Sub-cellular spectrochemical imaging of isolated human corneal cells employing synchrotron radiation-based Fourier-transform infrared microspectroscopy.
Understanding stem cell (SC) biology remains challenging and one of the few human tissues within which their in situ location is well characterized is the cornea. Individual human corneal epithelial cells were isolated from biopsies of live tissues using fluorescence-activated cell sorting (FACS); these were divided into putative SCs, transit-amplifying (TA) cells and terminally-differentiated (TD) cells. Employing synchrotron radiation-based Fourier-transform infrared (SR-FTIR) microspectroscopy with a focal plane array (FPA), sub-cellular spatial resolution analysis of unstained isolated cells was achieved as a consequence of the brilliance of a 12 collimated beams arrangement allowing rapid spectral acquisition. Infrared (IR) spectra were extracted and pre-processed. Subsequent categorization with multivariate analysis of IR spectra derived from FPA images was used to investigate biomolecular changes between classes. A progressive segregation in cell-specific spectral categories with differentiation from SC to TA cell to TD cell was noted. Multiple different absorption peaks that discriminated putative SCs, TA cells and TD cells across DNA, protein and lipid spectral regions were identified. DNA regions (1080 and 1225 cm(-1)) and some protein regions (1443 cm(-1)) primarily segregated SCs from TA cells and TD cells, whilst amide regions and lipids (1,550, 1650 and 1740 cm(-1)) segregated TA cells and TD cells. Scanning electron microscopy images verified the external phenotypic characteristics of the different isolated cell types. These findings highlight the applicability of SR-FTIR microspectroscopy towards distinguishing SCs, TA cells and TD cells, and suggest that cellular classification via traditional methods of immunolabelling can be greatly aided by the use of spectral biomarkers.


Plasma Aldosterone Concentration as a Determinant for Statin Use among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease.
The use of statin therapy on the prevention of atherosclerotic cardiovascular disease (ASCVD) is recommended by the American College of Cardiology (ACC) and the American Heart Association (AHA); nevertheless, its validation on primary aldosteronism (PA) patients has not been reported. We investigated the risk of incident ASCVD in middle-aged patients with PA compared with essential hypertension (EH) based on ACC/AHA recommendations. We enrolled 461 PA patients and 553 EH patients. Even though the ratio of metabolic syndrome in each group was similar, the PA group had higher systolic blood pressures, higher low-density lipoprotein levels, higher plasma aldosterone concentration (PAC), lower high-density lipoprotein levels, and higher 10-year ASCVD compared to the EH group. The discriminative power for predicting ASCVD by the recommended statin use from the ACC/AHA guidelines was proper in the PA group (i.e., under the receiver operating characteristic curve (95% confidence interval; 0.94 (0.91⁻0.96)). The generalized additive model showed patients with PAC higher than 60 ng/dL accompanying the standard timing of the statin use suggested by the ACC/AHA. The ACC/AHA guidelines have good discriminative power in the prediction of middle-aged high-risk hypertensive patients, while PAC identifies those high-risk individuals who may benefit from early statin therapy.


Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood-Brain Barrier System.
The blood-brain barrier (BBB) is an active and complex diffusion barrier that separates the circulating blood from the brain and extracellular fluid, regulates nutrient transportation, and provides protection against various toxic compounds and pathogens. Creating an in vitro microphysiological BBB system, particularly with relevant human cell types, will significantly facilitate the research of neuropharmaceutical drug delivery, screening, and transport, as well as improve our understanding of pathologies that are due to BBB damage. Currently, most of the in vitro BBB models are generated by culturing rodent astrocytes and endothelial cells, using commercially available transwell membranes. Those membranes are made of plastic biopolymers that are nonbiodegradable, porous, and stiff. In addition, distinct from rodent astrocytes, human astrocytes possess unique cell complexity and physiology, which are among the few characteristics that differentiate human brains from rodent brains. In this study, we established a novel human BBB microphysiologocal system, consisting of a three-dimensionally printed holder with a electrospun poly(lactic- co-glycolic) acid (PLGA) nanofibrous mesh, a bilayer coculture of human astrocytes, and endothelial cells, derived from human induced pluripotent stem cells (hiPSCs), on the electrospun PLGA mesh. This human BBB model achieved significant barrier integrity with tight junction protein expression, an effective permeability to sodium fluorescein, and higher transendothelial electrical resistance (TEER) comparing to electrospun mesh-based counterparts. Moreover, the coculture of hiPSC-derived astrocytes and endothielial cells promoted the tight junction protein expression and the TEER value. We further verified the barrier functions of our BBB model with antibrain tumor drugs (paclitaxel and bortezomib) and a neurotoxic peptide (amyloid β 1-42). The human microphysiological system generated in this study will potentially provide a new, powerful tool for research on human BBB physiology and pathology.


Patient and practitioner characteristics predict brief alcohol intervention in primary care.
The effectiveness of an evidence-based health care intervention depends on it being delivered consistently to appropriate patients. Brief alcohol intervention is known to be effective at reducing excessive drinking and its concomitant health and social problems. However, a recent implementation trial reported partial delivery of brief alcohol intervention by general practitioners (GPs) which is likely to have reduced its impact. To investigate patient-practitioner characteristics influencing brief alcohol intervention in primary care. Cross-sectional analysis of 12,814 completed Alcohol Use Disorders Identification Test (AUDIT) screening questionnaires. Eighty-four GPs who had implemented a brief alcohol intervention programme in a previous trial based in the Northeast of England. GPs were requested to screen all adults (aged over 16 years) presenting to their surgery and follow a structured protocol to give a brief intervention (five minutes of advice plus an information booklet) to all 'risk' drinkers. Anonymized carbon copies of the screening questionnaire were collected from all practices after a three-month implementation period. Although AUDIT identified 4080 'risk' drinkers, only 2043 (50%) received brief intervention. Risk drinkers that were most likely to receive brief intervention were males (58%), unemployed (61%), and technically-trained patients (55%). Risk drinkers that were least likely to receive brief intervention were females (44%), students (38%), and university educated patients (46%). Logistic regression modelling showed that patients' risk status was the most influential predictor of brief intervention. Also, GPs' experience of relevant training and longer average practice consultations predicted brief intervention. However, personal characteristics relating to patients and GPs also predicted brief intervention in routine practice. Interpersonal factors relating to patients and practitioners contributed to the selective provision of brief alcohol intervention in primary care. Ways should be found to remedy this situation or the impact of this evidence-based intervention may be reduced when implemented in routine practice.


Longitudinal analysis of cryptosporidium species-specific immunoglobulin G antibody responses in Peruvian children.
Cryptosporidium species are ubiquitous in the environment and are frequently detected in the stools of children who live where sanitation conditions are poor. To better characterize the immune response to these parasites, we monitored immunoglobulin G (IgG) antibody levels in a cohort of children from Lima, Peru. Two new enzyme-linked immunosorbent assays based on the C. parvum (bovine, subtype IIa) Iowa strain 17-kDa and 27-kDa antigens were used to measure IgG antibody levels in longitudinal serum samples. Antibody responses were detected during infections with C. parvum, C. felis, and C. meleagridis and with four different subtypes of C. hominis. We also noted that the magnitude of the antibody response was related to the number of previous infections and that older children generally had higher levels of antibodies to the two C. parvum antigens. Antibody responses were not associated with infections with either Cyclospora sp. or Giardia sp. We believe the antibody assays will be important tools for monitoring the success of future public health interventions.


Low interleukin-12 activity in severe Plasmodium falciparum malaria.
We compared interleukin-12 (IL-12) and other cytokine activities during and after an acute clinical episode in a matched-pair case-control study of young African children who presented with either mild or severe Plasmodium falciparum malaria. The acute-phase, pretreatment plasma IL-12 and alpha interferon (IFN-alpha) levels, as well as the acute-phase mitogen-stimulated whole-blood production capacity of IL-12, were significantly lower in children with severe rather than mild malaria. IL-12 levels, in addition, showed strong inverse correlations both with parasitemia and with the numbers of circulating malaria pigment-containing neutrophils. Acute-phase plasma tumor necrosis factor (TNF) and IL-10 levels were significantly higher in those with severe malaria, and the concentrations of both of these cytokines were positively correlated both with parasitemia and with the numbers of pigment-containing phagocytes in the blood. Children with severe anemia had the highest levels of TNF in plasma. In all the children, the levels in plasma and production capacities of all cytokines normalized when they were healthy and parasite free. The results indicate that severe but not mild P. falciparum malaria in young, nonimmune African children is characterized by down-regulated IL-12 activity, contrasting markedly with the up-regulation of both TNF and IL-10 in the same children. A combination of disturbed phagocyte functions resulting from hemozoin consumption, along with reduced IFN-gamma responses, may contribute to these differential effects.


Modularity, criticality, and evolvability of a developmental gene regulatory network.
The existence of discrete phenotypic traits suggests that the complex regulatory processes which produce them are functionally modular. These processes are usually represented by networks. Only modular networks can be partitioned into intelligible subcircuits able to evolve relatively independently. Traditionally, functional modularity is approximated by detection of modularity in network structure. However, the correlation between structure and function is loose. Many regulatory networks exhibit modular behaviour without structural modularity. Here we partition an experimentally tractable regulatory network-the gap gene system of dipteran insects-using an alternative approach. We show that this system, although not structurally modular, is composed of dynamical modules driving different aspects of whole-network behaviour. All these subcircuits share the same regulatory structure, but differ in components and sensitivity to regulatory interactions. Some subcircuits are in a state of criticality, while others are not, which explains the observed differential evolvability of the various expression features in the system.


Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear.
Research employing aversive conditioning paradigms has elucidated the neurocircuitry involved in acquiring and diminishing fear responses. However, the factors underlying individual differences in fear acquisition and inhibition are not presently well understood. In this study, we explored whether the magnitude of individuals' acquired fear responses and the modulation of these responses via 2 fear reduction methods were correlated with structural differences in brain regions involved in affective processing. Physiological and structural magnetic resonance imaging data were obtained from experiments exploring extinction retention and intentional cognitive regulation. Our results identified 2 regions in which individual variation in brain structure correlated with subjects' fear-related arousal. Confirming previous results, increased thickness in ventromedial prefrontal cortex was correlated with the degree of extinction retention. Additionally, subjects with greater thickness in the posterior insula exhibited larger conditioned responses during acquisition. The data suggest a trend toward a negative correlation between amygdala volume and fear acquisition magnitude. There was no significant correlation between fear reduction via cognitive regulation and thickness in our prefrontal regions of interest. Acquisition and regulation measures were uncorrelated, suggesting that while certain individuals may have a propensity toward increased expression of conditioned fear, these responses can be diminished via both extinction and cognitive regulation.


Identifying and prioritising epilepsy treatment uncertainties.
To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians. Failure to acknowledge and address genuine treatment uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research. The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis. Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy. Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.


The biphasic poroviscoelastic behavior of articular cartilage: role of the surface zone in governing the compressive behavior.
Surface fibrillation of articular cartilage is an early sign of degenerative changes in the development of osteoarthritis. To assess the influence of the surface zone on the viscoelastic properties of cartilage under compressive loading, we prepared osteochondral plugs from skeletally mature steers, with and without the surface zone of articular cartilage, for study in the confined compression creep experiment. The relative contributions of two viscoelastic mechanisms, i.e. a flow-independent mechanism [Hayes and Bodine, J. Biomechanics 11, 407-419 (1978)], and a flow-dependent mechanism [Mow et al. J. biomech. Engng 102, 73-84 (1980)], to the compressive creep response of these two types of specimens were determined using the biphasic poroviscoelastic theory proposed by Mak. [J. Biomechanics 20, 703-714 (1986)]. From the experimental results and the biphasic poroviscoelastic theory, we found that frictional drag associated with interstitial fluid flow and fluid pressurization are the dominant mechanisms of load support in the intact specimens, i.e. the flow-dependent mechanisms alone were sufficient to describe normal articular cartilage compressive creep behavior. For specimens with the surface removed, we found an increased creep rate which was derived from an increased tissue permeability, as well as significant changes in the flow-independent parameters of the viscoelastic solid matrix. permeability, as well as significant changes in the flow-independent parameters of the viscoelastic solid matrix. From these tissue properties and the biphasic poroviscoelastic theory, we determined that the flow-dependent mechanisms of load support, i.e. frictional drag and fluid pressurization, were greatly diminished in cartilage without the articular surface. Calculations based upon these material parameters show that for specimens with the surface zone removed, the cartilage solid matrix became more highly loaded during the early stages of creep. This suggests that an important function of the articular surface is to provide for a low fluid permeability, and thereby serve to restrict fluid exudation and increase interstitial fluid pressurization. Thus, it is likely that with increasing severity of damage to the articular surface, load support in cartilage under compression shifts from the flow-dependent modes of fluid drag and pressurization to increased solid matrix stress. This suggests that it is important to maintain the integrity of the articular surface in preserving normal compressive behavior of the tissue and normal load carriage in the joint.


Alzheimer's disease and non-demented high pathology control nonagenarians: comparing and contrasting the biochemistry of cognitively successful aging.
The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure.


Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy.
Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 126.96.36.199), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containing the muscle creatine kinase (MCK) (CK1) reduced glycogen content by approximately 50% in the heart and quadriceps in GAA-knockout (GAA-KO) mice; furthermore, an AAV2/8 vector containing the hybrid alpha-myosin heavy chain enhancer-/MCK enhancer-promoter (MHCK7) cassette reduced glycogen content by >95% in heart and >75% in the diaphragm and quadriceps. Transduction with an AAV2/8 vector was higher in the quadriceps than in the gastrocnemius. An AAV2/9 vector containing the MHCK7 cassette corrected GAA deficiency in the distal hindlimb, and glycogen accumulations were substantially cleared by human GAA (hGAA) expression therein; however, the analogous AAV2/7 vector achieved much lower efficacy. Administration of the MHCK7-containing vectors significantly increased striated muscle function as assessed by increased Rotarod times at 18 weeks after injection, whereas the CK1-containing vector did not increase Rotarod performance. Importantly, type IIb myofibers in the extensor digitalis longus (EDL) were transduced, thereby correcting a myofiber type that is unresponsive to enzyme replacement therapy. In summary, AAV8 and AAV9-pseudotyped vectors containing the MHCK7 regulatory cassette achieved enhanced efficacy in Pompe disease mice.


Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure.
A decrease in the myocardial level of the mRNA encoding the Ca2(+)-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human end-stage heart failure, we compared the SR Ca2(+)-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2(+)-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2(+)-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P less than 0.01 and -47%, P less than 0.05, respectively). The LV ratio of Ca2(+)-ATPase mRNA to 18S RNA positively correlated with cardiac index (P less than 0.02). The RV ratio correlated negatively with systolic, diastolic and mean pulmonary arterial pressures (P less than 0.02, P less than 0.02, and P less than 0.01, respectively). We suggest that a decrease of the SR Ca2(+)-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure.


Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection.
Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.


Nonsolvent-induced morphological changes and nanoporosity in poly(l-lactide) films.
The role of a nonsolvent in controlling the crystallization and morphology of solvent-crystallized poly(l-lactide) (PLLA) films was investigated using various microscopy techniques and small- and wide-angle X-ray scattering (SAXS/WAXS). PLLA films crystallized in THF and acetone had 40-80 μm spherulites. When water was present in the solvent, a completely different morphology was observed with nanosized voids and the surfaces of the films were smooth. In contrast, SEM studies revealed that the films crystallized in acetone and THF which had macroporous structures, had larger voids and film surfaces were rough because of the presence of globular structures. Voids appeared within the spherulites in the THF/water treated film, whereas crystals nucleated at the surface of the nanosized voids in acetone/water treated PLLA films. The formation of such voids is attributed to the interface-enhanced crystal nucleation in a solvent/nonsolvent system where the nonsolvent increases the polymer crystal nucleation and the subsequent evaporation of the nonsolvent. The method described in this work can be extended to other polymers to control the morphologies of polymer films during solvent-induced crystallization.


Tooth loss caused by displaced elastic during simple preprosthetic orthodontic treatment.
The use of elastics to close a diastema or correct tooth malpositions can create unintended consequences if not properly controlled. The American Association of Orthodontists recently issued a consumer alert, warning of "a substantial risk for irreparable damage" from a new trend called "do-it-yourself" orthodontics, consisting of patients autonomously using elastics to correct tooth position. The elastics can work their way below the gums and around the roots of the teeth, causing damage to the periodontium and even resulting in tooth loss. The cost of implants to replace these teeth would well exceed the cost of proper orthodontic care. This damage could also occur in a dental office, when a general dentist tries to perform a simplified orthodontic correction of a minor tooth malposition. The present case report describes a case of tooth loss caused by a displaced intraoral elastic, which occurred during a simple preprosthetic orthodontic treatment.


A half-yearly aspect of circulating melatonin in pregnancies complicated by intrauterine growth retardation.
In investigating mechanisms underlying intrauterine growth retardation (IUGR), circulating melatonin and cortisol were radioimmunoassayed. Blood samples were collected every 4 hours during 24 hours on a strict 24-hour standardized routine in hospital from two groups of women in their third trimester of pregnancy. One group consisted of 14 healthy, uncomplicated pregnancies (HAGA); the other group consisted of 11 pregnancies complicated by intrauterine growth retardation (IUGR) confirmed at birth. The circadian characteristics of melatonin and cortisol were assessed for each woman and compared between the two groups by analyses of variance for repeated measures and by parameter tests based on the cosinor. Since a circasemiannual (about half-yearly) component prominently characterizes body weight and length at birth of children with birth characteristics below usual norms, the circadian characteristics of melatonin and cortisol were also analyzed transversely (across women within each group). The 24-hour average and the 24-hour and 12-hour amplitudes of melatonin of women in the IUGR, but not in the HAGA group, were indeed found to be modulated by an about half-yearly component. This study confirms the circadian rhythmicity of melatonin in healthy pregnant women and extends the finding to pregnancies complicated by IUGR, uncovering about half-yearly changes in melatonin in women with IUGR, thereby extending results obtained in healthy non-pregnant women and men. These variations may reflect influences from geomagnetic disturbances also characterized by a prominent half-yearly pattern, to which the pineal has been shown to be sensitive.


A study of decoding human brain activities from simultaneous data of EEG and fMRI using MVPA.
Neuroscientists have investigated the functionality of the brain in detail and achieved remarkable results but this area still need further research. Functional magnetic resonance imaging (fMRI) is considered as the most reliable and accurate technique to decode the human brain activity, on the other hand electroencephalography (EEG) is a portable and low cost solution in brain research. The purpose of this study is to find whether EEG can be used to decode the brain activity patterns like fMRI. In fMRI, data from a very specific brain region is enough to decode the brain activity patterns due to the quality of data. On the other hand, EEG can measure the rapid changes in neuronal activity patterns due to its higher temporal resolution i.e., in msec. These rapid changes mostly occur in different brain regions. In this study, multivariate pattern analysis (MVPA) is used both for EEG and fMRI data analysis and the information is extracted from distributed activation patterns of the brain. The significant information among different classes is extracted using two sample t test in both data sets. Finally, the classification analysis is done using the support vector machine. A fair comparison of both data sets is done using the same analysis techniques, moreover simultaneously collected data of EEG and fMRI is used for this comparison. The final analysis is done with the data of eight participants; the average result of all conditions are found which is 65.7% for EEG data set and 64.1% for fMRI data set. It concludes that EEG is capable of doing brain decoding with the data from multiple brain regions. In other words, decoding accuracy with EEG MVPA is as good as fMRI MVPA and is above chance level.


Child welfare in the midst of the coronavirus pandemic-Emerging evidence from Germany.
The coronavirus pandemic has had a major impact on the situation and well-being of children and their families, while simultaneously affecting the ability of welfare services for children and youth to support vulnerable families. As measures of contact restrictions were introduced to contain the virus, and schools and childcare facilities closed, the potential risk to child welfare could hardly be overlooked. Focusing on Germany, this article aims to explore some of the effects of the COVID-19 measures on children and families. Furthermore, it examines a number of key challenges for child protection practitioners. These include identifying potential cases of child maltreatment without the support normally provided by teachers and child carers; and establishing and maintaining contact with clients under physical distancing rules. The article is based on a review of German and English language scientific and journalistic articles, position papers from professional associations and other gray literature. It benefits from recently published (interim) results of empirical studies conducted in Germany, which explore child welfare issues in the pandemic. Under COVID-19, the child welfare system faces unprecedented challenges and uncertainty (e.g. (partial) loss of cooperation opportunities with key partners) whilst showing signs of remarkable resilience (e.g. child protection workers' ability to adjust to new conditions). While the potential of digitalising work processes in child protection has become apparent in the pandemic, the proven continuous face-to-face contact between practitioners and their clients is neither dispensable nor replaceable.


Lugol's dye spray chromoendoscopy establishes early diagnosis of esophageal cancer in patients with primary head and neck cancer.
Patients with primary head and neck cancer show a predisposition to develop esophageal cancer. The aim of this study was to investigate in these patients: the prevalence of esophageal cancer comparing the value of chromoendoscopy using Lugol's solution examination to standard endoscopy, in the early diagnosis of esophageal cancer. Prospective observational study at a state general university hospital in Sao Paulo, Brazil. 326 consecutive adult patients with primary head and neck cancer were evaluated. A standard endoscopy was performed, followed by a 2% Lugol's dye spray chromoendoscopy and histopathologic study. The prevalence of esophageal cancer was defined. The results of the two endoscopic methods were compared. Twenty-four patients with esophageal cancer and high-grade intraepithelial neoplasia were detected and had a prevalence of 7.36%. Chromoendoscopy and standard endoscopy were equivalent to the diagnosis of advanced and invasive esophageal cancer. However, standard endoscopy diagnosed 55% of high-grade intraepithelial neoplasia, in comparison to chromoendoscopy that detected 100%. Patients with primary head and neck cancer should be considered as high risks for the presence of esophageal cancer. Lugol's dye chromoendoscopy diagnosed high-grade intraepithelial neoplasia, which went unnoticed with standard endoscopy. It permits a more exact detection of lesion boundaries and facilitates a more precise targeting of biopsy fragments.


Deep-sea bacteria enriched by oil and dispersant from the Deepwater Horizon spill.
The Deepwater Horizon oil spill resulted in a massive influx of hydrocarbons into the Gulf of Mexico (the Gulf). To better understand the fate of the oil, we enriched and isolated indigenous hydrocarbon-degrading bacteria from deep, uncontaminated waters from the Gulf with oil (Macondo MC252) and dispersant used during the spill (COREXIT 9500). During 20 days of incubation at 5°C, CO(2) evolution, hydrocarbon concentrations and the microbial community composition were determined. Approximately 60% to 25% of the dissolved oil with or without COREXIT, respectively, was degraded, in addition to some hydrocarbons in the COREXIT. FeCl(2) addition initially increased respiration rates, but not the total amount of hydrocarbons degraded. 16S rRNA gene sequencing revealed a succession in the microbial community over time, with an increase in abundance of Colwellia and Oceanospirillales during the incubations. Flocs formed during incubations with oil and/or COREXIT in the absence of FeCl(2) . Synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectromicroscopy revealed that the flocs were comprised of oil, carbohydrates and biomass. Colwellia were the dominant bacteria in the flocs. Colwellia sp. strain RC25 was isolated from one of the enrichments and confirmed to rapidly degrade high amounts (approximately 75%) of the MC252 oil at 5°C. Together these data highlight several features that provide Colwellia with the capacity to degrade oil in cold, deep marine habitats, including aggregation together with oil droplets into flocs and hydrocarbon degradation ability.


Prognostic factors in acute pulmonary edema.
Over a six-month period, 106 admissions of 94 patients for acute pulmonary edema were identified and their charts were reviewed. Precipitating factors for acute pulmonary edema included progressively worsening congestive heart failure in 25.5% of cases, coronary insufficiency in 20.8%, subendocardial myocardial infarction in 16.0%, acute transmural myocardial infarction in 10.4%, arrhythmia in 8.5%, medical noncompliance in 6.6%, and other causes in 12.6%. In-hospital mortality was 17.0% (16 patients). Of those patients discharged from the hospital, an additional 27 (39.7%) were dead at one year, giving an overall one-year mortality of 51.2%. We found that patients with progressively worsening congestive heart failure have a better prognosis than patients with other precipitants. Also, patients with an initial systolic blood pressure in the emergency room of 160 mm Hg or higher had an improved survival over patients with an initial systolic blood pressure under 160 mm Hg. No other in-hospital or long-term prognostic factors were identified.


A novel strategy for cardiopulmonary support during lung transplantation.
Contemporary modalities for cardiopulmonary support during lung transplantation include traditional cardiopulmonary bypass (CPB) and venoarterial extracorporeal membrane oxygenation (VA-ECMO). While highly effective, both are associated with morbidities such as arteriopathy and bleeding diathesis. In this report, we describe a novel approach for cardiopulmonary support during double lung transplantation in a patient with end-stage lung disease, pulmonary hypertension and moderate right ventricle (RV) dysfunction, using a percutaneous dual lumen cannula placed via the jugular vein which allowed us to achieve both RV bypass and membrane oxygenation. The cannula was left in place to provide ongoing RV support and the patient was successfully decannulated at bedside on post-operative day (POD) 2. Lack of arterial cannulation, percutaneous access, and bedside decannulation are benefits of this strategy, rendering this approach a useful addition to the armamentarium for CPB techniques in lung transplantation.


Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer.
Neurotrophins (NTs) can stimulate cell proliferation and differentiation in various cell types, and play a role in certain human cancers. In this study we analyzed the expression and localization of NTs and their receptors in microdissected pancreatic cancer tissue samples, and studied their ability to stimulate cell growth. The expression of nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5, and the receptors tropomyosin receptor kinase A, B, and C, and P75 was studied in pancreatic cancer cell lines, and normal and pancreatic ductal adenocarcinoma (PDAC) tissue samples by quantitative reverse transcription-PCR. Laser capture microdissection was performed in 21 PDAC samples, and mRNA levels were determined in cancer cells, acinar cells, desmoplastic stroma areas, and nerve fibers. Cell growth assays with NTs and in coculture with dorsal root ganglia were performed. NT receptors were differentially expressed in the cancer cell lines, whereas tropomyosin receptor kinase C was not detectable. NTs modulated pancreatic cancer cell growth. Analysis of nonmicrodissected samples revealed that all of the receptors and tested ligands were overexpressed in PDAC when compared with normal pancreas. Analysis of laser captured samples revealed that NTs and their receptors were expressed in the cancer cells but were especially abundant in the intratumoral nerves. Coculture of dorsal root ganglia with T3M4 cells significantly enhanced the proliferation of this cell line. The abundance of NTs in the intratumoral nerves in PDAC and the presence of NT receptors in the cancer cells, in conjunction with the ability of NTs to modulate pancreatic cancer cell growth, point to potential paracrine and autocrine effects of NTs in PDAC. Thus, our findings provide additional evidence that blocking NT actions may have a therapeutic potential in PDAC.


Maternal control of embryogenesis by MEDEA, a polycomb group gene in Arabidopsis.
The gametophytic maternal effect mutant medea (mea) shows aberrant growth regulation during embryogenesis in Arabidopsis thaliana. Embryos derived from mea eggs grow excessively and die during seed desiccation. Embryo lethality is independent of the paternal contribution and gene dosage. The mea phenotype is consistent with the parental conflict theory for the evolution of parent-of-origin-specific effects. MEA encodes a SET domain protein similar to Enhancer of zeste, a member of the Polycomb group. In animals, Polycomb group proteins ensure the stable inheritance of expression patterns through cell division and regulate the control of cell proliferation.


Quantitative carotid phonoangiography.
One hundred and sixteen carotid artery bruits were assessed using quantitative phonoangiography (spectral bruit analysis - SBA). This technique uses the averaged break frequency of the bruit to calculate the diameter of he residual lumen at the site of stenosis. Biplanar contrast arteriography was performed on 43 (37%) of the sides. All 116 sides were also evaluated with an ultrasonic Duplex scanner. Ten (8.6%) bruits could not be analyzed by the SBA, leaving 106 sides in which the residual lumen diameter could be estimated. The diameter of the vessel at the site of stenosis estimated by SBA and arteriography were compared and found to agree within 1 mm of each other in 85% of patients. A linear relationship was demonstrated between absolute lumen diameter and percent stenosis as measured from the arteriograms, but we were unable to correlate the absolute diameter of hte residual lumen as assessed by arteriography or SBA with the assessment of the degree of the stenosis derived from spectral analysis of the pulsed Doppler signal. The significance of these findings is discussed with relevance to the clinical application of spectral bruit analysis.


Fermi resonance as a means to determine the hydrogen-bonding status of two infrared probes.
The C[double bond, length as m-dash]O/C[triple bond, length as m-dash]N stretching vibration arising from a carbonyl/nitrile functional group in various molecular systems has been frequently used to assess, for example, local hydrogen-bonding interactions, among other applications. However, in practice it is not always easy to ascertain whether the carbonyl or nitrile group in question is engaged in such interactions. Herein, we use 4-cyanoindole and cyclopentanone as models to show that, when a fundamental C[double bond, length as m-dash]O or C[triple bond, length as m-dash]N stretching mode is involved in Fermi resonance, the underlying vibrational coupling constant (W) is a convenient reporter of the hydrogen-bonding status of the corresponding carbonyl or nitrile group. Specifically, we find that for both groups a W value of 7.7 cm-1 or greater is indicative of their involvement in hydrogen-bonding interactions. Furthermore, we find that, as observed in similar studies, the Fermi resonance coupling leads to quantum beats in the two-dimensional infrared spectra of 4-cyanoindole in isopropanol, with a period of about 1.9 ps.


Caustic oesophagitis in children: prevalence, the corrosive agents involved, and management from primary care through to surgery.
Caustic substance ingestion (CSI) remains a major health issue, particularly in developing countries, where laws are not effectively enforced. This review offers a thorough analysis of the current epidemiology, clinical features, management, treatment, and long-term complications of CSI in children. Strong alkalis sold in liquid and granular forms, particularly crystalline grease cleaners (concentrated sodium hydroxide), are the principal causes of severe oesophageal damage. Currently, early endoscopy to assess the gastro-oesophageal mucosa is not considered necessary for all CSI cases. Oesophageal stricture is a major complication developing after CSI, and should be diagnosed and treated earlier, 10-14 days after CSI via commencement of a dilation program. Fluoroscopically guided oesophageal balloon dilatation seems to be safe, with a low frequency of complications and a high success rate. However, it should commence earlier than is currently the case, and should be performed gently, using balloons of gradually increasing diameter. If dilation fails after a few months, oesophageal replacement surgery should be performed. Unfortunately, neither dilatation treatment nor oesophageal bypass surgery can prevent the development of oesophageal carcinoma, the incidence of which is high after CSI. The continuing unacceptably high incidence of CSI accidents would be reduced if corrosive materials were sold in their original childproof containers, highlighting the need for preventive and adult education programmes.


The Calotropis Gigantea Methanolic Extract Induces Apoptosis in Human Breast Carcinoma Cells.
Calotropis gigantea (family: Asclepiadaceae) has been known to contain cardiac glycosides. The C. gigantea extracts have been reported as cytotoxic to a few cancer cell lines. The present study was designed to examine the effect of Calotropis gigantea methanolic extract (CGME) on the growth and apoptosis in human breast carcinoma cell line (MCF-7 cells). The study was conducted in Aurangabad (India) from 16 February to 10 June 2015. CGME treated MCF-7 cells were analyzed for growth inhibition and apoptosis. The exhibition of phosphatidylserine was analyzed with the Annexin-V Fluorescein isothiocyanate flow cytometry (FITC) method. Accumulated poly-caspases were determined with carboxyfluorescein poly-caspase assay, Apo-BrdU™ tunnel assay for DNA fragmentation and pro/anti-apoptotic gene expression with real-time polymerase chain reaction. The high-performance liquid chromatography analysis indicated the presence of two unknown cardenolides along with known cardenolides such as calactin, calatropagenin, usharin, afroside, calatoxin, and gamphoside. The Kruskal-Wallis and Wilcoxon tests (GraphPad Prism version 7.0) were used for statistical analyses. Upon treatment with 40 µg/ml CGME, about 56.9% of the cell population underwent apoptosis. Compared to paclitaxel, the accumulation of active caspases in CGME treated with MCF-7 cells was found to be dose-dependent, whereas the G2/M cell cycle arrest was time-dependent. The Apo-BrdU™ tunnel assay confirmed that CGME treatment caused DNA fragmentation and RT-PCR analyses indicated elevated transcription for pro-apoptotic gene expression. Kruskal-Wallis test results were significant; Bcl-2 (P=0.00193), Bak-1 (P=0.00021), and Bax (P=0.0019). CGME treatment caused the accumulation of phosphatidylserine on the cell membrane, recruitment of poly-caspases, DNA fragmentation, and enhanced transcription of pro-apoptotic gene expression.


Fringe-projection profilometry based on two-dimensional empirical mode decomposition.
In 3D shape measurement, because deformed fringes often contain low-frequency information degraded with random noise and background intensity information, a new fringe-projection profilometry is proposed based on 2D empirical mode decomposition (2D-EMD). The fringe pattern is first decomposed into numbers of intrinsic mode functions by 2D-EMD. Because the method has partial noise reduction, the background components can be removed to obtain the fundamental components needed to perform Hilbert transformation to retrieve the phase information. The 2D-EMD can effectively extract the modulation phase of a single direction fringe and an inclined fringe pattern because it is a full 2D analysis method and considers the relationship between adjacent lines of a fringe patterns. In addition, as the method does not add noise repeatedly, as does ensemble EMD, the data processing time is shortened. Computer simulations and experiments prove the feasibility of this method.


Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing.
Diverse biochemical rhythms are generated by thousands of cellular oscillators that somehow manage to operate synchronously. In fields ranging from circadian biology to endocrinology, it remains an exciting challenge to understand how collective rhythms emerge in multicellular structures. Using mathematical and computational modeling, we study the effect of coupling through intercell signaling in a population of Escherichia coli cells expressing a synthetic biological clock. Our results predict that a diverse and noisy community of such genetic oscillators interacting through a quorum-sensing mechanism should self-synchronize in a robust way, leading to a substantially improved global rhythmicity in the system. As such, the particular system of coupled genetic oscillators considered here might be a good candidate to provide the first quantitative example of a synchronization transition in a population of biological oscillators.


Complications and outcome of tibial lengthening using the Ilizarov method with or without a supplementary intramedullary nail: a case-matched comparative study.
We compared the complications and outcome of tibial lengthening using the Ilizarov method with and without the use of a supplementary intramedullary nail. In a retrospective case-matched series assembled from 176 patients with tibial lengthening, we matched 52 patients (26 pairs, group A with nail and group B without) according to the following criteria in order of importance: 1) difference in amount of lengthening (± 2 cm); 2) percentage difference in lengthening (± 5%); 3) difference in patient's age (± seven years); 4) aetiology of the shortening, and 5) level of difficulty in obtaining the correction. The outcome was evaluated using the external fixator index, the healing index and an outcome score according to the criteria of Paley. It was found that some complications were specific to group A or B respectively, but others were common to both groups. The outcome was generally better in lengthenings with a nail, although there was a higher incidence of rectifiable equinus deformity in these patients.


Red blood cell distribution and survival in patients with chronic obstructive pulmonary disease.
Cardiovascular disease (CVD) contributes significantly to mortality in chronic obstructive pulmonary disease (COPD). Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity that is largely overlooked, is a newly recognized mortality marker in patients with established CVD. It is unknown whether RDW is associated with mortality in COPD patients. To study the prognostic value of RDW in patients with COPD and to compare the value of this measurement with cardiac, respiratory, and hemotological status. We performed retrospective analyses of 270 patients stable with COPD who were admitted to our hospital between January 2007 and December 2009. Demographic, clinical, echocardiographic, and laboratory characteristics were registered and recorded COPD deaths were registered as outcomes. In the overall patients, the RDW level had a mean value of 15.1 ± 2.4. RDW was positively correlated with C-reactive protein (CRP) (p = 0.008, r = 0.21), right ventricular dysfunction (RVD) (p < 0.001, r = 0.25), and pulmonary arterial hypertension (PAH) (p = 0.03, r = 0.14). Variables (p < 0.1) included in the univariate survival analysis were forced expiratory volume in 1 second (FEV1% predicted), RDW levels, age, PaCO2, albumine and CRP levels, presence of CVD, presence of anemia, presence of RVD, and presence of PAH. Subsequent multivariate analysis suggested that RDW levels (1.12; 95% CI, 1.01 to 1.24; p = 0.01), and presence of RVD (2.6; 95% CI, 1.19 to 5.8; p = 0.01) were independently related to mortality. Elevated RDW levels were associated with increased mortality risk in stable COPD patients.


Comparative whole-grain intake of British adults in 1986-7 and 2000-1.
Epidemiological evidence suggests that higher consumption of whole-grain foods can significantly reduce the risk of chronic diseases such as CVD, type 2 diabetes and some cancers. The present study compares whole-grain intake of 2086 adults aged 16-64 years from the 1986-7 Dietary and Nutritional Survey of British Adults with that of 1692 adults aged 19-64 years from the 2000-1 National Diet and Nutrition Survey. For each survey, whole-grain intake was estimated from consumption of all foods containing > or = 10% whole-grain content (as DM/fresh weight of food) from 7d weighed dietary records. In 1986-7, median whole-grain intake was 16 (interquartile range 0-45) g/d v. 14 (interquartile range 0-36) g/d in 2000-1 (P< 0.001). In 1986-7, 77% of adults had less than three 16 g amounts of whole-grain intake/d; 25 % reported no whole-grain intake. In 2000-1, corresponding percentages were 84 and 29%, respectively. Foods with <51% whole-grain content provided 18% of whole-grain intake in 1986-7 v. 27% in 2000-1 (P<0.001). In both surveys, whole-grain intake was significantly lower among adults with a manual v. non-manual occupation (indicative of lower socio-economic status) and among smokers v. non-smokers, independent of occupational social class. In 1986-7, whole-grain breakfast cereals and wholemeal bread contributed 28 and 48% of whole-grain intake, respectively, v. 45 and 31% in 2000-1. At each time, one-third of adults consumed neither of these two largest contributors to whole-grain intake. Findings from the present study suggest that whole-grain intake of British adults was low in 1986-7 and became even lower over the subsequent decade.


Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study.
The Psychotic Symptom Rating Scales (PSYRATS) is an instrument designed to quantify the severity of delusions and hallucinations and is typically used in research studies and clinical settings focusing on people with psychosis and schizophrenia. It is comprised of the auditory hallucinations (AHS) and delusions subscales (DS), but these subscales do not necessarily reflect the psychological constructs causing intercorrelation between clusters of scale items. Identification of these constructs is important in some clinical and research contexts because item clustering may be caused by underlying etiological processes of interest. Previous attempts to identify these constructs have produced conflicting results. In this study, we compiled PSYRATS data from 12 sites in 7 countries, comprising 711 participants for AHS and 520 for DS. We compared previously proposed and novel models of underlying constructs using structural equation modeling. For the AHS, a novel 4-dimensional model provided the best fit, with latent variables labeled Distress (negative content, distress, and control), Frequency (frequency, duration, and disruption), Attribution (location and origin of voices), and Loudness (loudness item only). For the DS, a 2-dimensional solution was confirmed, with latent variables labeled Distress (amount/intensity) and Frequency (preoccupation, conviction, and disruption). The within-AHS and within-DS dimension intercorrelations were higher than those between subscales, with the exception of the AHS and DS Distress dimensions, which produced a correlation that approached the range of the within-scale correlations. Recommendations are provided for integrating these underlying constructs into research and clinical applications of the PSYRATS.


Studying insect diversity in the tropics.
Understanding the extent and causes of insect diversity in the humid tropics is one of the major challenges in modern ecology. We review some of the current approaches to this problem, and discuss how future progress may be made. Recent calculations that there may be more than 30 million species of insect on earth have focused attention on the magnitude of this problem and stimulated several new lines of research (although the true figure is now widely thought to be between five and ten million species). We discuss work based on insecticidal logging surveys; studies of herbivore and parasitoid specificity; macroecological approaches; and the construction of food webs. It is argued that progress in estimating insect diversity and in understanding insect community dynamics will be enhanced by building local inventories of species diversity, and in descriptive and experimental studies of the trophic structure of communities. As an illustration of work aimed at the last goal, we discuss the construction and analysis of quantitative host-parasitoid food webs, drawing on our work on leaf miner communities in Central America.


Factors affecting patient recruitment in an acute rehabilitation randomized controlled trial.
To evaluate factors associated with randomized controlled trial patient recruitment by therapists. Survey of 18 (of a possible 26) therapists who had agreed to recruit patients for a randomized controlled trial (78% response rate). Sixteen respondents had enrolled at least one patient. The site at which the therapist worked neither influenced the likelihood that a therapist would contact the researcher nor influenced the recruitment rate. Seventeen respondents reported that they contacted the researcher to discuss one or more of their patients for potential inclusion in the trial. Factors reported by therapists as reasons why they did not recommend the trial to eligible patients were not specific to study inclusion or exclusion criteria, rather were linked to personal judgments about patient suitability for the study. Regression analysis indicated that being enrolled or having completed master's level postgraduate studies, and choosing not to refer patients because of concern for their poor medical prognosis were the only factors that significantly influenced recruitment rate (p < 0.001). Recruitment practices vary amongst therapists. Selection of therapists with postgraduate qualifications as recruiters may be an effective way to enhance recruitment rate.


A thioredoxin of Sinorhizobium meliloti CE52G is required for melanin production and symbiotic nitrogen fixation.
A miniTn5-induced mutant of a melanin-producing strain of Sinorhizobium meliloti (CE52G) that does not produce melanin was mapped to a gene identified as a probable thioredoxin gene. It was proved that the thiol-reducing activity of the mutant was affected. Addition to the growth medium of substrates that induce the production of melanin (L-tyrosine, guaiacol, orcinol) increased the thioredoxin-like (trxL) mRNA level in the wild-type strain. The mutant strain was affected in the response to paraquat-induced oxidative stress, symbiotic nitrogen fixation, and both laccase and tyrosinase activities. The importance of thioredoxin in melanin production in bacteria, through the regulation of laccase or tyrosinase activities, or both, by the redox state of structural or catalytic SH groups, is discussed.


Physical Activity in Early- and Mid-Adulthood Are Independently Associated With Longitudinal Memory Trajectories in Later Life.
Physical activity (PA) in later life may reduce dementia risk, but little is known regarding long-term cognitive effects of PA that occurred earlier in adulthood or mechanisms underlying associations. PA patterns at different ages may independently contribute to dementia risk, which would implicate multiple critical periods for intervention. The current study tested whether retrospective reports of PA in early and mid-adulthood were independently associated with later-life longitudinal memory outcomes and whether associations were mediated by late-life cardiometabolic diseases. Participants comprised 5200 Health and Retirement Study Life History Mail Survey respondents. Latent growth curves estimated independent associations between retrospectively reported PA in early adulthood (age 18-29) and mid-adulthood (age 40-49) and 16-year episodic memory trajectories. Indirect pathways involving the maintenance of PA from early- to mid-adulthood and the influence of PA on later-life cardiometabolic diseases (hypertension, diabetes, and heart disease) were also estimated. PA in early- and mid-adulthood independently predicted higher initial memory level and slower memory decline in later life, respectively. Early-adulthood PA was indirectly associated with later-life memory level through higher mid-adulthood PA and lower rates of later-life hypertension, as well as with subsequent memory decline through higher mid-adulthood PA. The current findings highlight the importance of PA throughout adulthood, such that initiating and/or maintaining exercise in early- or mid-adulthood may be protective for later-life cognitive health, and hypertension appears to represent a key mediator of these effects.


Guidelines for medical technology in critical care. Technology Subcommittee of the Working Group on Critical Care, Ontario Ministry of Health.
To examine the current status of technology in critical care medicine and to present guidelines for technologies commonly used in Ontario critical care units. A computerized search of the medical literature, interviews with relevant people and a review of existing guidelines or standards were conducted. Nonrandomized trials and retrospective reviews were included because of a paucity of prospective randomized controlled trials. Technologies were assessed by individual committee members. The validity of the technologies was compared with accepted standards when available. All published clinical data were used to assess efficacy. After review of the data, discussion papers on ventilation, and electrocardiographic, hemodynamic and intracranial pressure monitoring were written by committee members and then reviewed by the subcommittee as a whole. For each technology an attempt was made to match need with the patient classifications of the Working Group on Critical Care. Critical care guidelines were then developed through the use of the nominal group and Delphi consensus-gathering techniques. The guidelines were reviewed by external experts. These guidelines should help in assessing quality assurance and the resources necessary for critical care. Also, they should enable health care providers and hospital administrators to make better decisions when acquiring critical care technology. Since the guidelines represent the current state of knowledge there must be a continuing assessment of the technology and review of the guidelines.


Recognize fish as food in policy discourse and development funding.
The international development community is off-track from meeting targets for alleviating global malnutrition. Meanwhile, there is growing consensus across scientific disciplines that fish plays a crucial role in food and nutrition security. However, this 'fish as food' perspective has yet to translate into policy and development funding priorities. We argue that the traditional framing of fish as a natural resource emphasizes economic development and biodiversity conservation objectives, whereas situating fish within a food systems perspective can lead to innovative policies and investments that promote nutrition-sensitive and socially equitable capture fisheries and aquaculture. This paper highlights four pillars of research needs and policy directions toward this end. Ultimately, recognizing and working to enhance the role of fish in alleviating hunger and malnutrition can provide an additional long-term development incentive, beyond revenue generation and biodiversity conservation, for governments, international development organizations, and society more broadly to invest in the sustainability of capture fisheries and aquaculture.


Prediction of Minimum Inhibitory Concentrations of Antimicrobials for Neisseria gonorrhoeae Using Whole-Genome Sequencing.
Bacterial whole-genome sequencing is now increasingly available to researchers, reference laboratories and individual healthcare institutions. It can be possible to predict antimicrobial minimum inhibitory concentrations (MICs) for Neisseria gonorrhoeae using sequencing data, for many antimicrobials within one or two MIC doubling dilutions of the phenotypic value. With emerging rapid sequencing technologies, it may be possible in future to predict antimicrobial resistance faster than existing culture-based methods. Sequencing also provides insights into the genetic mechanisms underlying antimicrobial resistance, their spread in time and space, as well as the molecular epidemiology of the gonococcal strains.


Postoperative outcome of cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: case series and systematic review.
Despite its accessible superficial location, the indication for surgical evacuation in cases of lobar intracerebral hemorrhage (LICH) suspected to be related to cerebral amyloid angiopathy (CAA) is controversial because of advanced patient age and concerns about postoperative hemostasis. To examine factors associated with postoperative outcome in CAA-related LICH. Review of consecutive patients with pathologically proven CAA who underwent LICH evacuation at Saint Marys Hospital, Rochester, Minnesota, between 1987 and 2006. End points were length of stay and postoperative outcome at discharge and last follow-up using the Glasgow Outcome Scale. We also performed a systematic review of all published studies evaluating the outcome of surgically treated CCA-related LICH published between 1984 and 2010. We identified 23 patients with CAA-related LICH treated surgically. Favorable outcome (Glasgow Outcome Scale >3) at discharge was noted in 5 patients (22%), and at 6- to 12-month follow-up (n = 15) in 7 patients (47%). Three (13%) died in the hospital, including 1 of 4 patients with postoperative hemorrhage. Intraventricular hemorrhage (IVH) was associated with poor outcome at discharge. Older age (≥75 years), history of hypertension, and degree of preoperative midline shift were associated with more prolonged length of stay. In our systematic review, we identified 14 studies including 278 cases. Overall mortality rate was 25%, and poor postoperative outcome was associated with older age, IVH, and preoperative dementia. Neurosurgical evacuation may be performed with acceptable safety in patients with CAA-related LICH. A systematic literature review indicates that older age, preexistent dementia, and presurgical IVH portend poor postoperative outcome.


Exploring the Benefits of Molecular Testing for Gonorrhoea Antibiotic Resistance Surveillance in Remote Settings.
Surveillance for gonorrhoea antimicrobial resistance (AMR) is compromised by a move away from culture-based testing in favour of more convenient nucleic acid amplification test (NAAT) tests. We assessed the potential benefit of a molecular resistance test in terms of the timeliness of detection of gonorrhoea AMR. An individual-based mathematical model was developed to describe the transmission of gonorrhoea in a remote Indigenous population in Australia. We estimated the impact of the molecular test on the time delay between first importation and the first confirmation that the prevalence of gonorrhoea AMR (resistance proportion) has breached the WHO-recommended 5% threshold (when a change in antibiotic should occur). In the remote setting evaluated in this study, the model predicts that when culture is the only available means of testing for AMR, the breach will only be detected when the actual prevalence of AMR in the population has already reached 8 - 18%, with an associated delay of ~43 - 69 months between first importation and detection. With the addition of a molecular resistance test, the number of samples for which AMR can be determined increases facilitating earlier detection at a lower resistance proportion. For the best case scenario, where AMR can be determined for all diagnostic samples, the alert would be triggered at least 8 months earlier than using culture alone and the resistance proportion will have only slightly exceeded the 5% notification threshold. Molecular tests have the potential to provide more timely warning of the emergence of gonorrhoea AMR. This in turn will facilitate earlier treatment switching and more targeted treatment, which has the potential to reduce the population impact of gonorrhoea AMR.


[Connexin astrocytopathy and novel therapeutic strategy targeting connexin hemichannels in demyelinating disease].
Recently, we reported aquaporin-4 (AQP4) loss without perivascular deposition of complements or immunoglobulins in autopsied cases with multiple sclerosis (MS), neuromyelitis optica (NMO) and Baló's disease (BD). To investigate the relationship between astrocytopathy and demyelination, we examined the expression of connexins (Cx), which form gap junction channels between astrocytes and oligodendrocytes. We pathologically evaluated the expressions of astrocytic Cx43/Cx30 and oligodendroglial Cx47/Cx32 relative to those of other astrocytic and oligodendrocyte/myelin markers among the autopsied cases. In all BD cases, Cx43, Cx32 and Cx47 were extensively diminished. In the leading edge of Baló's lesions, Cx43 and AQP4 loss preceded Cx47 loss. Two cases with MS and six with NMO showed preferential Cx43 and AQP4 loss far beyond the demyelinated areas, while vasculocentric deposition of immunoglobulins or complements was observed in four of the six NMO cases. The other cases showed AQP4 and Cx43 preservation. Some NMO cases showed preferential myelin-associated glycoprotein (MAG) loss in AQP4- and Cx43-diminished active lesions. Our findings indicate that disruption of Cx gap junction and preferential MAG loss could occur in MS, BD and NMO, and could be a common denominator. Inhibition of Cx hemichannels is a possible therapeutic target for demyelinating disorders.


Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins.
Amyloidoses are diseases characterized by abnormal protein folding and self-assembly, for which no cure is available. Inhibition or modulation of abnormal protein self-assembly, therefore, is an attractive strategy for prevention and treatment of amyloidoses. We examined Lys-specific molecular tweezers and discovered a lead compound termed CLR01, which is capable of inhibiting the aggregation and toxicity of multiple amyloidogenic proteins by binding to Lys residues and disrupting hydrophobic and electrostatic interactions important for nucleation, oligomerization, and fibril elongation. Importantly, CLR01 shows no toxicity at concentrations substantially higher than those needed for inhibition. We used amyloid β-protein (Aβ) to further explore the binding site(s) of CLR01 and the impact of its binding on the assembly process. Mass spectrometry and solution-state NMR demonstrated binding of CLR01 to the Lys residues in Aβ at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology from Aβ oligomers but were nontoxic and were not recognized by the oligomer-specific antibody A11. Thus, CLR01 binds already at the monomer stage and modulates the assembly reaction into formation of nontoxic structures. The data suggest that molecular tweezers are unique, process-specific inhibitors of aberrant protein aggregation and toxicity, which hold promise for developing disease-modifying therapy for amyloidoses.


Levels of burnout and their associated factors among physicians working in Northeast Anatolia.
The concept of burnout is a condition seen in occupational groups working face-to-face with people and resulting in emotional exhaustion, depersonalization, and low professional productivity. The purpose of this study was to determine burnout levels and associated factors in physicians practicing in Erzurum, Northeast Anatolia, Turkey. This research was designed as a cross-sectional descriptive study. The research sample size was calculated at 663 participants with a 99% confidence interval and a 3% margin of error using Epi Info software. A 10% incomplete or nonresponse rate was added, for a target cohort of 730 individuals. Seven hundred and eleven physicians agreeing to take part were enrolled. A questionnaire consisting of questions concerning sociodemographic characteristics and the Maslach Burnout Inventory (MBI) was used as the data collection tool. The questionnaires were distributed by the authors and completed by the physicians in person. Descriptive data were expressed as percentage, mean, median, and standard deviation. Data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests and binary logistic regression analysis. P < 0.05 was regarded as statistically significant. Statistical analyses were performed on SPSS 15.00 software. The mean age of the physicians in the study was 34.4 ± 7.7 years. Mean MBI subdimension scores were 15.6 ± 7.0 for emotional exhaustion, 5.7 ± 3.9 for depersonalization, and 21.0 ± 4.4 for personal accomplishment. Mean emotional exhaustion and depersonalization scores were significantly higher and personal accomplishment scores significantly lower in physicians aged under 25, not taking vacations, working in public hospitals, who were working as research assistants. Burnout levels among the participants were low (emotional exhaustion in 75%, depersonalization in 76.2%, and low personal accomplishment in 69.6%).


Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation.
We have established an efficient synthetic methodology for the 13-oxyingenol natural derivative (13-oxyingenol-13-dodecanoate-20-hexanoate), featuring a ring-closing olefin metathesis reaction for the "direct" construction of a highly strained inside-outside framework and a Mislow-Evans-type [2,3]-sigmatropic rearrangement for the stereoselective introduction of the hydroxy group at C5. We also synthesized artificial analogs of 13-oxyingenol and ingenol by using our synthetic strategy. In vitro activation assays of protein kinase C (PKC) α and δ revealed that the dodecanoyl group at O13 on 13-oxyingenol analogs had a significant role in PKCδ activation. The PKCα- or PKCδ-activating 13-oxyingenol and ingenol analogs induced both distinct morphological changes and increases of CD11b expression in HL-60 cells, which would be typical signs of HL-60 cell differentiation to macrophage-like cells, as expected by previous reports. Intriguingly, however, similar differentiation phenotypes were observed with the use of 13-oxyingenol natural derivatives and 13-oxyingenol-13-dodecanoate showing a remarkably less potent PKCα or PKCδ activation ability, which the PKC inhibitor Gö6983 diminished. This indicated the involvement of other PKC isozymes or related kinase activities. 13-Oxyingenol analogs, which induced HL-60 cell differentiation, also induced HL-60 cell death, similar to the action of a phorbol ester, a strong PKC activator.


Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service.
An assessment of clinical and laboratory findings is generally required to distinguish between septic and aseptic loosening of a hip implant. In order to evaluate the diagnostic utility of histological and microbiological investigative techniques to differentiate between these two conditions, we analysed their results in 617 patients with hip implant loosening. Histology and microbiology study confirmed the clinical diagnosis of septic loosening in approximately 98% and 89%. respectively. The clinical diagnosis of aseptic loosening was confirmed by histology in 99% of cases. In all but 2 of 81 cases of septic loosening, in which an organism was isolated on microbiological culture, the histological diagnosis of septic loosening was made on the basis of the degree of the acute inflammatory infiltrate (i.e. the presence of 1 or more neutrophil polymorphs per high power field (x 400) on average after examination of at least 10 high power fields) in periprosthetic tissues. In 10 patients for whom there was a strong clinical suspicion of septic loosening but no organisms were isolated on microbiological culture, the histological findings, using the above criteria, were in keeping with the clinical diagnosis of septic loosening. As almost 11% of cases of septic loosening would not have been diagnosed by microbiological investigation alone, our findings indicate that histological examination of periprosthetic tissues should form part of the investigative protocol to distinguish between aseptic and septic loosening.


A survey of aspartate-phenylalanine and glutamate-phenylalanine interactions in the protein data bank: searching for anion-π pairs.
Protein structures are stabilized using noncovalent interactions. In addition to the traditional noncovalent interactions, newer types of interactions are thought to be present in proteins. One such interaction, an anion-π pair, in which the positively charged edge of an aromatic ring interacts with an anion, forming a favorable anion-quadrupole interaction, has been previously proposed [Jackson, M. R., et al. (2007) J. Phys. Chem. B111, 8242-8249]. To study the role of anion-π interactions in stabilizing protein structure, we analyzed pairwise interactions between phenylalanine (Phe) and the anionic amino acids, aspartate (Asp) and glutamate (Glu). Particular emphasis was focused on identification of Phe-Asp or -Glu pairs separated by less than 7 Å in the high-resolution, nonredundant Protein Data Bank. Simplifying Phe to benzene and Asp or Glu to formate molecules facilitated in silico analysis of the pairs. Kitaura-Morokuma energy calculations were performed on roughly 19000 benzene-formate pairs and the resulting energies analyzed as a function of distance and angle. Edgewise interactions typically produced strongly stabilizing interaction energies (-2 to -7.3 kcal/mol), while interactions involving the ring face resulted in weakly stabilizing to repulsive interaction energies. The strongest, most stabilizing interactions were identified as preferentially occurring in buried residues. Anion-π pairs are found throughout protein structures, in helices as well as β strands. Numerous pairs also had nearby cation-π interactions as well as potential π-π stacking. While more than 1000 structures did not contain an anion-π pair, the 3134 remaining structures contained approximately 2.6 anion-π pairs per protein, suggesting it is a reasonably common motif that could contribute to the overall structural stability of a protein.


Monoclonal antibodies to Pseudomonas pseudomallei and their potential for diagnosis of melioidosis.
Monoclonal antibodies (MAbs) specific for Pseudomonas pseudomallei antigens were produced by immunizing BALB/c mice with a crude whole cell extract. Hybrids secreting MAbs specific for P. pseudomallei antigens were identified by an indirect enzyme-linked immunosorbent assay (ELISA) against a panel of crude whole cell extracts from P. pseudomallei, P. cepacia, P. aeruginosa, P. putida, P. alcaligenes, Xanthomonas maltophilia, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Salmonella typhi, S. krefeld, S. enteritidis, Proteus mirabilis, and Staphylococcus aureus. Of the six specific clones, clone 5F8, which was IgM-producing and which reacted with all 56 P. pseudomallei isolates, was selected for further characterization and evaluation of its possible diagnostic potential. Results obtained from the indirect ELISA against various P. pseudomallei antigens, from direct bacterial agglutination, and from immunofluorescence tests suggested that 5F8 reacted with the surface envelope, and probably specifically with an epitope of the lipopolysaccharide. The antibody could be readily used to identify P. pseudomallei in primary culture or in a simulated hemoculture. The antibody was also used to prepare an affinity-purified antigen for use in an indirect ELISA that was highly sensitive and specific for the detection of circulating antibody in patients with acute septicemic melioidosis.


Effects of Motor Learning on Clinical Isokinetic Test Performance in Knee Osteoarthritis Patients.
To analyze the effects of motor learning on knee extension-flexion isokinetic performance in knee osteoarthritis patients. One hundred and thirty-six middle-aged and older sedentary individuals (111 women, 64.3±9.9 years) with knee osteoarthritis (130 patients with bilateral) and who had never performed isokinetic testing underwent two bilateral knee extension-flexion (concentric-concentric) isokinetic evaluations (5 repetitions) at 60°/sec. The tests were first performed on the dominant leg with 2 min of recovery between test, and following a standardized warm-up that included 3 submaximal isokinetic repetitions. The same procedure was repeated on the non-dominant leg. The peak torque, peak torque adjusted for the body weight, total work, coefficient of variation and agonist/antagonist ratio were compared between tests. Patients showed significant improvements in test 2 compared to test 1, including higher levels of peak torque, peak torque adjusted for body weight and total work, as well as lower coefficients of variation. The agonist/antagonist relationship did not significantly change between tests. No significant differences were found between the right and left legs for all variables. The results suggest that performing two tests with a short recovery (2 min) between them could be used to reduce motor learning effects on clinical isokinetic testing of the knee joint in knee osteoarthritis patients.


[Glocalization: the outlook for Taiwan evidence based health care].
Public attention to evidence-based health care (EBHC) has increased significantly in recent years. Key problems related to applying EBHC in current healthcare practice include the timely update of up-to-date knowledge and skills and the methodology used to implement EBHC in clinical settings. EBHC has been introduced to the Taiwan healthcare system for the past two decades. The annual EBM (Evidence based medicine) National Competition is a unique and important EBHC activity in Taiwan. EBHC has been promoted widely in medicine, nursing, pharmacy, public health and other professions, and EBHC-related organizations such as the Taiwan Evidence Based Medicine Association (TEBMA), and Taiwan Evidence Based Nursing Association (TEBNA), have increased in number and grown in membership. In addition to domestic developments, Taiwan is also actively involved in global organizations, such as the Cochrane Collaboration, East Asian Cochrane Alliance (EACA), and the International Society for Evidence Based Health Care (ISEHC). In Taiwan, most medical professionals work cooperatively to promote EBHC, which facilitates the gradual improvement of healthcare quality.


A unique dual activity amino acid hydroxylase in Toxoplasma gondii.
The genome of the protozoan parasite Toxoplasma gondii was found to contain two genes encoding tyrosine hydroxylase; that produces L-DOPA. The encoded enzymes metabolize phenylalanine as well as tyrosine with substrate preference for tyrosine. Thus the enzymes catabolize phenylalanine to tyrosine and tyrosine to L-DOPA. The catalytic domain descriptive of this class of enzymes is conserved with the parasite enzyme and exhibits similar kinetic properties to metazoan tyrosine hydroxylases, but contains a unique N-terminal extension with a signal sequence motif. One of the genes, TgAaaH1, is constitutively expressed while the other gene, TgAaaH2, is induced during formation of the bradyzoites of the cyst stages of the life cycle. This is the first description of an aromatic amino acid hydroxylase in an apicomplexan parasite. Extensive searching of apicomplexan genome sequences revealed an ortholog in Neospora caninum but not in Eimeria, Cryptosporidium, Theileria, or Plasmodium. Possible role(s) of these bi-functional enzymes during host infection are discussed.


A catalytic role of XoxF1 as La3+-dependent methanol dehydrogenase in Methylobacterium extorquens strain AM1.
In the methylotrophic bacterium Methylobacterium extorquens strain AM1, MxaF, a Ca(2+)-dependent methanol dehydrogenase (MDH), is the main enzyme catalyzing methanol oxidation during growth on methanol. The genome of strain AM1 contains another MDH gene homologue, xoxF1, whose function in methanol metabolism has remained unclear. In this work, we show that XoxF1 also functions as an MDH and is La(3+)-dependent. Despite the absence of Ca(2+) in the medium strain AM1 was able to grow on methanol in the presence of La(3+). Addition of La(3+) increased MDH activity but the addition had no effect on mxaF or xoxF1 expression level. We purified MDH from strain AM1 grown on methanol in the presence of La(3+), and its N-terminal amino acid sequence corresponded to that of XoxF1. The enzyme contained La(3+) as a cofactor. The ΔmxaF mutant strain could not grow on methanol in the presence of Ca(2+), but was able to grow after supplementation with La(3+). Taken together, these results show that XoxF1 participates in methanol metabolism as a La(3+)-dependent MDH in strain AM1.


Spinal cord stimulation for neuropathic pain: current perspectives.
Neuropathic pain constitutes a significant portion of chronic pain. Patients with neuropathic pain are usually more heavily burdened than patients with nociceptive pain. They suffer more often from insomnia, anxiety, and depression. Moreover, analgesic medication often has an insufficient effect on neuropathic pain. Spinal cord stimulation constitutes a therapy alternative that, to date, remains underused. In the last 10 to 15 years, it has undergone constant technical advancement. This review gives an overview of the present practice of spinal cord stimulation for chronic neuropathic pain and current developments such as high-frequency stimulation and peripheral nerve field stimulation.


Five new extinct species of rails (Aves: Gruiformes: Rallidae) from the Macaronesian Islands (North Atlantic Ocean).
Five new species of recently extinct rails from two Macaronesian archipelagoes (Madeira and Azores) are described. All the species are smaller in size than their presumed ancestor, the European rail Rallus aquaticus. Two species inhabited the Madeira archipelago: (1) Rallus lowei n. sp., the stouter of the species described herein, was a flightless rail with a robust tarsometatarsus and reduced wings that lived on Madeira Island; (2) Rallus adolfocaesaris n. sp., a flightless and more gracile species than its Madeiran counterpart, inhabited Porto Santo. So far, six Azorean islands have been paleontologically explored, and the remains of fossil rails have been found on all of them. Here we formally describe the best-preserved remains from three islands (Pico, São Miguel and São Jorge): (1) Rallus montivagorum n. sp., a rail smaller than R. aquaticus with a somewhat reduced flying capability, inhabited Pico; (2) Rallus carvaoensis n. sp., a small flightless rail with short and stout legs and a bill apparently more curved than in R. aquaticus, was restricted to São Miguel; (3) Rallus minutus n. sp., a very small (approaching Atlantisia rogersi in size) flightless rail with a shortened robust tarsometatarsus, lived in São Jorge. We note also the presence of rail fossils on three other Azorean islands (Terceira, Graciosa and Santa Maria). In addition, we describe an extraordinarily complete fossil of an unnamed Rallus preserved in silica from the locality of Algar do Carvão on Terceira.


Estimating the incidence, prevalence and true cost of asthma in the UK: secondary analysis of national stand-alone and linked databases in England, Northern Ireland, Scotland and Wales-a study protocol.
Asthma is now one of the most common long-term conditions in the UK. It is therefore important to develop a comprehensive appreciation of the healthcare and societal costs in order to inform decisions on care provision and planning. We plan to build on our earlier estimates of national prevalence and costs from asthma by filling the data gaps previously identified in relation to healthcare and broadening the field of enquiry to include societal costs. This work will provide the first UK-wide estimates of the costs of asthma. In the context of asthma for the UK and its member countries (ie, England, Northern Ireland, Scotland and Wales), we seek to: (1) produce a detailed overview of estimates of incidence, prevalence and healthcare utilisation; (2) estimate health and societal costs; (3) identify any remaining information gaps and explore the feasibility of filling these and (4) provide insights into future research that has the potential to inform changes in policy leading to the provision of more cost-effective care. Secondary analyses of data from national health surveys, primary care, prescribing, emergency care, hospital, mortality and administrative data sources will be undertaken to estimate prevalence, healthcare utilisation and outcomes from asthma. Data linkages and economic modelling will be undertaken in an attempt to populate data gaps and estimate costs. Separate prevalence and cost estimates will be calculated for each of the UK-member countries and these will then be aggregated to generate UK-wide estimates. Approvals have been obtained from the NHS Scotland Information Services Division's Privacy Advisory Committee, the Secure Anonymised Information Linkage Collaboration Review System, the NHS South-East Scotland Research Ethics Service and The University of Edinburgh's Centre for Population Health Sciences Research Ethics Committee. We will produce a report for Asthma-UK, submit papers to peer-reviewed journals and construct an interactive map.


Nanotechnology and Immunotherapy in Ovarian Cancer: Tracing New Landscapes.
Ovarian cancer (OC) is the seventh most common cancer in women worldwide. Standard therapeutic treatments involve debulking surgery combined with platinum-based chemotherapies. Of the patients with advanced-stage cancer who initially respond to current treatments, 50%-75% relapse. Immunotherapy-based approaches aimed at boosting antitumor immunity have recently emerged as promising tools to challenge tumor progression. Treatments with inhibitors of immune checkpoint molecules have shown impressive results in other types of tumors. However, only 15% of checkpoint inhibitors evaluated have proven successful in OC due to the immunosuppressive environment of the tumor and the transport barriers. This limits the efficacy of the existing immunotherapies. Nanotechnology-based delivery systems hold the potential to overcome such limitations. Various nanoformulations including polymeric, liposomes, and lipid-polymer hybrid nanoparticles have already been proposed to improve the biodistribution and targeting capabilities of drugs against tumor-associated immune cells, including dendritic cells and macrophages. In this review, we examine the impact of immunotherapeutic approaches that are currently under consideration for the treatment of OC. In this review, we also provide a comprehensive analysis of the existing nanoparticle-based synthetic strategies and their limitations and advantages over standard treatments. Furthermore, we discuss how the strength of the combination of nanotechnology with immunotherapy may help to overcome the current therapeutic limitations associated with their individual application and unravel a new paradigm in the treatment of this malignancy.


On resolution and viewing of holographic image generated by 3D holographic display.
In the paper Wigner Distribution (WD) representation analysis of holographic display is presented. The display reconstructs holographic image by means of Spatial Light Modulator. Two major aspects are covered: imaging and viewing. Optically reconstructed images are characterized by low and spatially variant resolution. Utilizing WD representation we present a simple formula for resolution as a function of both coordinates: transverse and longitudinal. The analysis of an aliasing effect allows for meaningful extension of the field of view. All theoretical results are proven experimentally. The WD representation of angularly and spatially limited holographic image is extended to cover its visual perception as well. Angular resolution and field of view are theoretically examined. Both monocular and binocular perception are studied and illustrated experimentally.


The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design.
Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well-established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines. The objective is to evaluate the clinical and economic impact of early invasive management with coronary angiography in T2MI in terms of all-cause mortality and cost effectiveness. This prospective, pragmatic, multicenter, randomized trial among patients with suspected supply demand ischemia leading to troponin elevation (n=1,800; T2MI [1,500], chronic myocardial injury [300]) compares the impact of invasive angiography (or computed tomography angiography as per local preference) within 5 days of randomization versus conservative management (with or without functional testing at clinician discretion) on all-cause mortality by 2 years. Randomized treatment allocation will be stratified by baseline estimated risk of mortality using the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III risk score. Cost-effectiveness will be evaluated by follow-up on clinical events, quality of life, and resource utilization over 24 months. Ascertaining the most appropriate first-line investigative strategy for these commonly encountered high-risk T2MI patients in a randomized comparative study will be pivotal in informing evidence-based guidelines that lead to better patient and health care outcomes.


Early intracellular events in the replication of bacteriophage T4 deoxyribonucleic acid. VI. Newly synthesized proteins in the T4 protein-deoxyribonucleic acid complex.
Shortly after infection of Escherichia coli B with T4 phage, the phage deoxyribonucleic acid (DNA) can be isolated as a fast-sedimenting, proteinaceous complex. Formation of the complex is inhibited by the addition of chloramphenicol between 3 and 4 min after infection, suggesting that phage-coded proteins are necessary to form the complex and may contribute to its structure. To determine whether the phage DNA is associated with a random collection of proteins after infection or whether the complex contained a specific set of proteins, total protein from phage-infected cell lysates was compared to complex protein isolated from similar lysates by gel acrylamide electrophoresis. The proteins obtained from complexes exhibited a distinctly different pattern of separation, indicating that the complex contained a specific set of those proteins newly synthesized after infection. The proteins of the complex appear to be associated directly with the DNA rather than with some other component which could impart the characteristic of fast sedimentation to the complex. Fast-sedimenting complexes were isolated from a (3)H-leucine-labeled cell lysate. Part of this material was treated with pancreatic deoxyribonuclease. Deoxyribonuclease-treated and untreated complexes were resedimented in sucrose gradients. Virtually all the untreated complex remained fast-sedimenting, whereas most of the (3)H-leucine label of the deoxyribonuclease-treated material was located toward the top of the gradient. These data suggest a direct association of DNA and protein in the complex.


Multi-institutional phase I/II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung carcinoma.
To determine the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP) and thoracic radiotherapy. Thirty-one patients were enrolled onto this study. During the phase I section of this study, the dose of paclitaxel was escalated in groups of three or more patients. Cycles were repeated every 21 days. For cycles 1 and 2, paclitaxel was administered according to the dose-escalation schema at doses of 100, 135, or 170 mg/m(2) intravenously over 3 hours on day 1. Once the maximum-tolerated dose (MTD) of paclitaxel (for cycles 1 and 2, concurrent with radiation) was determined, that dose was used in all subsequent patients entered onto the phase II section of this study. For cycles 3 and 4, the paclitaxel dose was fixed at 170 mg/m(2) in all patients. On day 2, cisplatin 60 mg/m(2) was administered for all cycles. On days 1, 2, and 3, etoposide 60 mg/m(2)/d (cycles 1 and 2) or 80 mg/m(2)/d (cycles 3 and 4) was administered. Chest radiation was given at 9 Gy/wk in five fractions for 5 weeks beginning on day 1 of cycle 1. Granulocyte colony-stimulating factors were used during cycles 3 and 4 only. Twenty-eight patients were assessable. The MTD of paclitaxel was 135 mg/m(2), with the dose-limiting toxicity being grade 4 neutropenia. Cycles 1 and 2 were associated with grade 4 neutropenia in 32% of courses, with fever occurring in 7% of courses and grade 2/3 esophagitis in 13%. Cycles 3 and 4 were complicated by grade 4 neutropenia in 20% of courses, with fever occurring in 6% of courses and grade 2/3 esophagitis in 16%. The overall response rate was 96% (complete responses, 39%; partial responses, 57%). After a median follow-up period of 23 months (range, 9 to 40 months), the median survival time was 22.3 months (95% confidence interval, 15.1 to 34.3 months) The MTD of paclitaxel with radiation and EP treatment is 135 mg/m(2) given over 3 hours. In this schedule of administration, a high response rate and acceptable toxicity can be anticipated.