functions of the BCW and linked to specific Behaviour Change Techniques (BCT). Searches yielded 6871 citations of which 43 were included. Nineteen studies were randomized, 24 were non-randomized. Studies evaluated deprescribing in terms of medication changes, feasibility, and prescriber/patient perspectives. Deprescribing strategies involved various professionals (physicians, pharmacists, nurses), as well as patients and were generally multifaceted. A wide range of intervention functions were identified, with 41 BCTs mapped to Environmental restructuring, 38 BCTs mapped to Enablement, and 34 BCTs mapped to Persuasion. Deprescribing strategies in primary health care have used a variety of BCTs to address individual professionals (e.g. education) as well as strategies that addressed the practice setting, including support from additional team members (e.g. pharmacists, nurses and patients). Further research is warranted to determine comparative effectiveness of different BCTs, which can help facilitate implementation of deprescribing strategies, thereby reducing polypharmacy, in primary health care.


Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress, and neuroinflammation in APP/PS1 transgenic mice.
Amyloid-β peptide (Aβ) initiates a cascade of pathological events, including activation of microglial cells, oxidative stress, and inflammation, leading to neuronal death and the typical pathological changes in Alzheimer's disease (AD). Flavonoids have been reported to exert neuroprotective activities, not only through their generally accepted antioxidant effects, but also through their ability to protect against neurotoxin-induced injury. Flavonoids reduce Aβ production, inhibit neuroinflammation, increase cerebrovascular function, and improve cognitive performance. Here, we analyzed the effects of a flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FLDK) in APP/PS1 transgenic mice. We found that oral treatment with FLDK reversed learning and memory impairment, reduced Aβ burden and expression of β-site amyloid precursor protein cleavage enzyme 1 (BACE1), and decreased microglial activation in senile plaques. FLDK restored antioxidant enzyme activities, as well as reduced the lipid peroxidation product, malondialdehyde, and inflammatory mediators. These results demonstrate that FLDK alleviates cognitive decline and reduces Aβ burden, microglial activation, oxidative stress, and inflammation responses. Thus, FLDK treatment may be a potential therapeutic strategy for preventing and treating AD, at least in part via its anti-oxidant and anti-inflammatory biological activities and its effect on the Aβ producing enzyme BACE1.


Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion.
Androgen receptor (AR) activity is associated with cancer development and progression. In hepatocellular carcinoma (HCC), AR contributes to HCC incidence, but the role of AR in HCC cell migration and invasion remains largely unknown. In this study, we found that AR was expressed at high levels in a subgroup of HCC cell lines with high metastatic potential. Experiments using lentiviral overexpression or small hairpin RNA knockdown of AR as well as activation of AR by its ligand indicated that AR activation promoted HCC cell migration and invasion. We also found that AR activation enhanced the expression of a metastasis-promoting gene, ID1, which led to increased HCC cell migration and invasion. An AR antagonist was able to block this process, suggesting that AR activation in AR-positive HCC may be therapeutically inhibited as a potential intervention strategy.


Effect of single mutations in the OGG1 gene found in human tumors on the substrate specificity of the Ogg1 protein.
We have investigated the effect of single amino acid substitutions of conserved arginines on the catalytic activities of the human Ogg1 protein (alpha-hOgg1-Ser(326)) (wild-type alpha-hOgg1). Mutant forms of hOgg1 with mutations Arg(46)-->Gln (alpha-hOgg1-Gln(46)) and Arg(154)-->His (alpha-hOgg1-His(154)) have previously been identified in human tumors. The mutant proteins alpha-hOgg1-Gln(46) and alpha-hOgg1-His(154) were expressed in Escherichia coli and purified to homogeneity. The substrate specificities of these proteins and wild-type alpha-hOgg1 were investigated using gamma-irradiated DNA and the technique of gas chromatography/isotope-dilution mass spectrometry. All three enzymes excised 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 8-hydroxyguanine (8-OH-Gua) from gamma-irradiated DNA containing a multiplicity of base lesions. Michaelis-Menten kinetics of excision were measured. Significant differences between excision kinetics of these three enzymes were observed. Excision of FapyGua and 8-OH-Gua by wild-type alpha-hOgg1 was greater than that by alpha-hOgg1-Gln(46) and alpha-hOgg1-His(154). The latter mutant protein was less active than the former. The diminished activity of the mutant proteins was more pronounced for 8-OH-Gua than for FapyGua. Cleavage assays were also performed using (32)P-labeled 34mer oligonucleotide duplexes containing a single 8-OH-Gua paired to each of the four DNA bases. The results obtained with the oligonucleotide containing the 8-OH-Gua/Cyt pair were in good agreement with those observed with gamma-irradiated DNA. Wild-type alpha-hOgg1 and its mutants repaired the three mismatches less efficiently than the 8-OH-Gua/Cyt pair. The substitution of Arg(154), in addition to diminishing the activity on 8-OH-Gua, relaxes the selectivity found in the wild-type alpha-hOgg1 for the base opposite 8-OH-Gua. Taken together the results show that the mutant forms alpha-hOgg1-Gln(46) and alpha-hOgg1-His(154) found in human tumors are defective in their catalytic capacities.


Vascular Response to Low-intensity Ultrasound Stimulation.
Low-intensity ultrasound stimulation (LIUS) is an emerging neuro- and vascular-modulation technique. Studies on humans and animals have shown that LIUS could induce changes in neuronal oscillations or blood flow. However, it is still inconclusive whether the hemodynamic response to LIUS is due to neurovascular coupling (NVC), direct ultrasound-vessel interactions, or both. This study aims to detect the direct effect of LIUS on vessels using optical imaging. Fluorescence images with indocyanine green (ICG) were used to identify and quantify the morphological change in the auricle vessels of rats. Diameters of vessels were measured before, during, and post LIUS. The results indicated that LIUS could significantly increase the vessel diameters (p = 0.031). Further exploratory analysis showed that vessel dilation occurred among the majority of randomly selected vessels (i.e., 21/30 animals (70%), dilation: 6.84±1.95µm, 95% CI: [3.02,10.66]), with a significant confounding effect of the vessel size. The results provided indirect evidence for two distinct pathways in LIUS-based neurovascular modulation, i.e., the NVC and the direct ultrasound-vessel interactions.