Variability of placental expression of cyclin E low molecular weight variants.
Cyclin E, a G(1) cyclin serving to activate cyclin-dependent kinase 2, is the only cyclin gene for which alternative splicing leading to structurally different proteins has been described. Different cyclin E proteins are present in tumor tissues but absent from normal (steady) tissues. Cyclin E contributes to the regulation of cell proliferation and ongoing differentiation and aging. Because trophoblast has invasive properties and differentiates into syncytium and placental aging may develop at term, we examined cyclin E protein variants in human placenta. Placental samples were collected from 27 deliveries between 33 and 41 wk and were compared with ovarian cancer (positive control). Both placental and tumor tissues showed seven cyclin E low molecular weight (LMW) bands migrating between 50 and 36 kDa. Placental expression of cyclin E showed certain variability among cases. Lowest cyclin E expression was detected in normal placentas (strong expression of Thy-1 differentiation protein in villous core and low dilatation of villous blood sinusoids). Abnormal placentas (significant depletion of Thy-1 and more or less pronounced dilatation of sinusoids) showed significant increase either of all (early stages of placental aging) or only certain cyclin E proteins (advanced aging). Our studies indicate that a similar spectrum of cyclin E protein variants is expressed in the placental and tumor tissues. Low cyclin E expression in normal placentas suggests a steady state. Overexpression of all cyclin E proteins may indicate an activation of cellular proliferation and differentiation to compensate for developing placental insufficiency. However, an enhanced expression of some cyclin E LMW proteins only might reflect an association of cyclin E isoforms with placental aging or an inefficient placental adaptation.


Memory T cells are anergic to the superantigen staphylococcal enterotoxin B.
We have used staphylococcal enterotoxin B (SEB) to study the role of naive and memory T cells in the induction of peripheral tolerance. After administration of SEB to mice, the numbers of naive and memory T cells increase, as does the proportion of memory T cells, which are unresponsive to further stimulation with SEB in vitro. In addition, memory T cells generated in response to conventional antigen, which proliferate and provide help to B cells in the presence of the conventional antigen, fail to respond to superantigen. Hence, memory T cells, in general, are anergized by SEB. These results suggest that SEB-induced activation and anergy reflect the combined responses of naive and memory T cells. The differential activation vs. anergy of naive and memory T cells by superantigen may be related to cytokine production and may play an important role in the etiology of autoimmune diseases or immunodeficiency diseases such as acquired immune deficiency syndrome.


The global structure of the visual light field and its relation to the physical light field.
Human observers have been demonstrated to be sensitive to the local (physical) light field, or more precisely, to the primary direction, intensity, and diffuseness of the light at a point in a space. In the present study we focused on the question of whether it is possible to reconstruct the global visual light field, based on observers' inferences of the local light properties. Observers adjusted the illumination on a probe in order to visually fit it in three diversely lit scenes. For each scene they made 36 settings on a regular grid. The global structure of the first order properties of the light field could then indeed be reconstructed by interpolation of light vectors coefficients representing the local settings. We demonstrate that the resulting visual light fields (individual and averaged) can be visualized and we show how they can be compared to physical measurements in the same scenes. Our findings suggest that human observers have a robust impression of the light field that is simplified with respect to the physical light field. In particular, the subtle spatial variations of the physical light fields are largely neglected and the visual light fields were more similar to simple diverging fields than to the actual physical light fields.


10 GHz regeneratively mode-locked semiconductor optical amplifier fiber ring laser and its linewidth characteristics.
A 10 GHz regeneratively mode-locked semiconductor optical amplifier fiber ring laser with a picosecond pulse duration was newly constructed, and the linewidth change of a longitudinal mode was measured for various laser cavity lengths using a delayed self-heterodyne detection method. The detected line shape was approximately Gaussian for cavity lengths of 3.4-171 m. This result indicates that the laser linewidth depends strongly on thermal or acoustic cavity length fluctuations. The linewidth was proportional to the inverse square root of the cavity length, and a linewidth of 1.7 kHz was obtained for a cavity length of 171 m.


Infrared thermography in newborns: the first hour after birth.
It was the aim of this study to investigate the surface temperature in newborns within the first hour after delivery. Furthermore, the influence of different environmental conditions with regard to surface temperature was documented. Body surface temperature was recorded under several environmental conditions by use of infrared thermography. 42 newborns, all delivered at term and with weight appropriate for date, were investigated under controlled conditions. The surface temperature immediately after birth shows a uniform picture of the whole body; however, it is significantly lower than the core temperature. Soon after birth, peripheral sites become cooler whereas a constant temperature is maintained at the trunk. Bathing in warm water again leads to a more even temperature profile. Radiant heaters and skin-to-skin contact with the mother are both effective methods to prevent heat loss in neonates. Infrared thermography is a simple and reliable tool for the measurement of skin temperature profiles in neonates. Without the need of direct skin contact, it may be helpful for optimizing environmental conditions at delivery suites and neonatal intensive-care units.


Vitritis in pediatric genetic retinal disorders.
To determine which types of pediatric retinal degeneration are associated with inflammatory cells in the anterior vitreous. Retrospective, observational study in humans. Retrospective chart review was performed for pediatric patients with suspected retinal degeneration presenting to a single examiner from 2008 to 2013. Age, visual acuity (VA), slit-lamp examination of anterior vitreous (SLAV), and clinical and molecular genetic diagnoses were documented. Anterior vitreous cells were graded clinically with SLAV from rare cells (1-4) to 1+ (5-9), 2+ (10-30), or 3+ (>30). Cells were also counted in magnified slit beam photographs masked to molecular diagnosis when obtainable. Cell counts in SLAV, best-corrected VA, and molecular and clinical diagnoses. We evaluated 105 charts, 68 of which (64.8%) included SLAV data. Numerous (1+ or greater) cells were present in 22 of 68 patients (32.4%), whereas 4 of 68 (5.9%) had rare cells and 42 of 68 (61.8%) had no cells. The average age between patients with cells, no cells, and rare cells did not differ significantly (P = 0.25). The VA averaged 20/124 in patients with cells, 20/143 in patients with no cells, and 20/68 in patients with rare cells (P = 0.70). The most frequent diagnoses with cells included Bardet Biedl syndrome (BBS), Leber congenital amaurosis (LCA), and retinitis pigmentosa. The most frequent diagnoses without cells included congenital stationary night blindness (CSNB), LCA, Stargardt disease, and blue cone monochromacy. A nonrandom subset of pediatric retinal degenerations exhibit vitritis. Cells were present in 5 of 5 BBS patients (a progressive degeneration), whereas cells were not detected in any of the 12 patients with CSNB (a stable dysfunction). Studying vitritis in pediatric retinal degenerations may reveal whether inflammation accompanies progressive vision loss in certain subtypes. Potentially, inflammation could be treated. In addition, SLAV may aid in clinical diagnosis.


Injury patterns in clashes between citizens and security forces during forced evacuation.
Clashes between state security forces and civilian populations can lead to mass casualty incidents (MCI), challenging emergency medical service (EMS) systems, hospitals and medical management systems. In January 2006, clashes erupted between Israeli security forces and settlers, around the forced evacuation of the Amona outpost. Data collected during the events and in subsequent formal debriefings were processed to identify the specifics of an MCI caused by forced evacuation. Pre-event preparedness, time and types of injuries encountered were evaluated among evacuated civilians and security forces members, their transport to hospitals, care received and follow-up. The event is described according to DISAST-CIR methodology. Data were entered on MS Excel (2003) and analysis was carried out using SPSS version 12. 4000 police personnel (backed by army forces) clashed for 12 h with approximately 5000 settlers. 229 injured (174 settlers and 55 security personnel) were cared for at six receiving hospitals. A total of 16 were evacuated by aeromedical evacuation, including one severely head-injured policeman. Settlers used sticks, stones and cement blocks, whereas police used mounted riders, batons and shields. Head injuries were the most common injuries among settlers (50%), whereas extremity injuries dominated among security forces members (72.7%). Large-scale clashes between state security forces and citizens may cause numerous injuries, even if firearms and explosives are not used. Despite the fact that almost all injuries were mild, the incident burdened local medical teams, EMS and Jerusalem hospitals. A predominance of head injuries was found among injured settlers and extremity injuries among injured security forces.


Sequencing technologies and tools for short tandem repeat variation detection.
Short tandem repeats are highly polymorphic and associated with a wide range of phenotypic variation, some of which cause neurodegenerative disease in humans. With advances in high-throughput sequencing technologies, there are novel opportunities to study genetic variation. While available sequencing technologies and bioinformatics tools provide options for mining high-throughput sequencing data, their suitability for analysis of repeat variation is an open question, with tools for quantifying variability in repetitive sequence still in their infancy. We present here a comprehensive survey and empirical evaluation of current sequencing technologies and bioinformatics tools in all stages of an analysis pipeline. While there is not one optimal pipeline to suit all circumstances, we find that the choice of alignment and repeat genotyping tools greatly impacts the accuracy and efficiency by which short tandem repeat variation can be detected. We further note that to detect variation relevant to many repeat diseases, it is essential to choose technologies that offer either long read-lengths or paired-end sequencing, coupled with specific genotyping tools.


Association between maternal symptoms of sleep disordered breathing and fetal telomere length.
Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length. Pregnant women were recruited upon hospital delivery admission. Sleep exposure outcomes were measured using the Berlin Questionnaire to quantify sleep apnea and the Epworth Sleepiness Scale to measure daytime sleepiness. Participants were classified as "High Risk" or "Low Risk" for sleep apnea based on responses to the Berlin, while "Normal" or "Abnormal" daytime sleepiness was determined based on responses to the Epworth. Neonatal umbilical cord blood samples (N = 67) were collected and genomic DNA was isolated from cord blood leukocytes using Quantitative PCR. A ratio of relative telomere length was derived by telomere repeat copy number and single copy gene copy number (T/S ratio) and used to compare telomere lengths. Bootstrap and ANOVA statistical procedures were employed. On the Berlin, 68.7% of participants were classified as Low Risk while 31.3% were classified as High Risk for sleep apnea. According to the Epworth scale, 80.6% were determined to have Normal daytime sleepiness, and 19.4% were found to have Abnormal daytime sleepiness. The T/S ratio among pregnant women at High Risk for sleep apnea was significantly shorter than for those at Low Risk (P value < 0.05), and the T/S ratio among habitual snorers was significantly shorter than among non-habitual snorers (P value < 0.05). Although those with Normal Sleepiness had a longer T/S ratio than those with Abnormal Sleepiness, the difference was not statistically significant. Our results provide the first evidence demonstrating shortened telomere length among fetuses exposed to maternal symptoms of sleep disordered breathing during pregnancy, and suggest sleep disordered breathing as a possible mechanism of accelerated chromosomal aging.


Pharmacological properties of glutamatergic drugs targeting NMDA receptors and their application in major depression.
A growing body of evidence suggests that glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology of major depressive disorders. An imbalance in glutamatergic neurotransmission may contribute to increased levels of NMDA agonism, thereby enhancing excitatory activity in most brain circuits involved in major depression. Although NMDA receptor antagonists have been demonstrated to possess antidepressant-like activity, the molecular changes underlying abnormal glutamatergic signaling still remain poorly understood. Therefore, we aimed to review the current literature focusing on the main pharmacological properties and the impact of glutamatergic drugs targeting NMDA receptors in major depression. A detailed literature search in PubMed/Medline and ScienceDirect databases using the terms glutamate, depression and major depressive disorder has been performed. Most drugs acting at glutamatergic receptors showed biochemical effects indicative of antidepressant activity in both clinical and preclinical studies. Recent neuroimaging and genetic contributions also confirm the antidepressant properties of these medications. However, human studies including NMDA receptor antagonists provided mixed results. In overall, glutamatergic receptor modulation may facilitate neuronal stem cell enhancement (neurogenesis) as well as the release of neurotransmitters associated with treatment response to depression in humans. Cognitive side effects and psychotomimetic properties complicate the application and the development of clinically useful agents. Glutamatergic system represents a target for effective intervention in major depression. Specifically, those glutamatergic medications targeting NMDA receptors by inhibiting the release of neurotransmitters or modulating its post-synaptic responses may serve as molecule modulators with specific antidepressant properties.


Mechanism of antiinflammatory actions of curcumine and boswellic acids.
Curcumine from Curcuma longa and the gum resin of Boswellia serrata, which were demonstrated to act as anti-inflammatories in in vivo animal models, were studied in a set of in vitro experiments in order to elucidate the mechanism of their beneficial effects. Curcumine inhibited the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets. In a cell free peroxidation system curcumine exerted strong antioxidative activity. Thus, its effects on the dioxygenases are probably due to its reducing capacity. Boswellic acids were isolated from the gum resin of Boswellia serrata and identified as the active principles. Boswellic acids inhibited the leukotriene synthesis via 5-lipoxygenase, but did not affect the 12-lipoxygenase and the cyclooxygenase activities. Additionally, boswellic acids did not impair the peroxidation of arachidonic acid by iron and ascorbate. The data suggest that boswellic acids are specific, non-redox inhibitors of leukotriene synthesis either interacting directly with 5-lipoxygenase or blocking its translocation.


Copper deficiency-induced pancytopenia after taking an excessive amount of zinc formulation during maintenance hemodialysis.
Erythropoiesis-stimulating agent (ESA) has been recognized as an effective way in the treatment of anemia due to chronic kidney disease, but we sometimes see intractable hemodialysis (HD) patients. The causes of ESA-resistant anemia in HD patients include deficiency of trace elements. We report the case of an 89-year-old male who developed pancytopenia after taking an excessive amount of zinc formulation for ESA-resistant anemia during maintenance dialysis. He was prescribed zinc acetate hydrate formulation about 6 months before his presentation. He was found to have pancytopenia 1 month before his presentation, at which point he was introduced to our hospital. We suspected a copper deficiency at the first visit and stopped zinc and added copper, and his condition subsequently improved without being handicapped. Zinc antagonizes copper, so we must take care to diagnose patients ingesting zinc supplements.


Socioeconomic conditions in childhood and ischaemic heart disease during middle age.
To examine the association between socioeconomic conditions in childhood and ischaemic heart disease in middle aged men, including the role of physiological and behavioural risk factors. Prevalence study with extensive examination and testing and with recall of childhood conditions. Population based study in Kuopio, Finland. Representative sample of 2679 men aged 42, 48, 54, and 60. Ischaemic findings on progressive maximal exercise test. Low socioeconomic style in childhood was associated with significantly higher prevalence of findings indicating ischaemias. Compared with those in the highest tertile of childhood socioeconomic conditions, the age adjusted odds ratio for subjects in the lowest tertile was 1.44 and for those in the middle tertile 1.35. Adjustment for years of cigarette smoking times the average number of cigarettes smoked, ratio of high density lipoprotein to low density lipoprotein cholesterol, fibrinogen and serum selenium concentrations, and adult height did not appreciably weaken the association. Adjustment for adult socioeconomic state resulted in a 16% decline in the association. The association was reduced to non-significance by adjustment for measures of prevalent cardiovascular illness. Socioeconomic state in childhood was significantly associated with ischaemic heart disease in middle aged men. Levels of risk factors measured at middle age did not account for this association, nor did adult height. Because childhood socioeconomic conditions precede the development of ischaemic heart disease the substantial impact of prevalent illness on the observed association suggests that ischaemic heart disease develops earlier in those with lower socioeconomic state during childhood.


Dissecting Wnt signalling pathways and Wnt-sensitive developmental processes through transient misexpression analyses in embryos of Xenopus laevis.
We review evidence that Xenopus Wnts (Xwnts) have activities consistent with their hypothesized roles as secreted signalling factors involved in multiple developmental processes. Transient misexpression of different Xwnts has distinct effects upon early development, and upon the formation of tissues in UV-irradiated embryos. Misexpression of Xwnts also has distinct effects on the in vitro differentiation of blastula cap explants. Cellular responses to Xwnt signals include changes in gap junctional permeability, altered responsiveness to growth factors, and possibly changes in cell adhesion. Current data suggest that a maternal Xwnt- or noggin-like activity is involved in the Nieuwkoop center activity during mesoderm induction, that Xwnt-8 participates in a pathway of differentiation as ventral mesoderm, and that Xwnt-5A is a potential modulator of morphogenetic movements.


Assessment of post-stroke fatigue: the fatigue scale for motor and cognitive functions.
Post-stroke fatigue (PSF) is an important but still controversial issue since knowledge on its nature is still humble. The aim of the present study was to characterize PSF beyond the subacute phase. Thirty-one stroke patients (gender: 6 female, 25 male; age range: 35-76 years; 28 patients with ischemic stroke, 3 patients with hemorrhagic stroke; mean delay after stroke: 50.65 ± 31.57 days) were recruited and assessed by measures of fatigue (Fatigue Scale for Motor and Cognitive Functions [FSMC], Fatigue Severity Scale, and Modified Fatigue Impact Scale), depression (Beck Depression Inventory Fast Screen), cognition (Brief Repeatable Battery of Neuropsychological Tests) and upper and lower extremity functions (Nine-Hole Peg Test and 25-foot walk). Depending on the different scales, PSF prevalence ranged from 16.1 to 58.1%. Depression measures correlated significantly (r(29) ≥ 0.46; p < 0.01) with the results of all fatigue scales. Seventy-one percent of patients showed cognitive deficits in at least one cognitive domain. Cognitive fatigue measured by one subscale of the FSMC correlated most significantly with mental speed, working memory, and verbal short-term memory, while the motor subscale was associated with upper and lower extremity functions, mental speed, visual short-term memory, and working memory. A differentiation between lesion localization and fatigue severity in the motor or cognitive domain was only possible when applying the FSMC. Patients with cortical lesions scored higher on the cognitive subscale, while patients with subcortical lesions showed higher physical subscale scores. The present pilot study revealed differences between lesion localization and subdomains of fatigue after stroke by applying a new fatigue scale (FSMC). The results underline the necessity for separate assessment of motor and cognitive fatigue in stroke patients.


Classification and treatment of endothermal heat-induced thrombosis: Recommendations from the American Venous Forum and the Society for Vascular Surgery This Practice Guidelines document has been co-published in Phlebology [DOI: 10.1177/0268355520953759] and Journal of Vascular Surgery: Venous and Lymphatic Disorders [DOI: 10.1016/j.jvsv.2020.06.008]. The publications are identical except for minor stylistic and spelling differences in keeping with each journal's style. The contribution has been published under a Attribution-Non Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0), (https://creativecommons.org/licenses/by-nc-nd/4.0/).
The American Venous Forum (AVF) and the Society for Vascular Surgery set forth these guidelines for the management of endothermal heat-induced thrombosis (EHIT). The guidelines serve to compile the body of literature on EHIT and to put forth evidence-based recommendations. The guidelines are divided into the following categories: classification of EHIT, risk factors and prevention, and treatment of EHIT.One major feature is to standardize the reporting under one classification system. The Kabnick and Lawrence classification systems are now combined into the AVF EHIT classification system. The novel classification system affords standardization in reporting but also allows continued combined evaluation with the current body of literature. Recommendations codify the use of duplex ultrasound for the diagnosis of EHIT. Risk factor assessments and methods of prevention including mechanical prophylaxis, chemical prophylaxis, and ablation distance are discussed.Treatment guidelines are tailored to the AVF EHIT class (ie, I, II, III, IV). Reference is made to the use of surveillance, antiplatelet therapy, and anticoagulants as deemed indicated, and the recommendations incorporate the use of the novel direct oral anticoagulants. Last, EHIT management as it relates to the great and small saphenous veins is discussed.


Research Ethics with Gender and Sexually Diverse Persons.
Identifying and developing inclusive policy and practice responses to health and social inequities in gender and sexually diverse persons require inclusive research ethics and methods in order to develop sound data. This article articulates 12 ethical principles for researchers undertaking gender and sexually diverse social, health, and related research. We have called these the 'Montréal Ethical Principles for Inclusive Research.' While writing from an international social work perspective, our aim is to promote ethical research that benefits people being researched by all disciplines. This paper targets four groups of interest: 1. Cisgender and heterosexual researchers; 2. Researchers who research 'general' populations; 3. and sexually diverse researchers; 4. Human ethics committees. This article was stimulated by the 2018 Global Social Work Statement of Ethical Principles, which positions human dignity at its core. It is critically important to understand and account for the intersectionality of gender and sexuality with discourses of race, ethnicity, colonialism, dis/ability, age, etc. Taking this intersectionality into consideration, this article draws on scholarship that underpins ethical principles developed for other minoritized communities, to ensure that research addresses the autonomy of these participants at every stage. Research that positions inclusive research ethics at its foundation can provide a solid basis for policy and practice responses to health and social inequities in gender and sexually diverse persons.


Membrane tension regulates motility by controlling lamellipodium organization.
Many cell movements proceed via a crawling mechanism, where polymerization of the cytoskeletal protein actin pushes out the leading edge membrane. In this model, membrane tension has been seen as an impediment to filament growth and cell motility. Here we use a simple model of cell motility, the Caenorhabditis elegans sperm cell, to test how membrane tension affects movement and cytoskeleton dynamics. To enable these analyses, we create transgenic worm strains carrying sperm with a fluorescently labeled cytoskeleton. Via osmotic shock and deoxycholate treatments, we relax or tense the cell membrane and quantify apparent membrane tension changes by the membrane tether technique. Surprisingly, we find that membrane tension reduction is correlated with a decrease in cell displacement speed, whereas an increase in membrane tension enhances motility. We further demonstrate that apparent polymerization rates follow the same trends. We observe that membrane tension reduction leads to an unorganized, rough lamellipodium, composed of short filaments angled away from the direction of movement. On the other hand, an increase in tension reduces lateral membrane protrusions in the lamellipodium, and filaments are longer and more oriented toward the direction of movement. Overall we propose that membrane tension optimizes motility by streamlining polymerization in the direction of movement, thus adding a layer of complexity to our current understanding of how membrane tension enters into the motility equation.


Communication: Barium ions and helium nanodroplets: solvation and desolvation.
The solvation of Ba(+) ions created by the photoionization of barium atoms located on the surface of helium nanodroplets has been investigated. The excitation spectra corresponding to the 6p (2)P(1/2) ← 6s (2)S(1/2) and 6p (2)P(3/2) ← 6s (2)S(1/2) transitions of Ba(+) are found to be identical to those recorded in bulk He II [H. J. Reyher, H. Bauer, C. Huber, R. Mayer, A. Schafer, and A. Winnacker, Phys. Lett. A 115, 238 (1986)], indicating that the ions formed at the surface of the helium droplets become fully solvated by the helium. Time-of-flight mass spectra suggest that following the excitation of the solvated Ba(+) ions, these are being ejected from the helium droplets either as bare Ba(+) ions or as small Ba(+)He(n) (n < 20) complexes.


C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study.
Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 ± 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85-2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps.


Neuroprotective Effects of the Herbal Formula B401 in Both Cell and Mouse Models of Alzheimer's Disease.
In this study, we have reported the herbal formula B401 that has neuroprotective effects via multifunction, multitarget characteristics. It is possible that the herbal formula B401 may also provide new insights for AD. Here, we studied protective effects in the Tet-On Aβ42-GFP SH-SY5Y cell model and the APP/PS1/Tau triple transgenic mouse model by the herbal formula B401. In in vitro experiments, we showed that the herbal formula B401 treatment effectively reduces glutamate-induced excitotoxicity and acetylcholinesterase activity in Tet-On Aβ42-GFP SH-SY5Y cells. In in vivo experiments, we found that oral B401 treatment effectively ameliorates neurocognitive dysfunctions of 3× Tg-AD mice via motor and cognitive behavior tests. By using magnetic resonance imaging, moorFLPI instruments, and chemiluminescence methods, we reported that oral B401 treatment effectively alleviates brain atrophy, improves subcutaneous blood flow, and reduces blood ROS in 3× Tg-AD mice. As observed from results of immunohistochemistry staining and western blotting, we found that oral B401 treatment significantly enhances expressions of neuroprotective proteins, while reducing expressions of AD derived proteins such as amyloid beta, phosphorylated Tau, neurofibrillary tangles, and 3-nitrotyrosine in the brain of 3× Tg-AD mice. Thus, the herbal formula B401 may have the potential to be developed into optimum TCM for AD patients.


Challenging issues in molecular-targeted therapy.
There are variety of anticancer treatments including chemotherapeutic drugs, which are known to induce cell growth arrest and apoptosis through DNA damage and cytoskeleton toxicity. Meanwhile, histone deacetylase (HDAC) inhibitors could apply their antitumor activity through chromatin remodeling and gene expression modulation that affect the cell cycle and survival pathways. This paper proposes an anticancer three-drug compound and discusses several challenging issues in relation to designing multidrug compounds that could possibly lead to molecular-targeted therapies.


Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus.
The Pro12Ala polymorphism of the Peroxisome Proliferator Activated Receptor gamma2 (PPARgamma2) gene has been inconsistently associated with body mass index variations and non-insulin-dependent diabetes mellitus (NIDDM). We investigated the impact of this polymorphism on obesity markers, lipid and glucose variables in a sample of French subjects and evaluated its possible role in the onset of NIDDM. Within the framework of the WHO-MONICA project, a population study composed of 1195 subjects aged 35-64 y was randomly sampled from the electoral rolls of the urban community of Lille, in northern France. Subjects receiving medical treatment for hypercholesterolemia, hypertension or diabetes mellitus were excluded for the analyses, to avoid any interferences between medical treatment and biological variables. This resulted in a sample size of 839 subjects (421 men/418 women, age=49.4+/-8.1 y, body mass index (BMI)=25.7+/-4.4 kg/m2). To evaluate the role of the Pro12Ala polymorphism in the onset of NIDDM, we evaluated its distribution in 170 Caucasian NIDDM subjects from a clinical series (117 men/53 women, age=62.3+/-9.0 y, BMI=30.1+/-3.6 kg/m2). The PPARgamma2 Pro12Ala polymorphism genotyping was carried out with allele specific oligonucleotides hybridisation. Data were statistically analysed for association with various obesity markers (body weight (BW), BMI, waist-to-hip ratio (WHR), plasma leptin concentrations, lipid and glucose variables. In the WHO-MONICA population, the Ala allele frequency was 0.11. The presence of the Ala allele was significantly associated with higher body weight (P=0.002), BMI (P=0.02), height (P=0.02) and waist circumference (P=0.04). Increased plasma concentrations of total cholesterol (P=0.01), LDL-cholesterol (P=0.004) and apolipoprotein B (P=0.01) were also detected in Ala allele bearers. The distribution of the Pro12Ala polymorphism was similar in NIDDM subjects (Ala allele frequency: 0.10) and in the WHO-MONICA population subjects. Our results suggest that genetic variability of PPARgamma2 affects body weight control and lipid homeostasis in humans and do not support a significant role for the PPARgamma2 Pro12Ala polymorphism in the aetiology of NIDDM. International Journal of Obesity (2000) 24, 195-199


Multiple molecular effect pathways of an environmental oestrogen in fish.
Complex interrelationships in the signalling of oestrogenic effects mean that environmental oestrogens present in the aquatic environment have the potential to disrupt physiological function in fish in a more complex manner than portrayed in the present literature. Taking a broader approach to investigate the possible effect pathways and the likely consequences of environmental oestrogen exposure in fish, the effects of 17beta-oestradiol (E(2)) were studied on the expression of a suite of genes which interact to mediate growth, development and thyroid and interrenal function (growth hormone GH (gh), GH receptor (ghr ), insulin-like growth factor (IGF-I) (igf1), IGF-I receptor (igf1r ), thyroid hormone receptors-alpha (thra) and -beta (thrb) and glucocorticoid receptor (gr )) together with the expression analyses of sex-steroid receptors and ten other genes centrally involved in sexual development and reproduction in fathead minnow (fhm; Pimephales promelas). Exposure of adult fhm to 35 ng E(2)/l for 14 days induced classic oestrogen biomarker responses (hepatic oestrogen receptor 1 and plasma vitellogenin), and impacted on the reproductive axis, feminising "male" steroidogenic enzyme expression profiles and suppressing genes involved in testis differentiation. However, E(2) also triggered a cascade of responses for gh, ghr, igf1, igf1r, thra, thrb and gr in the pituitary, brain, liver, gonad and gill, with potential consequences for the functioning of many physiological processes, not just reproduction. Molecular responses to E(2) were complex, with most genes showing differential responses between tissues and sexes. For example, igf1 expression increased in brain but decreased in gill on exposure to E(2), and responded in an opposite way in males compared with females in liver, gonad and pituitary. These findings demonstrate the importance of developing a deeper understanding of the endocrine interactions for unravelling the mechanisms of environmental oestrogen action and predicting the likely health consequences.


Spontaneous recovery of tolerance to the analgesic effect of morphine.
There is now substantial evidence that associative processes contribute to the development and expression of narcotic tolerance. Like other conditioned responses, the compensatory response (CR) thought to mediate tolerance can be extinguished by repeatedly presenting the conditioned stimulus (CS, drug-paired contextual cues) alone. In the present experiments, rats were used to determine if conditioned tolerance to the analgesic effect of morphine would spontaneously recover following a sufficient delay between the last extinction trial and reexposure to the CS. It was found that tolerance spontaneously recovered 72, but not 24 h following the last of nine extinction trials. As well as providing support for a Pavlovian model of narcotic tolerance, this finding has important clinical implications for cue-exposure drug and alcohol rehabilitation strategies.


INSIGHT Responsive Parenting Intervention and Infant Sleep.
Inadequate sleep during infancy is associated with adverse outcomes for infants and families. We sought to improve sleep behaviors and duration through a responsive parenting (RP) intervention designed for obesity prevention. The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study is a randomized trial comparing a RP intervention with a safety control. Primiparous mother-newborn dyads were randomized after childbirth, and research nurses delivered intervention content at home visits at infant ages 3, 16, 28, and 40 weeks and at a research center visit at 1 year. The RP sleep component included developmentally appropriate messages about bedtime routines, sleep location and behaviors, and responses to wakings. Portions of the Brief Infant Sleep Questionnaire were administered 2, 8, and 52 weeks after birth with expanded sleep-related data collection at 16 and 40 weeks. Two hundred and seventy-nine dyads completed the first home visit; 90.7% completed the 1-year visit. Compared with controls, RP group infants were less likely to have prolonged bedtime routines >45 minutes and more likely to have earlier bedtimes at 16 and 40 weeks. They were less likely to be fed immediately before bed and more likely to self-soothe to sleep. At 8, 16, and 40 weeks, RP group nocturnal sleep duration was longer by 35, 25, and 22 minutes, respectively (P < .05 for all). Sleep duration at 1 year was similar between groups. The INSIGHT RP intervention positively influenced developmentally appropriate bedtime routines, sleep-related behaviors, and sleep duration for infants.


Restructuring of the male mice peripheral circadian network after bariatric surgery.
Bariatric surgery is still the most effective long-term weight-loss therapy. Recent data indicate that surgical outcomes may be affected by diurnal food intake patterns. In this study, we aimed to investigate how surgery-induced metabolic adaptations (i.e. weight loss) interact with circadian clock function. For that reason, vertical sleeve gastrectomy (VSG) was performed in obese mice and rhythms in behavior, tissue rhythmicity, and white adipose tissue transcriptome were evaluated. VSG under constant darkness conditions led to a maximum weight loss of 18% compared to a loss of 3% after sham surgery. Post-surgical weight development was characterized by two distinct intervals of catabolic and subsequent anabolic metabolic state. Locomotor activity was not affected. However, VSG significantly increased active phase meal frequency in the anabolic state. No significant effects on clock gene rhythmicity were detected in adrenal and white adipose tissue (WAT) explant cultures. Transcriptome rhythm analyses of subcutaneous WAT revealed a reduction of cycling genes after VSG (sham: 2493 vs VSG: 1013) independent of sustained rhythms in core clock gene expression. This may be a consequence of weight loss-induced morphological reconstruction of WAT that overwrites the direct influence of the local clock machinery on the transcriptome. However, VSG altered rhythmic transcriptional regulation of WAT lipid metabolism pathways. Thus, our data suggest a reorganization of diurnal metabolic rhythms after VSG downstream of the molecular clock machinery.


Extracellular ATP-Induced Alterations in Extracellular H+ Fluxes From Cultured Cortical and Hippocampal Astrocytes.
Small alterations in the level of extracellular H+ can profoundly alter neuronal activity throughout the nervous system. In this study, self-referencing H+-selective microelectrodes were used to examine extracellular H+ fluxes from individual astrocytes. Activation of astrocytes cultured from mouse hippocampus and rat cortex with extracellular ATP produced a pronounced increase in extracellular H+ flux. The ATP-elicited increase in H+ flux appeared to be independent of bicarbonate transport, as ATP increased H+ flux regardless of whether the primary extracellular pH buffer was 26 mM bicarbonate or 1 mM HEPES, and persisted when atmospheric levels of CO2 were replaced by oxygen. Adenosine failed to elicit any change in extracellular H+ fluxes, and ATP-mediated increases in H+ flux were inhibited by the P2 inhibitors suramin and PPADS suggesting direct activation of ATP receptors. Extracellular ATP also induced an intracellular rise in calcium in cultured astrocytes, and ATP-induced rises in both calcium and H+ efflux were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin. Replacement of extracellular sodium with choline did not significantly reduce the size of the ATP-induced increases in H+ flux, and the increases in H+ flux were not significantly affected by addition of EIPA, suggesting little involvement of Na+/H+ exchangers in ATP-elicited increases in H+ flux. Given the high sensitivity of voltage-sensitive calcium channels on neurons to small changes in levels of free H+, we hypothesize that the ATP-mediated extrusion of H+ from astrocytes may play a key role in regulating signaling at synapses within the nervous system.


Comparison of Silent Gap in Noise Cortical Auditory Evoked Potentials in Matched Tinnitus and No-Tinnitus Control Subjects.
Purpose Previous research suggests the existence of gap detection impairments because of tinnitus. The current study aimed to determine whether there was objective evidence of gap impairment in individuals with tinnitus by recording silent gap in white noise cortical auditory evoked potentials (CAEPs) in a chronic tinnitus group and a no-tinnitus group. The results were compared to previous gap-evoked potential and behavioral gap detection studies. Method Chronic tinnitus and no-tinnitus groups were formed by matching pairs of subjects ( n = 26) based on age, gender, and hearing thresholds. Behaviorally determined gap detection thresholds were used to define the electrophysiological gap duration conditions of subthreshold, threshold, and suprathreshold gaps in white noise. Amplitude, latency, and area of the CAEP were analyzed by group and condition using mixed-model analyses of variance. Results Across all participants, as the duration of the gap increased, amplitude and area of the CAEP increased. There were no significant differences by tinnitus status between groups for any outcome measures, except for a significant interaction between group and gap duration for P1 latency. Conclusions Silent gap-evoked CAEPs can be recorded in adults with and without tinnitus. Amplitude and area were sensitive to gap duration across groups; latency was not. Contrary to hypotheses, there was little evidence supporting differences in gap-evoked CAEPs between the tinnitus and control groups. Stimulus and other factors that may have contributed to the lack of a group difference in the current study are discussed, as well as implications for future studies of objective measures of tinnitus perception. Supplemental Material https://doi.org/10.23641/asha.7822601.


Chemical and Photochemical Water Oxidation Mediated by an Efficient Single-Site Ruthenium Catalyst.
Water oxidation is a fundamental step in artificial photosynthesis for solar fuels production. In this study, we report a single-site Ru-based water oxidation catalyst, housing a dicarboxylate-benzimidazole ligand, that mediates both chemical and light-driven oxidation of water efficiently under neutral conditions. The importance of the incorporation of the negatively charged ligand framework is manifested in the low redox potentials of the developed complex, which allows water oxidation to be driven by the mild one-electron oxidant [Ru(bpy)3 ]3+ (bpy=2,2'-bipyridine). Furthermore, combined experimental and DFT studies provide insight into the mechanistic details of the catalytic cycle.


The challenge of controlling notifiable avian influenza by means of vaccination.
Avian influenza (AI) is an Office International des Epizooties listed disease that has become a disease of great importance both for animal and human health. The increased relevance of AI in animal and human health has highlighted the lack of scientific information on several aspects of the disease, which has hampered the adequate management of some of the recent crises. Millions of animals have died, and there is growing concern over the loss of human lives and over the management of the pandemic potential. The present article reviews the currently available control methods for notifiable AI infections in poultry. The application of control policies, ranging from stamping out to emergency and prophylactic vaccination, is discussed on the basis of data generated in recent outbreaks and in light of new regulations, also in view of the maintenance of animal welfare. Poultry veterinarians working for the industry or for the public sector represent the first line of defense against the pandemic threat and for the prevention and control of this infection in poultry and in wild birds.


Decarboxylation of fatty acids to terminal alkenes by cytochrome P450 compound I.
OleT(JE), a cytochrome P450, catalyzes the conversion of fatty acids to terminal alkenes using hydrogen peroxide as a cosubstrate. Analytical studies with an eicosanoic acid substrate show that the enzyme predominantly generates nonadecene and that carbon dioxide is the one carbon coproduct of the reaction. The addition of hydrogen peroxide to a deuterated substrate-enzyme (E-S) complex results in the transient formation of an iron(IV) oxo π cation radical (Compound I) intermediate which is spectroscopically indistinguishable from those that perform oxygen insertion chemistries. A kinetic isotope effect for Compound I decay suggests that it abstracts a substrate hydrogen atom to initiate fatty acid decarboxylation. Together, these results indicate that the initial mechanism for alkene formation, which does not result from oxygen rebound, is similar to that widely suggested for P450 monooxygenation reactions.


Method of developing all-optical trinary JK, D-type, and T-type flip-flops using semiconductor optical amplifiers.
To meet the demand of very fast and agile optical networks, the optical processors in a network system should have a very fast execution rate, large information handling, and large information storage capacities. Multivalued logic operations and multistate optical flip-flops are the basic building blocks for such fast running optical computing and data processing systems. In the past two decades, many methods of implementing all-optical flip-flops have been proposed. Most of these suffer from speed limitations because of the low switching response of active devices. The frequency encoding technique has been used because of its many advantages. It can preserve its identity throughout data communication irrespective of loss of light energy due to reflection, refraction, attenuation, etc. The action of polarization-rotation-based very fast switching of semiconductor optical amplifiers increases processing speed. At the same time, tristate optical flip-flops increase information handling capacity.


Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole.
The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.


Intestinal Epithelial Expression of MHCII Determines Severity of Chemical, T-Cell-Induced, and Infectious Colitis in Mice.
Intestinal epithelial cells (IECs) provide a barrier that separates the mucosal immune system from the luminal microbiota. IECs constitutively express low levels of major histocompatibility complex (MHC) class II proteins, which are upregulated upon exposure to interferon gamma. We investigated the effects of deleting MHCII proteins specifically in mice with infectious, dextran sodium sulfate (DSS)-, and T-cell-induced colitis. We disrupted the histocompatibility 2, class II antigen A, beta 1 gene (H2-Ab1) in IECs of C57BL/6 mice (I-AbΔIEC) or Rag1-/- mice (Rag1-/-I-AbΔIEC); we used I-AbWT mice as controls. Colitis was induced by administration of DSS, transfer of CD4+CD45RBhi T cells, or infection with Citrobacter rodentium. Colon tissues were collected and analyzed by histology, immunofluorescence, xMAP, and reverse-transcription polymerase chain reaction and organoids were generated. Microbiota (total and immunoglobulin [Ig]A-coated) in intestinal samples were analyzed by16S amplicon profiling. IgA+CD138+ plasma cells from Peyer's patches and lamina propria were analyzed by flow cytometry and IgA repertoire was determined by next-generation sequencing. Mice with IEC-specific loss of MHCII (I-AbΔIEC mice) developed less severe DSS- or T-cell transfer-induced colitis than control mice. Intestinal tissues from I-AbΔIEC mice had a lower proportion of IgA-coated bacteria compared with control mice, and a reduced luminal concentration of secretory IgA (SIgA) following infection with C rodentium. There was no significant difference in the mucosal IgA repertoire of I-AbΔIEC vs control mice, but opsonization of cultured C rodentium by SIgA isolated from I-AbΔIEC mice was 50% lower than that of SIgA from mAbWT mice. Fifty percent of I-AbΔIEC mice died after infection with C rodentium, compared with none of the control mice. We observed a transient but significant expansion of the pathogen in the feces of I-AbΔIEC mice compared with I-AbWT mice. In mice with DSS or T-cell-induced colitis, loss of MHCII from IECs reduces but does not eliminate mucosal inflammation. However, in mice with C rodentium-induced colitis, loss of MHCII reduces bacterial clearance by decreasing binding of IgA to commensal and pathogenic bacteria.


Considering Systemic Barriers to Treating Tobacco Use in Clinical Settings in the United States.
The Comorbidity Workgroup of the Tobacco Treatment Research Network, within the Society for Research on Nicotine and Tobacco, previously highlighted the need to provide tobacco treatment to patients diagnosed with comorbid physical and mental health conditions. Yet, systemic barriers in the United States health care system prevent many patients who present for medical treatment from getting the evidence-based tobacco treatment that they need. The identified barriers include insufficient training in the epidemiologic impact of tobacco use, related disorders, and pharmacological and behavioral treatment approaches; misunderstanding among clinicians about the effectiveness of tobacco treatment; lack of therapeutic support from clinical staff; insufficient use of health information technology to improve tobacco use identification and treatment; and limited time and reimbursement for clinicians to provide treatment. We highlight three vignettes demonstrating the complexities of practical barriers at the health care system level. We consider each of the barriers in turn and discuss evidence-based strategies that could be implemented in the clinical care of patients with comorbid conditions. In addition, in the absence of compelling data to guide implementation approaches, we offer suggestions for potential strategies and avenues for future research. Implications: Three vignettes highlighted in this article illustrate some systemic barriers to providing tobacco treatment for patients being treated for comorbid conditions. We explore the barriers to tobacco treatment and offer suggestions for changes in training, health care systems, clinical workflow, and payment systems that could enhance the reach and the quality of tobacco treatment within the US health care system.


Posterior orbitofrontal sulcogyral pattern associated with orbitofrontal cortex volume reduction and anxiety trait in panic disorder.
The posterior region of the orbitofrontal cortex (OFC), which forms its sulcogyral pattern during neurodevelopment, receives multisensory inputs. The purpose of the present study was to assess the relationship between posterior OFC sulcogyral pattern and OFC volume difference in patients with panic disorder. The anatomical pattern of the posterior orbital sulcus (POS) was classified into three subtypes (absent POS, single POS, double POS) using 3-D high-spatial resolution magnetic resonance images obtained from 28 patients with panic disorder and 28 age- and gender-matched healthy controls. Optimized voxel-based morphometry (VBM) was performed to assess OFC volume differences between the two groups by subtype. Categorical regression analysis was applied to examine the association of POS subtypes with State-Trait Anxiety Inventory and Revised Neuroticism-Extraversion-Openness Personality Inventory scores. No significant difference was found in POS subtype distribution between control subjects and patients with panic disorder. VBM, however, indicated volume reduction in the right posterior-medial OFC region in panic disorder patients with absent POS and single POS. Single POS was positively associated with Trait-Anxiety (beta = 0.446, F = 6.409, P = 0.020), and absent POS was negatively associated with Trait-Anxiety (beta = -0.394, F = 5.341, P = 0.032) and Neuroticism trait (beta = -0.492, F = 6.989, P = 0.017). POS subtypes may be relevant to volume reduction in OFC and the anxiety trait in patients with panic disorder. These findings suggest that volume reduction in OFC in panic disorder may be associated with neurodevelopment.


Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients.
Aberrant promoter hypermethylation is common in head and neck cancer and may be useful as a marker for cancer cells. We examined whether cells with tumor-specific aberrant DNA-methylation might be found in the saliva of affected patients. We tested 30 patients with primary head and neck tumors using methylation-specific PCR searching for promoter hypermethylation of the tumor suppressor gene p16 (CDKN2A), the DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) and the putative metastasis suppressor gene death-associated protein kinase (DAP-K). Aberrant methylation of at least one of these genes was detected in 17 (56%) of 30 head and neck primary tumors; 14 (47%) of 30 at p16, 10 (33%) of 30 at Dap-K and 7 (23%) of 30 at MGMT. In 11 (65%) of 17 methylated primary tumors abnormal methylated DNA was detected in the matched saliva samples. Abnormal promoter methylation in saliva DNA was found in all tumor stages and more frequently in tumors located in the oral cavity. Moreover, none of the saliva from patients with methylation-negative tumors displayed methylation of any marker. Of 30 saliva samples from healthy control subjects (15 smokers and 15 nonsmokers), only one sample from a smoking patient was positive for DNA methylation at two target genes. Detection of aberrant promoter hypermethylation patterns of cancer-related genes in saliva of head and cancer patients is feasible and may be potentially useful for detecting and monitoring disease recurrence. Long-term longitudinal studies are needed to evaluate this approach for early detection of head and neck cancer in at-risk populations.


Aquaporin-4 antibody isoform binding specificities do not explain clinical variations in NMO.
To assess the clinical relevance of the differential binding of antibodies against the 2 main aquaporin-4 (AQP4) isoforms in neuromyelitis optica (NMO) patient sera using stably transfected human embryonic kidney cells. Flow cytometry of human embryonic kidney cells stably transfected with either M23 or M1 AQP4 was used to measure antibody endpoint titers in 52 remission samples and 26 relapse samples from 34 patients with clinically well-characterized AQP4 antibody-positive NMO/NMO spectrum disorder. The AQP4 M23 (40-61,440) and AQP4 M1 (<20-20,480) titers varied widely between patients, as did the M23:M1 antibody ratio (1-192). In 76 of 78 samples, binding to M23 was higher than binding to M1, including during relapses and remissions (p < 0.0001), and the M23:M1 ratio was relatively constant within an individual patient. Titers usually fell after immunosuppression, but the titers at which relapses occurred varied markedly; no threshold level for relapses could be identified, and relapses could occur without a rise in titers. Relapse severity did not correlate with M23 or M1 antibody titers, although there was a correlation between the earliest M23 titers and annualized relapse rates. The M23:M1 ratio and absolute M23 and M1 titers did not relate to age at disease onset, ethnicity, disease severity, phenotype, or relapses at different anatomical sites. Relative AQP4 antibody binding to M23 and M1 isoforms differs between patients but there is no consistent association between these differences and clinical characteristics of disease. Nevertheless, the M23 isoform provided a slightly more sensitive substrate for AQP4-antibody assays, particularly for follow-up studies.


Superficial cortical landmarks for localization of the hippocampus: Application for temporal lobectomy and amygdalohippocampectomy.
Accessing the hippocampus for amygdalohippocampectomy and procedures such as depth electrode placement requires accurate knowledge regarding the location of the hippocampus. The authors removed 10 human cadaveric brains (20 sides) from their crania, noted relationships between the lateral temporal neocortex and underlying hippocampus, and measured the distance between the hippocampus and superficial landmarks. Mean distances were as follows: 3.8 cm from the tip of the temporal lobe to the head of the hippocampus; 6.5 cm from the tip of the temporal lobe to the junction of the fornix and hippocampus; and 3.5 cm between the tail and head of the hippocampus. The head of the hippocampus ranged from 0 to 5 mm inferior to the inferior temporal sulcus. The tail of the hippocampus ranged from 2.2 to 7 mm superior to the inferior temporal sulcus. In two specimens, the tail was deep to the superior temporal sulcus. Generally the length of the hippocampus was along the inferior temporal sulcus and inferior aspect of the middle temporal gyrus. The hippocampus tended to be more superiorly located and shorter in females and left sides, but this was not statistically significant. Additional landmarks for localizing the underlying hippocampus may be helpful in temporal lobe surgery. Our study showed relatively constant anatomic landmarks between the hippocampus and overlying temporal cortex that may help localize the hippocampus during amygdalohippocampectomy and depth electrode implantation, verify the accuracy of image-guided methods, and used as adjuvant methodologies when these latter technologies are unavailable.


Mathematical modelling of juxtacrine patterning.
Spatial pattern formation is one of the key issues in developmental biology. Some patterns arising in early development have a very small spatial scale and a natural explanation is that they arise by direct cell-cell signalling in epithelia. This necessitates the use of a spatially discrete model, in contrast to the continuum-based approach of the widely studied Turing and mechanochemical models. In this work, we consider the pattern-forming potential of a model for juxtacrine communication, in which signalling molecules anchored in the cell membrane bind to and activate receptors on the surface of immediately neighbouring cells. The key assumption is that ligand and receptor production are both up-regulated by binding. By linear analysis, we show that conditions for pattern formation are dependent on the feedback functions of the model. We investigate the form of the pattern: specifically, we look at how the range of unstable wavenumbers varies with the parameter regime and find an estimate for the wavenumber associated with the fastest growing mode. A previous juxtacrine model for Delta-Notch signalling studied by Collier et al. (1996, J. Theor. Biol. 183, 429-446) only gives rise to patterning with a length scale of one or two cells, consistent with the fine-grained patterns seen in a number of developmental processes. However, there is evidence of longer range patterns in early development of the fruit fly Drosophila. The analysis we carry out predicts that patterns longer than one or two cell lengths are possible with our positive feedback mechanism, and numerical simulations confirm this. Our work shows that juxtacrine signalling provides a novel and robust mechanism for the generation of spatial patterns.


Analysis of malignancy detected by needle-localized breast biopsy.
The medical records of 192 women with nonpalpable mammographically detected breast lesions who underwent needle-localized breast biopsy between January 1989 and January 1991 and between March 1992 and March 1994 were reviewed. Of the 192 patients examined, 100 underwent biopsy for evaluation of microcalcifications suggestive of malignancy. Ninety-two biopsies were performed for non-specific radiodensities not inclusive of microcalcifications. This study examines the radiographic characteristics of the nonpalpable breast lesion. Although presence of microcalcifications on mammograms are an important finding in detection of breast carcinoma, it must not be considered pathognomonic. Other distinguishing factors require evaluation to assess the indication for biopsy. Central to this study was the presence of microcalcifications alone or as detected in association with a dominant mass. Cancer was discriminated in 38 (20%) of the patients studied. Mammographic findings with microcalcification, regardless of the presence of a mass, were found to be malignant in 20% of patients undergoing biopsy. Nine percent of biopsies done to evaluate microcalcifications alone were malignant. The finding of microcalcification associated with a dominant mass proved malignant in 34% of patients who had a biopsy done. The authors include guidelines for increasing the effectiveness of needle-localized biopsies of the breast.


Association of Gestational Age With Verbal Ability and Spatial Working Memory at Age 11.
Although children born very preterm (gestation <32 weeks) have an increased risk of cognitive impairment compared with full-term children (39-41 weeks), the risk for children born moderately (32-33 weeks) to late preterm (34-36 weeks) and early term (37-38 weeks) is unclear. This study describes the relationship between gestational age and cognitive outcomes at 11 years and the trajectory of deficits in verbal ability from age 3 to 11 years. Cognitive ability was assessed by using the Spatial Working Memory test from the Cambridge Neuropsychological Test Automated Working Battery (n = 11 395) and British Ability Scale Verbal Similarities test (n = 11 889) in the UK Millennium Cohort Study. Each gestational group was compared with the full-term group by using differences in z scores and odds ratios for delay (scoring ≥1 SD below the mean). Very and moderately preterm children demonstrated significantly lower working memory scores compared with full-term children (adjusted difference -0.2 to -0.6) and were more likely to be delayed. There was no significant relationship between late-preterm or early-term birth and working memory (adjusted differences < -0.1), or between gestational age and verbal ability at 11 years. There appears to be a general attenuation in odds ratios as the child ages. Very preterm children exhibited working memory deficits at 11 years. However, the absence of delayed verbal skills at 11 years despite earlier delays could indicate "catch-up" effects.


Ge/SiGe quantum confined Stark effect electro-absorption modulation with low voltage swing at λ = 1550 nm.
Low-voltage swing (≤1.0 V) high-contrast ratio (6 dB) electro-absorption modulation covering 1460 to 1560 nm wavelength has been demonstrated using Ge/SiGe quantum confined Stark effect (QCSE) diodes grown on a silicon substrate. The heterolayers for the devices were designed using an 8-band k.p Poisson-Schrödinger solver which demonstrated excellent agreement with the experimental results. Modelling and experimental results demonstrate that by changing the quantum well width of the device, low power Ge/SiGe QCSE modulators can be designed to cover the S- and C-telecommunications bands.


Measurement issues in trials of pediatric acute diarrheal diseases: a systematic review.
Worldwide, diarrheal diseases rank second among conditions that afflict children. Despite the disease burden, there is limited consensus on how to define and measure pediatric acute diarrhea in trials. In RCTs of children involving acute diarrhea as the primary outcome, we documented (1) how acute diarrhea and its resolution were defined, (2) all primary outcomes, (3) the psychometric properties of instruments used to measure acute diarrhea and (4) the methodologic quality of included trials, as reported. We searched CENTRAL, Embase, Global Health, and Medline from inception to February 2009. English-language RCTs of children younger than 19 years that measured acute diarrhea as a primary outcome were chosen. We identified 138 RCTs reporting on 1 or more primary outcomes related to pediatric acute diarrhea/diseases. Included trials used 64 unique definitions of diarrhea, 69 unique definitions of diarrhea resolution, and 46 unique primary outcomes. The majority of included trials evaluated short-term clinical disease activity (incidence and duration of diarrhea), laboratory outcomes, or a composite of these end points. Thirty-two trials used instruments (eg, single and multidomain scoring systems) to support assessment of disease activity. Of these, 3 trials stated that their instrument was valid; however, none of the trials (or their citations) reported evidence of this validity. The overall methodologic quality of included trials was good. Even in what would be considered methodologically sound clinical trials, definitions of diarrhea, primary outcomes, and instruments employed in RCTs of pediatric acute diarrhea are heterogeneous, lack evidence of validity, and focus on indices that may not be important to participants.


Modeling the combination of motion, stereo, and vergence angle cues to visual depth.
Three models of visual cue combination were simulated: a weak fusion model, a modified weak model, and a strong model. Their relative strengths and weaknesses are evaluated on the basis of their performances on the tasks of judging the depth and shape of an ellipse. The models differ in the amount of interaction that they permit among the cues of stereo, motion, and vergence angle. Results suggest that the constrained nonlinear interaction of the modified weak model allows better performance than either the linear interaction of the weak model or the unconstrained nonlinear interaction of the strong model. Further examination of the modified weak model revealed that its weighting of motion and stereo cues was dependent on the task, the viewing distance, and, to a lesser degree, the noise model. Although the dependencies were sensible from a computational viewpoint, they were sometimes inconsistent with psychophysical experimental data. In a second set of experiments, the modified weak model was given contradictory motion and stereo information. One cue was informative in the sense that it indicated an ellipse, while the other cue indicated a flat surface. The modified weak model rapidly reweighted its use of stereo and motion cues as a function of each cue's informativeness. Overall, the simulation results suggest that relative to the weak and strong models, the modified weak fusion model is a good candidate model of the combination of motion, stereo, and vergence angle cues, although the results also highlight areas in which this model needs modification or further elaboration.


Effect of food consistency on temporomandibular joint morphology: an experimental study in pigs.
To investigate whether there are any correlations between increased masticatory loading, degree of tooth wear, and the size, form, and macroscopic surface of the temporomandibular joints (TMJs). The degree of tooth wear and different TMJ variables were compared in 2 groups of domestic pigs. One group of 8 pigs had been raised indoors (ID group), and the other group of 9 pigs had been raised outdoors (OD group). The pigs in the ID group were fed a soft diet and were not provided any straw in their pens. The OD group was fed a solid diet and could also grub in the soil, resulting in an exposure to more abrasive components and to greater chewing demands. All pigs were sacrificed at the age of 22 months. The pigs in the OD group exhibited significantly more tooth wear compared to the ID group. No difference in mediolateral size of the condyles could be found between the 2 groups. Form and surface changes of the TMJs varied substantially between individuals, but not between the 2 groups. No correlation could be found between the degree of tooth wear and any of the TMJ variables. Exposure to a tougher diet containing more abrasive substances has a significant impact on the degree of tooth wear but seems to have no consequences either for the size of the TMJ condyles or for form or surface changes of the TMJs.


How much is a 'pea-sized amount'? A study of dentifrice dosing by parents in three countries.
To provide optimal fluoride effectiveness against caries while minimising risk of negative effects from excessive ingestion from toothbrushing, the fluoride dose delivered at each occasion is critical. This is particularly important for young children, so using a 'pea-sized amount' is generally recommended. However, there appears little guidance regarding what this means in practice, although it has been indicated to be 0.25 g. This study investigated, using conventional toothpastes and toothbrushes in Germany, the USA and the UK, how much toothpaste parents dispense for their 3- to 6 year-old children, and their interpretation of a 'pea-sized' amount of toothpaste. When asked to dispense the amount they would normally for their child, the majority of parents dosed substantially more than 0.25 g; in Germany, all parents over-dispensed. The amount dispensed varied widely: those parents at the 75th centile dispensed approximately twice the amount dispensed by those at the 25th centile, irrespective of country. When asked to dispense a pea-sized amount, the mean amount dosed decreased significantly in all countries. In the USA, electric toothbrush users dispensed about 0.1 g more than manual toothbrush users. While over-dispensing of fluoride toothpaste remains a cause for concern, it may be argued that the general recommendation to use a pea-sized amount of toothpaste generally works well in practice to balance the conflicting demands of risk and benefit from toothbrushing with fluoride toothpaste in young children.


Does the surface tension make the lung inherently unstable?
Many authors regard the human lung as a collection of 300 million bubbles independently connected by cylindrical tubes. Under surface tension such a model is inherently unstable in the sense that the small alveoli would empty into the large ones so that the lung would consist only of collapses and hyperinflated alveoli. It has been demonstrated that this basic model is wrong. My observation is based on the well-known fact that both sides of each interalveolar septum are exposed to ventilated air. When the topological relationship between the alveolar septa is properly taken into account, it can be shown that each interalveolar septum is a minimal surface and that there is no problem of inherent instability in the sense mentioned earlier. However, the lung structure is flimsy and can become unstable in the same sense that an airplane structure or an Atlas rocket can become unstable. The clarification of lung inflation and atelectasis can proceed in a rational manner when the confusion of an erroneous model is removed.


Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.
The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. NCT00825929.


Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.
Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.


New advances in nanographene chemistry.
Nanographenes, or extended polycyclic aromatic hydrocarbons, have been attracting renewed and more widespread attention since the first experimental demonstration of graphene in 2004. However, the atomically precise fabrication of nanographenes has thus far been achieved only through synthetic organic chemistry. The precise synthesis of quasi-zero-dimensional nanographenes, i.e. graphene molecules, has witnessed rapid developments over the past few years, and these developments can be summarized in four categories: (1) non-conventional methods, (2) structures incorporating seven- or eight-membered rings, (3) selective heteroatom doping, and (4) direct edge functionalization. On the other hand, one-dimensional extension of the graphene molecules leads to the formation of graphene nanoribbons (GNRs) with high aspect ratios. The synthesis of structurally well-defined GNRs has been achieved by extending nanographene synthesis to longitudinally extended polymeric systems. Access to GNRs thus becomes possible through the solution-mediated or surface-assisted cyclodehydrogenation, or "graphitization," of tailor-made polyphenylene precursors. In this review, we describe recent progress in the "bottom-up" chemical syntheses of structurally well-defined nanographenes, namely graphene molecules and GNRs.


A critical assessment of abattoir surveillance as a screening test for swine ascariasis.
The following data on ascarid burden were collected on an individual basis for 380 hogs marketed in the fall of 1987: a series of fecal ascarid-egg counts during the growing period; the level of milk spot lesions on the liver at slaughter; and the number of ascarids in the small intestines at slaughter. The presence of milk spots had a high sensitivity, very low specificity, and a high negative predictive value as a screening test for ascariasis in individual hogs. Results were consistent whether ascariasis was measured as the presence of intestinal ascarids at slaughter (sensitivity 91%, specificity 22%, negative predictive value 82%), or by a positive fecal egg count during the hog's lifetime (sensitivity 96%, specificity 24%, negative predictive value 93%). The presence of milk spots does not necessarily indicate that an ascarid infection has been established in the small intestine. The absence of milk spots, however, is a reliable indicator of the absence of an established ascarid infection, provided that the prevalence of ascariasis is equal to or less than that observed in this study. The severity of the ascarid infection in an individual hog could not be ascertained by the number of milk spot lesions on the liver.


Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique.
We investigated the role of pancreatic stone protein (PSP) in predicting the occurrence of infection in the postoperative course of cardiac surgery patients. Several biomarkers indicating the presence of inflammation and infection are available in the clinical routine; yet, their utility in the postoperative course of patients following cardiac surgery remains uncertain. Moreover, cardiopulmonary bypass, also referred to as "on-pump surgery", increases the susceptibility to an exaggerated inflammatory state. However, the impact of such extracorporeal circulation on circulating PSP levels remains poorly understood. In a prospective cohort of unselected patients undergoing cardiac surgery, we set out to elucidate the diagnostic accuracy of serum PSP levels as opposed to canonical biomarkers (CRP, WBC) of inflammation to discriminate between the presence of infection and surgical trauma,. In addition, we investigated whether the biomarkers were influenced by the surgical technique employed, i.e. on-pump vs. off-pump and minimally invasive surgery vs. sternotomy. Levels of circulating PSP and routine inflammatory biomarkers (CRP, WBC) were measured in samples taken from 120 patients at baseline as well as at postoperative day 1-3. Univariate analysis showed that among the biomarkers investigated, only PSP levels had discriminatory power to differentiate infection from surgical trauma in the postoperative course of the entire cohort of patients following cardiac surgery. With regard to cardiac surgical interventions, there was no significant association between the absence or presence of extracorporeal circulation and PSP levels. However, there was a significant difference in the slope of the rise of postoperative PSP between minimally invasive surgery as opposed to patients subjected to sternotomy. In an unselected population of cardiac surgery patients, post-operative serum PSP levels were significantly associated with the presence of infection in both the on-pump and off-pump setting. Of note, the surgical technique employed (sternotomy vs. minimally invasive approach) had a significant impact on postoperative PSP levels.


Parents and end-of-life decision-making for their child: roles and responsibilities.
Whether parents want to be and should be the decision-maker for their child in end-of-life matters are contested clinical and ethical questions. Previous research outcomes are equivocal. A qualitative interview method was used to examine the views and experiences of 25 bereaved parents in end-of-life decision-making for their child. Data were analysed thematically. Three types of decision-making roles were identified: self-determined, guided (both involving active decision-making) and acquiescent (passive).The majority of parents had been active in the decision-making process for their child. They perceived themselves as the ultimate end-of-life decision-maker. This was perceived as part of their parental responsibility. A minority of parents did not consider that they had been an active, ultimate decision-maker. Generally, parents in the self-determined and guided groups reported no negative consequences from their decision-making involvement. Importantly, parents in the acquiescent group described their experience as difficult at the time and subsequently, although not all difficulties related directly to decision-making. Parents considered that in principle parents should be the end-of-life decision-maker for their child, but understood personal characteristics and preference could prevent some parents from taking this role. This study unequivocally supports parents' desire to fulfil the end-of-life decision-making role. It provides a nuanced understanding of parents' roles and contributes evidence for the ethical position that parents should be the end-of-life decision-makers for their child, unless not in the child's best interests. On the whole, parents want this role and can manage its consequences. Indeed, not being the end-of-life decision-maker could be detrimental to parents' well-being.


Nonlinear model identification and spectral submanifolds for multi-degree-of-freedom mechanical vibrations.
In a nonlinear oscillatory system, spectral submanifolds (SSMs) are the smoothest invariant manifolds tangent to linear modal subspaces of an equilibrium. Amplitude-frequency plots of the dynamics on SSMs provide the classic backbone curves sought in experimental nonlinear model identification. We develop here, a methodology to compute analytically both the shape of SSMs and their corresponding backbone curves from a data-assimilating model fitted to experimental vibration signals. This model identification utilizes Taken's delay-embedding theorem, as well as a least square fit to the Taylor expansion of the sampling map associated with that embedding. The SSMs are then constructed for the sampling map using the parametrization method for invariant manifolds, which assumes that the manifold is an embedding of, rather than a graph over, a spectral subspace. Using examples of both synthetic and real experimental data, we demonstrate that this approach reproduces backbone curves with high accuracy.


Cognitive-behavioural group therapy improves a psychophysiological marker of stress in caregivers of patients with Alzheimer's disease.
Family caregivers of patients with dementia frequently experience psychological stress, depression and disturbed psychophysiological activity, with increased levels of diurnal cortisol secretion. To compare the effects of a cognitive-behavioural group therapy (CBT) to a psychoeducation group programme (EDUC) on cortisol secretion in caregivers of patients with moderate Alzheimer's disease (AD). Caregivers of AD outpatients were semi-randomly allocated to one of two intervention programmes (CBT or EDUC) consisting of eight weekly sessions. Twenty-six participants completed the study. Before and after intervention, salivary cortisol was collected at four different times of the day. Effects of the interventions were evaluated with self-report psychological scales and questionnaires related to functional abilities and neuropsychiatric symptoms of the AD relative. Only in the CBT group did salivary cortisol levels significantly decrease after intervention, with a large effect size and high achieved power. Both groups reported a reduction of neuropsychiatric symptoms of their AD relative after intervention. Psychoeducation for caregivers may contribute to a reduction of neuropsychiatric symptoms of AD patients while CBT additionally attenuates psychophysiological responses to stressful situations in caregivers, by reducing diurnal cortisol levels. This may lead to a positive impact in the general health of the caregiver, eventually resulting in better care of the AD patient.


Quantitative, directional measurement of electric field heterogeneity in the active site of ketosteroid isomerase.
Understanding the electrostatic forces and features within highly heterogeneous, anisotropic, and chemically complex enzyme active sites and their connection to biological catalysis remains a longstanding challenge, in part due to the paucity of incisive experimental probes of electrostatic properties within proteins. To quantitatively assess the landscape of electrostatic fields at discrete locations and orientations within an enzyme active site, we have incorporated site-specific thiocyanate vibrational probes into multiple positions within bacterial ketosteroid isomerase. A battery of X-ray crystallographic, vibrational Stark spectroscopy, and NMR studies revealed electrostatic field heterogeneity of 8 MV/cm between active site probe locations and widely differing sensitivities of discrete probes to common electrostatic perturbations from mutation, ligand binding, and pH changes. Electrostatic calculations based on active site ionization states assigned by literature precedent and computational pK(a) prediction were unable to quantitatively account for the observed vibrational band shifts. However, electrostatic models of the D40N mutant gave qualitative agreement with the observed vibrational effects when an unusual ionization of an active site tyrosine with a pK(a) near 7 was included. UV-absorbance and (13)C NMR experiments confirmed the presence of a tyrosinate in the active site, in agreement with electrostatic models. This work provides the most direct measure of the heterogeneous and anisotropic nature of the electrostatic environment within an enzyme active site, and these measurements provide incisive benchmarks for further developing accurate computational models and a foundation for future tests of electrostatics in enzymatic catalysis.


da Vinci robotic single-incision cholecystectomy and hepatectomy using single-channel GelPort access.
Minimally invasive surgery including laparoscopic and robotic surgery was recently approved for clinical use in hepatobiliary surgery. The purpose of this article is to evaluate the feasibility and technical aspects of robotic single incision for hepatobiliary surgery using the GelPort laparoscopic system in a preliminary animal study. We performed eight robotic single-incision laparoscopic surgery (SILS) procedures, including four cholecystectomies and four lateral segmentectomy of the liver, in a porcine study using the da Vinci S-HD Surgical System. A single-channel GelPort access was placed through a 2.5-cm single incision for robotic access. A 12-mm camera port, two 8-mm ports for the robotic arms and one 5-mm port for the patient-side assistant were inserted. A Mini Loop Retractor was applied to retract the fundus of the gallbladder. The EndoWrist dissector and grasping forceps was introduced to fine-dissect Calot's triangle. The instruments were crossed to avoid "sword fighting" and clashing of instruments in the abdomen. The cystic duct was divided after double ligation and the gallbladder was removed. Hepatic transection was performed with bipolar Harmonic shears and LigaSure for vascular pedicles. All robotic SILS procedures were completed (8/8, 100%). The cholecystectomies and hepatectomies were safely performed in average operating times of 70 min (±15) and 60 min (±20), respectively, with minimal blood loss. There were no conversions, re-interventions or extension of the skin incision. Robotic hepatobiliary SILS is technically feasible and safe using GelPort as a single-incision access platform. Robotic SILS is becoming established and is enormously advantageous to the patient.


Antidysrhythmic agents.
Antidysrhythmic therapy is used to suppress supraventricular and ventricular dysrhythmias, thus relieving symptoms and reducing the risk of sudden cardiac death. The Cardiac Arrhythmia Suppression Trial (CAST) found an increased mortality rate in a group of patients treated with two antidysrhythmic agents. This result has had a profound impact on the prescribing and monitoring of antidysrhythmic therapy. Prodysrhythmia is a frequent and serious complication of antidysrhythmics and is unpredictable. Assessment of benefit versus risk of drug therapy for each patient is recommended. The nurse's knowledge of antidysrhythmic pharmacology, including symptoms that indicate adverse reactions, and prodysrhythmia influences the patient outcome.


Characterization of bevacizumab by dynamic light scattering while maintaining its native structure.
Bevacizumab, is a humanized monoclonal antibody and patents on Avastin® (Bevacizumab, Roche) will expire in the US in 2019 and in Europe in 2022. Therefore, bevacizumab is a popular target for biosimilar developers. One of the most common problems in the formulation of antibody drugs is protein aggregation. Dynamic light scattering (DLS) is a well-established method for the determination of hydrodynamic dimensions, aggregates, and aggregation points of proteins. In contradistinction to other techniques that require diluted samples or specific conditions, proteins and aggregates can maintain their native structure during DLS measurements. In recent studies, bevacizumab was characterized by DLS using diluted samples. In this study, we aimed at investigating the hydrodynamic dimensions, aggregates, and aggregation onset of bevacizumab (Altuzan®, Turkey, Roche) by DLS, while maintaining its native structure. The intensity, volume, and number-based particle size distribution profiles of the test samples were evaluated and the aggregation onset of the formulation was successfully determined against increasing temperature. It is shown that the preservation of the native structure of commercial formulations in DLS measurements provides an opportunity to the characterization of commercial products and development of biosimilars.


Cauda equina syndrome.
Cauda equina syndrome is a relatively uncommon condition typically associated with a large, space-occupying lesion within the canal of the lumbosacral spine. The syndrome is characterized by varying patterns of low back pain, sciatica, lower extremity sensorimotor loss, and bowel and bladder dysfunction. The pathophysiology remains unclear but may be related to damage to the nerve roots composing the cauda equina from direct mechanical compression and venous congestion or ischemia. Early diagnosis is often challenging because the initial signs and symptoms frequently are subtle. Classically, the full-blown syndrome includes urinary retention, saddle anesthesia of the perineum, bilateral lower extremity pain, numbness, and weakness. Decreased rectal tone may be a relatively late finding. Early signs and symptoms of a developing postoperative cauda equina syndrome are often attributed to common postoperative findings. Therefore, a high index of suspicion is necessary in the postoperative spine patient with back and/or leg pain refractory to analgesia, especially in the setting of urinary retention. Regardless of the setting, when cauda equina syndrome is diagnosed, the treatment is urgent surgical decompression of the spinal canal.


The effect of L-carnitine treatment on levels of malondialdehyde and glutathione in patients with age related macular degeneration.
The aim of this study was to determine the antioxidant properties of the L-carnitine (LC) in the treatment of patients with age-related macular degeneration (AMD). This study involved 60 patients diagnosed with early AMD. The patients were divided into two groups. Group I was the study group that received LC supplementation for 3 months. Group II was the control group and did not consent to LC supplementation over the 3 months. At the end of the 3-month period, markers of lipid peroxidation, malondialdehyde (MDA) and reduced glutathione (GSH) were measured in the two groups. In the study group, the MDA level was significantly reduced, while the GSH level was significantly increased at the end of the 3-month period (P<0.001). Our results suggest that LC may protect against oxidative damage by decreasing the MDA level, a marker of lipid peroxidation, and increasing GSH.