Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites.
Research on the complex interactions among host nutritional status, parasitic infection and immune responsiveness has focused on the detrimental consequences of parasitic infections on host nutritional status and on mechanisms by which malnutrition impairs immunocompetence. Curiously, relatively few studies have examined the effects of malnutrition on the immune response in the parasite-infected host, and even fewer have considered the events occurring at the intestinal level, where absorption of nutrients occurs, intestinal parasites reside, and the gastrointestinal-associated lymphoid tissues play a role in directing both the local and the more systemic immune responses. Our work using a zinc-deficient nematode-infected mouse model reveals that parasites are better able to survive in the zinc-deficient hosts than in well-nourished hosts; that the production of interleukin-4 in the spleen of zinc-deficient mice is depressed, leading to depressed levels of IgE, IgG(1) and eosinophils; and that the function of T cells and antigen-presenting cells is impaired by zinc deficiency as well as by energy restriction. Given the paramount role of the gastrointestinal-associated lymphoid tissues in inducing and regulating immune responses to intestinal parasites and in orchestrating responses in the spleen and peripheral circulation, we conclude that zinc deficiency (in association with energy restriction) exerts profound effects on the gut mucosal immune system, leading to changes in systemically disseminated immune responses and, importantly, to prolonged parasite survival.


Threat Neurocircuitry Predicts the Development of Anxiety and Depression Symptoms in a Longitudinal Study.
Owing to high heterogeneity and comorbidity, the shared and unique neural mechanisms underlying the development of anxiety and major depressive disorders remain unclear. Using a dimensional model describing shared versus unique symptoms associated with anxiety and depression, this study investigated how longitudinal changes in symptom dimensions relate to threat neurocircuitry. Participants were 18- to 19-year-olds (N = 279, 186 females) who completed self-report measures of anxiety and depression at baseline and at 10, 20, and 30 months. Linear slopes of symptom dimensions of general distress, fear, and anhedonia-apprehension were estimated through a trilevel factorial model. In addition, functional magnetic resonance imaging scans were obtained while participants performed Pavlovian fear conditioning tasks at baseline and 30 months, including three phases of fear acquisition, extinction, and extinction recall. Neural responses in regions of interest related to threat neural circuitry (e.g., amygdala, ventromedial prefrontal cortex, and subgenual anterior cingulate cortex) were extracted. Linear mixed models used to estimate relationships between changes of symptom dimensions and neural responses revealed two major findings: 1) greater neural responses to threatening stimuli during fear acquisition at baseline were associated with a greater increase in fear symptoms during the 30-month prospective period; and 2) elevated neural responses to the extinguished stimulus during extinction recall at 30 months were negatively associated with changes in general distress, suggesting that greater increases in general distress are associated with larger deficits in extinction memory. These findings improve our understanding of pathophysiological pathways underlying the development of anxiety and depression, while separating symptom dimensions that are shared versus unique between the two disorders.


The importance of viruses in ventilator-associated pneumonia.
Ventilator-associated pneumonia (VAP) remains a challenge. The importance of viruses in VAP is not established. We sought to determine the prevalence of viruses in VAP and the outcomes of viral VAP. Retrospective study of VAP over 3 years. The frequency of a viral process represented the primary endpoint. Clinical outcomes served as secondary endpoints. We identified variables independently associated with a virus and conducted sensitivity analyses to assess the interaction between type of infection and patient characteristics. Tertiary-care referral center. The final cohort consisted of 710 patients and a virus was isolated in 5.1%. None. The most common viruses included: rhinovirus, influenza A, and cytomegalovirus. Baseline characteristics were similar between those with and without viral infections. In logistic regression, immunosuppression (adjusted odds ratio [aOR], 2.97; 95% confidence interval [CI], 1.44-6.14) and stem-cell transplantation (SCT, aOR, 3.58; 95% CI, 1.17-10.99) were independently associated with a virus. The presence of either variable performed poorly as a screening test for a virus. In-hospital (22.4% vs 21.6%; P = .869) and 30-day (32.8% vs 27.9%; P = .448) mortality rates were similar between the cohorts, respectively. Sensitivity analyses restricted to patients without a mixed viral and bacterial infection or those who were immunocompetent yielded similar results. Although infrequent, a range of viruses may cause VAP. Viruses more often complicate SCT and immunosuppression, but one can isolate viruses in immunocompetent subjects. Viral VAP produces severe infection and results in high mortality rates. Clinical features do not differentiate viral from nonviral VAP.


Crystal structure of antithrombin in a heparin-bound intermediate state.
Antithrombin is activated as an inhibitor of the coagulation proteases through its specific interaction with a heparin pentasaccharide. The binding of heparin induces a global conformational change in antithrombin which results in the freeing of its reactive center loop for interaction with target proteases and a 1000-fold increase in heparin affinity. The allosteric mechanism by which the properties of antithrombin are altered by its interactions with the specific pentasaccharide sequence of heparin is of great interest to the medical and protein biochemistry communities. Heparin binding has previously been characterized as a two-step, three-state mechanism where, after an initial weak interaction, antithrombin undergoes a conformational change to its high-affinity state. Although the native and heparin-activated states have been determined through protein crystallography, the number and magnitude of conformational changes render problematic the task of determining which account for the improved heparin affinity and how the heparin binding region is linked to the expulsion of the reactive center loop. Here we present the structure of an intermediate pentasaccharide-bound conformation of antithrombin which has undergone all of the conformational changes associated with activation except loop expulsion and helix D elongation. We conclude that the basis of the high-affinity state is not improved interaction with the pentasaccharide but a lowering of the global free energy due to conformational changes elsewhere in antithrombin. We suggest a mechanism in which the role of helix D elongation is to lock antithrombin in the five-stranded fully activated conformation.


Human vascular endothelial cells express epithelial growth factor in response to infection by Bartonella bacilliformis.
Bartonella are Gram-negative bacterial pathogens that trigger pathological angiogenesis during infection of humans. Bartonella bacilliformis (Bb) is a neglected tropical agent endemic to South America, where it causes Carrión's disease. Little is known about Bb's virulence determinants or how the pathogen elicits hyperproliferation of the vasculature, culminating in Peruvian warts (verruga peruana) of the skin. In this study, we determined that active infection of human umbilical vein endothelial cells (HUVECs) by live Bb induced host cell secretion of epidermal growth factor (EGF) using ELISA. Killed bacteria or lysates of various Bb strains did not cause EGF production, suggesting that an active infection was necessary for the response. Bb also caused hyperproliferation of infected HUVECs, and the mitogenic response could be inhibited by the EGF-receptor (EGFR) inhibitor, AG1478. Bb strains engineered to overexpress recombinant GroEL, evoked greater EGF production and hyperproliferation of HUVECs compared to control strains. Conditioned (spent) media from cultured HUVECs that had been previously infected by Bb were found to be mitogenic for naïve HUVECs, and the response could be inhibited by EGFR blocking with AG1478. Bb cells and cell lysates stimulated HUVEC migration and capillary-like tube formation in transmigration and Matrigel assays, respectively. To our knowledge, this is the first demonstration of EGF production by Bb-infected endothelial cells; an association that could contribute to hyperproliferation of the vascular bed during bartonellosis.


Aging issues in the workplace. Assisting workers who provide eldercare.
1. With increased aged, chronic disabilities that limit the ability to provide self care also increase. As self care declines, elderly persons depend on their children for assistance. 2. Families provide 80% of home based care for the elderly. Employees' children often provide care. 3. Caregiving has both positive and negative aspects. Caregiving often leads to psychological stress and, over time, physical illness for the caregiver. 4. Occupational health nurses can assist employee caregivers in protecting their own health and locating services for their care recipients.


Serum 25-hydroxyvitamin D increases with NB-UVB and UVA/UVB phototherapy in patients with psoriasis and atopic dermatitis in Western Australia.
The benefit of NB-UVB phototherapy on serum 25-hydroxyvitamin D [25(OH)D] levels in patients with inflammatory skin conditions has been reported in the northern hemisphere. Vitamin D status is known to differ between geographical latitudes. The objective of this study was to investigate the influence of NB-UVB and UVA/UVB phototherapy on the 25(OH)D serum levels in patients with psoriasis and atopic dermatitis in Western Australia. A total of 35 patients with psoriasis or atopic dermatitis requiring phototherapy thrice weekly for a minimum of 4 weeks were enrolled. Of these, 20 patients completed the study. Serum vitamin D levels were measured at baseline and at approximately 6 weeks into phototherapy. Data were adjusted for season, patients' age, sex, skin condition and Fitzpatrick skin phototype. There was a statistically significant increase in serum 25(OH)D from pre- to post-NB-UVB and UVA/UVB phototherapy (P < 0.0001), with a mean raw increase of 34.6 (25) nmol/L; or 45.1 (7.5) nmol/L when adjusted for covariates. This was also true for patients receiving NB-UVB phototherapy with a baseline vitamin D of <80 nmol/L (P < 0.05) and >80 nmol/L (P < 0.004). NB-UVB and UVA/UVB phototherapy significantly increased 25(OH)D serum level in patients with psoriasis and atopic dermatitis in Western Australia. Our study cohort had a higher baseline vitamin D level and a lower percentage increase of serum 25(OH)D post-phototherapy than the increases reported in the literature from cohorts in the northern hemisphere.


Spontaneous formation of γ-hydroxybutyric acid from γ-butyrolactone in tap water solutions.
The spontaneous conversion of γ-butyrolactone (GBL) to γ-hydroxybutyric acid (GHB) in seven different Swedish tap waters was investigated. The waters used in the study were selected to represent the diversity among Swedish tap waters as well as possible, which was enabled by principal component analysis (PCA) of a number of water quality parameters. GBL solutions (5, 25 and 50% v/v) were prepared in each of the tap waters and in deionized water and the formation of GHB was followed over time. The GHB quantifications were made using a CZE method, employing a carrier electrolyte consisting of 25mM benzoic acid, 54mM tris(hydroxymethyl)aminomethane (Tris) and 1.7mM tetradecyltrimethylammonium bromide (TTAB), which was developed as a part of the current study. Data evaluation showed that the formation of GHB was largely dependent on the type of tap water. For example, there was a negative correlation between the kinetics of the GHB formation and the alkalinity of the tap waters (r(2)=0.990). This could be explained by a faster decrease in pH in the waters with low buffering capacity (i.e. low alkalinity), which catalysed the hydrolysis of GBL. Equilibrium was reached after 40-250 days depending on the initial GBL concentration and the type of tap water. The level of the equilibrium appeared to be dependent on the initial GBL concentration and ranged from 26 to 37%. Gained knowledge on the levels of the GHB/GBL equilibrium and the kinetics of the formation of GHB in tap water solutions of GBL, including the influence of the tap water quality, may be useful information for casework with the GHB/GBL problem in focus.


High-level transient expression of recombinant protein in lettuce.
Transient expression following agroinfiltration of plant tissue was investigated as a system for producing recombinant protein. As a model system, Agrobacterium tumefaciens containing the beta-glucuronidase (GUS) gene was vacuum infiltrated into lettuce leaf disks. Infiltration with a suspension of 10(9) colony forming units/mL followed by incubation for 72 h at 22 degrees C in continuous darkness produced a maximum of 0.16% GUS protein based on dry tissue or 1.1% GUS protein based on total soluble protein. This compares favorably to expression levels for commercially manufactured GUS protein from transgenic corn seeds. A. tumefaciens culture medium pH between 5.6 and 7.0 and surfactant concentrations < or = 100 ppm in the vacuum infiltration did not affect GUS expression, while infiltration with an A. tumefaciens density of 10(7) and 10(8) colony forming units/mL, incubation at 29 degrees C, and a surfactant concentration of 1,000 ppm significantly reduced expression. Incubation in continuous light caused lettuce to produce GUS protein more rapidly, but final levels did not exceed the GUS production in leaves incubated in continuous darkness after 72 h at 22 degrees C. The kinetics of GUS expression during incubation in continuous light and dark were represented well using a logistic model, with rate constants of 0.30 and 0.29/h, respectively. To semi-quantitatively measure the GUS expression in large numbers of leaf disks, a photometric enhancement of the standard histochemical staining method was developed. A linear relationship with an R2 value of 0.90 was determined between log10 (% leaf darkness) versus log10 (GUS activity). Although variability in expression level was observed, agroinfiltration appears to be a promising technology that could potentially be scaled up to produce high-value recombinant proteins in planta.


Public attitude toward pesticides. A random survey of pesticide use in Allegheny County, Pa.
Pesticide use was examined by means of a random survey in Allegheny County, Pa., in October and November 1973. The objectives included gaining insight into the need for a new community pesticide program and estimating its public acceptance. The 110 survey sites were grouped as single-family dwellings, commercial and recreational lawns, institutions, farms, rights-of-way, and wasteland. In the single-family dwellings, most householders (85 percent) used a pesticide in the previous 12 months, usually an aerosol insecticide (76 percent) or herbicide (55 percent). Their pesticide selections were most often based on advertisements of availabel products. A high percentage lacked either the interest or the knowledge of the information on the pesticide's label. No observation in this or any other study supports the need for a new special program in pesticides or indicates that a substantial segment of the public would use its services. The main users of "hard" pesticides were the golf courses, rights-of-way, and one farm-nursery. The rights-of-way used chemicals only for vegetation control. Utilities and railroads contracted with pesticide companies for this work. Municipal users applied pesticides recommended by dealers. The golf courses and a farm-nursery used a broad range of fungicides, insecticides, and herbicides, which they selected because of information received from the Pennsylvania Extension Service and professional organizations.


Inserting Small Molecules across Membrane Mixtures: Insight from the Potential of Mean Force.
Small solutes have been shown to alter the lateral organization of cell membranes and reconstituted phospholipid bilayers; however, the mechanisms by which these changes happen are still largely unknown. Traditionally, both experiment and simulation studies have been restricted to testing only a few compounds at a time, failing to identify general molecular descriptors or chemical properties that would allow extrapolating beyond the subset of considered solutes. In this work, we probe the competing energetics of inserting a solute in different membrane environments by means of the potential of mean force. We show that these calculations can be used as a computationally efficient proxy to establish whether a solute will stabilize or destabilize domain phase separation. Combined with umbrella-sampling simulations and coarse-grained molecular dynamics simulations, we are able to screen solutes across a wide range of chemistries and polarities. Our results indicate that for the system under consideration, preferential partitioning and therefore effectiveness in altering membrane phase separation are strictly linked to the location of insertion in the bilayer (i.e., midplane or interface). Our approach represents a fast and simple tool for obtaining structural and thermodynamic insight into the partitioning of small molecules between lipid domains and its relation to phase separation, ultimately providing a platform for identifying the key determinants of this process.


[Population fluctuation of Xyleborus ferrugineus and X. affinis (Coleoptera: Curculionidae) in ecosystems of Tabasco, Mexico].
The Scolytinae insects are commonly known as bark or ambrosial beetles because of their feeding habits. Among them, some species restrict their reproductive activity to a host plant or a small number of them, whereas others are highly polyphagous. In order to evaluate the population dynamics of Scolytinae species, populations of Xyleborusferrugineus and X. affinis in ecosystems from Tabasco, Mexico were studied. The study was carried out from November 2010-July 2011, February 2010-January 2011 and 2007. The trapping methods used were alcohol traps, light traps and direct capture on their host plants. A total of 688 specimens ofX ferrugineus and 3 911 specimens of X. affinis were collected. The population dynamics of X. ferrugineus showed low size population in the studied ecosystems, without any marked seasonality. The highest population sizes were recorded both in dry season (March-May) and rainy season (September-December). Unlike the populations of X. ferrugineus, those of X. affinis were more abundant and showed the highest peaks during the rainy seasons (except in May at the Botanical Garden "José Narciso Rovisora"). Alcohol and light traps can be complementary methods for monitoring the populations of these types of insects. They occur most of the year and theirs population dynamics depends on food resources availability as well as environmental factors such as temperature and humidity. Judging by the observed abundance it is suggested that X. affinis has been adapted and exploited resources in a better way than X. ferrugineus in those ecosystems. Correlations between abundance and climatic factors had both positive and negative values. The results reflect the behavior of populations. However, a detail assessment of the biological and abiotic factors that influence the fluctuations of these insects is required.


Design, synthesis and DNA-binding capacity of a new peptidic bifunctional intercalating agent.
A lysyl-lysine bifunctional derivative of 9-aminoacridine has been synthesized and its DNA-binding capacity established by electron-paramagnetic-resonance study. For this purpose the binding parameters of a spin-labelled aminoacridine probe were estimated and the affinities of the lysylacridinyl-lysyldiamino-octane dimer and of 9-amino-acridine could be evaluated by competitive assays. The competition study provided quantitative results concerning the dissociation constant (KD) of the dimer. The obtained value was closely similar to the KD of 9-aminoacridine determined by the same method and to the KD previously reported for the anti-tumour and antibiotic bifunctional intercalator quinomycins.


Characteristics of Listeria monocytogenes Strains Isolated from Milk and Humans and the Possibility of Milk-Borne Strains Transmission.
Listeria monocytogenes is the etiological factor of listeriosis. The main source of these organisms is food, including dairy products. The aim was to determine the multiple correlations between the drug susceptibility, virulence genes (VGs), and biofilm formation on silicone teat cups of milk-borne and human L. monocytogenes strains. The spread of L. monocytogenes via contaminated teat rubbers was assessed. The L. monocytogenes strains recovered from milk (18), human blood (10), and the reference strain ATCC®19111™ were used in the study. Penicillin resistance was the most prevalent resistance in the milk isolates (n=8; 44.4%), whereas among clinical strains erythromycin resistance was predominating - (n=6; 60%). The most frequent VGs among strains isolated from milk were hlyA (100%) and plcB (100%) whereas in strains isolated from blood - hlyA (100%) and prfA (90%). All tested VGs were present in 50% of blood isolates and 11% of milk-borne strains. The strains isolated from milk formed a significantly stronger biofilm. The strains with more numerous virulence genes were resistant to more antibiotics and formed a stronger biofilm. It was shown that contaminated teat cups might contribute to the transmission of L. monocytogenes in the herd. It seems reasonable to monitor the occurrence of L. monocytogenes biofilm in a dairy processing environment. Listeria monocytogenes is the etiological factor of listeriosis. The main source of these organisms is food, including dairy products. The aim was to determine the multiple correlations between the drug susceptibility, virulence genes (VGs), and biofilm formation on silicone teat cups of milk-borne and human L. monocytogenes strains. The spread of L. monocytogenes via contaminated teat rubbers was assessed. The L. monocytogenes strains recovered from milk (18), human blood (10), and the reference strain ATCC®19111™ were used in the study. Penicillin resistance was the most prevalent resistance in the milk isolates (n=8; 44.4%), whereas among clinical strains erythromycin resistance was predominating – (n=6; 60%). The most frequent VGs among strains isolated from milk were hlyA (100%) and plcB (100%) whereas in strains isolated from blood – hlyA (100%) and prfA (90%). All tested VGs were present in 50% of blood isolates and 11% of milk-borne strains. The strains isolated from milk formed a significantly stronger biofilm. The strains with more numerous virulence genes were resistant to more antibiotics and formed a stronger biofilm. It was shown that contaminated teat cups might contribute to the transmission of L. monocytogenes in the herd. It seems reasonable to monitor the occurrence of L. monocytogenes biofilm in a dairy processing environment.


A meta-analysis of etidronate for the treatment of postmenopausal osteoporosis.
The aim of the study was to review the effect of etidronate on bone density and fractures in postmenopausal women. We searched MEDLINE from 1966 to 1998, examined citations of relevant articles, and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies, primary authors, and pharmaceutical industry sources for unpublished data. We included 13 trials that randomized women to etidronate or an alternative (placebo or calcium and/or vitamin D) and measured bone density for at least 1 year. For each trial, three independent reviewers assessed the methodologic quality and abstracted data. The data suggested a reduction in vertebral fractures with a pooled relative risk of 0.63 (95% CI 0.44 to 0.92). There was no effect on nonvertebral fractures (relative risk 0.99, (95% CI 0.69 to 1.42). Etidronate, relative to control, increased bone density after 1-3 years of treatment in the lumbar spine by 4.06% (95% CI 3.12 to 5.00), in the femoral neck by 2.35% (95% CI 1.66 to 3.04) and in the total body by 0.97% (95% CI 0.39 to 1.55). Effects were larger at 4 years, though the number of patients followed much smaller. Etidronate increases bone density in the lumbar spine and femoral neck for up to 4 years. The pooled estimates of fracture reduction with etidronate suggest a reduction in vertebral fractures, but no effect on nonvertebral fractures.


Systemic inflammatory responses in patients with type 2 diabetes with chronic periodontitis.
The objective of this case-control study was to quantify the immune responsiveness in individuals with type 2 diabetes (T2D) as compared with patients without diabetes (NT2D) diagnosed with periodontitis. Peripheral blood was collected from 20 patients with moderate-to-severe chronic periodontitis (10 T2D, 10 NT2D). Blood samples were stimulated with ultrapure Porphyromonas gingivalis and Escherichia coli lipopolysaccharide (LPS) for 24 hours. 14 cytokines/chemokines were quantified in culture supernatants using multiplex technology. T2D individuals demonstrated higher unstimulated levels of interleukin 6 (IL-6), IL-1β, tumor necrosis factor α, interferon γ, IL-10, IL-8, macrophage inflammatory protein 1α (MIP1α), and 1β (MIP1β), and higher stimulated levels of IL-6, IL-8, IL-10, MIP1α and MIP1β, along with lower unstimulated and stimulated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) when compared with NT2D (p<0.05). Importantly, the LPS-induced levels of IL-6, IL-8, IL-10 and MIP1α strongly correlated with severity of disease, measured by pocket depths (PD), within the T2D group (r(2)≥0.7, p<0.05), but not within NT2D. Among patients with chronic periodontitis, patients with T2D seem to have an enhanced LPS-induced immune responsiveness than individuals without diabetes, which correlates with periodontal disease severity, concomitant with a less robust GM-CSF response. This data may in part explain the higher predisposition to periodontitis in this population.


[Blocking action of pyridoxal-5'-phosphate on nonadrenergic synaptic inhibition of human small intestine smooth muscle].
We investigated the inhibitory synaptic potentials (ISP) in isolated smooth muscle strips of the human duodenum circular layer from the ulcer adjacent region (I group) as well as ileum and distal part of small intestine, which were on a distance of some dozen centimeters from the place of disturbance under the different gastrointestinal diseases (II group). ISP amplitude was several times smaller in the muscle strips of the I group compare to the II group. It could depend on the alterations of smooth muscles cable properties, increase of connective tissue mass, changes in the intestinal nervous system and synaptic transmission in the region adjacent to duodenum ulcer. Pyridoxal-5'-phosphate effectively decreased amplitude and increased ISP latent period in the muscle strips from both groups. N(omega)-nitro-L-arginine, the blocker of NO-synthase did not affect pyridoxal-5'-phosphate activity in smooth muscles. Phosphate group was essential for realization of its influence on ISP in smooth muscles because pyridoxal did not influence both ISP amplitude and ISP latent period.


Cloning of the exonuclease III gene of Escherichia coli.
Overproducers of exonuclease III (exo III) were found within a colony bank containing ColE1-Escherichia coli hybrid plasmids. Through the enzymatic ligation of restriction enzyme fragments, the exo III gene, xth, was transferred to a thermoinducible, integration-proficient lambda phage and to a chimeric ColE1-lambda plasmid that was thermoinducible for lambda-directed DNA replication. Transfer of the xth gene was facilitated by a technique involving prior selection for Tn5 insertions into plasmid, thereby linking the gene to additional restriction sites and to a selectable (drug resistance) marker. After heat induction, cells bearing the thermoinducible ColE1-lambda-xth plasmid produced 120-fold more exo III than did plasmid-free cells. Enzyme production was not further enhanced by any of the following chromosomal mutations: dnaA, recBC, tob, or nusA snu. Several observations suggested that enzyme over-synthesis was the result primarily of lambda-detected replication rather than lambda-directed transcription.


Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia.
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.


Translesion synthesis DNA polymerases promote error-free replication through the minor-groove DNA adduct 3-deaza-3-methyladenine.
N3-Methyladenine (3-MeA) is formed in DNA by reaction with S-adenosylmethionine, the reactive methyl donor, and by reaction with alkylating agents. 3-MeA protrudes into the DNA minor groove and strongly blocks synthesis by replicative DNA polymerases (Pols). However, the mechanisms for replicating through this lesion in human cells remain unidentified. Here we analyzed the roles of translesion synthesis (TLS) Pols in the replication of 3-MeA-damaged DNA in human cells. Because 3-MeA has a short half-life in vitro, we used the stable 3-deaza analog, 3-deaza-3-methyladenine (3-dMeA), which blocks the DNA minor groove similarly to 3-MeA. We found that replication through the 3-dMeA adduct is mediated via three different pathways, dependent upon Polι/Polκ, Polθ, and Polζ. As inferred from biochemical studies, in the Polι/Polκ pathway, Polι inserts a nucleotide (nt) opposite 3-dMeA and Polκ extends synthesis from the inserted nt. In the Polθ pathway, Polθ carries out both the insertion and extension steps of TLS opposite 3-dMeA, and in the Polζ pathway, Polζ extends synthesis following nt insertion by an as yet unidentified Pol. Steady-state kinetic analyses indicated that Polι and Polθ insert the correct nt T opposite 3-dMeA with a much reduced catalytic efficiency and that both Pols exhibit a high propensity for inserting a wrong nt opposite this adduct. However, despite their low fidelity of synthesis opposite 3-dMeA, TLS opposite this lesion replicates DNA in a highly error-free manner in human cells. We discuss the implications of these observations for TLS mechanisms in human cells.


Renomedullary and intestinal hyaluronan content during body water excess: a study in rats and gerbils.
Our previous studies in rats have suggested a role for renomedullary hyaluronan (HA) in water homeostasis. The gerbil is known for its unique ability to conserve water. In the present study renal papillary and intestinal HA were compared between groups of anaesthetized gerbils and rats before and after up to 6 h of I.V. water loading. Baseline papillary HA in gerbils was only 37 % of that in the rat. Water loading in rats increased the papillary HA content. Elevation was maximal (+27 %, P < 0.05) after 2 h of water loading and then declined to control levels after 6 h of water loading (+3 %, n.s.). In contrast, the gerbil responded with a decreased papillary HA content during water loading. The depression was maximal after 2 h (-49 %, P < 0.05) and was still 41 % below the control values after 6 h (P < 0.05). The urine flow rate increased rapidly in the rat and its maximum, 21 times above the control level (P < 0.05), occurred at the HA peak, i.e. after 2 h of water loading while in the gerbil, the urine flow rate increased slowly and slightly and was only six times above control values after 6 h of water loading (P < 0.05). The HA content along the intestine was similar in the two species: lowest in the duodenum and jejunum and highest in the distal colon. To conclude, in the rat, the elevation of papillary interstitial HA during acute water loading would counteract water reabsorption by changing the physico-chemical characteristics of the interstitial matrix favouring rapid water diuresis. This would work as a complement to the powerful regulation by ADH. The gerbil has a diametrically different regulation of papillary HA turnover during water loading. The decreased papillary HA level during water loading and the slow and small diuretic response may represent a genetic difference in adaptation to enhance the ability to conserve water in an arid environment.


Liquid Crystals-Enabled AC Electrokinetics.
Phenomena of electrically driven fluid flows, known as electro-osmosis, and particle transport in a liquid electrolyte, known as electrophoresis, collectively form a subject of electrokinetics. Electrokinetics shows a great potential in microscopic manipulation of matter for various scientific and technological applications. Electrokinetics is usually studied for isotropic electrolytes. Recently it has been demonstrated that replacement of an isotropic electrolyte with an anisotropic, or liquid crystal (LC), electrolyte, brings about entirely new mechanisms of spatial charge formation and electrokinetic effects. This review presents the main features of liquid crystal-enabled electrokinetics (LCEK) rooted in the field-assisted separation of electric charges at deformations of the director that describes local molecular orientation of the LC. Since the electric field separates the charges and then drives the charges, the resulting electro-osmotic and electrophoretic velocities grow as the square of the applied electric field. We describe a number of related phenomena, such as alternating current (AC) LC-enabled electrophoresis of colloidal solid particles and fluid droplets in uniform and spatially-patterned LCs, swarming of colloids guided by photoactivated surface patterns, control of LCEK polarity through the material properties of the LC electrolyte, LCEK-assisted mixing at microscale, separation and sorting of small particles. LC-enabled electrokinetics brings a new dimension to our ability to manipulate dynamics of matter at small scales and holds a major promise for future technologies of microfluidics, pumping, mixing, sensing, and diagnostics.


Physiological skeletal gains and losses in rat mothers during pregnancy and lactation are not observed following uteroplacental insufficiency.
Fluctuations in maternal bone mass during pregnancy and lactation facilitate calcium transfer to offspring. Uteroplacental insufficiency causes fetal growth restriction and programs poor adult bone health. We aimed to characterise maternal skeletal phenotype during normal pregnancy and pregnancy complicated by uteroplacental insufficiency. Uteroplacental restriction (Restricted) or sham surgery (Control) was performed on gestational Day 18 (term=22 days) in pregnant Wistar-Kyoto rats. Maternal right femurs were collected on embryonic Day 20, postnatal Day 1 and Weeks 5, 7 and 9 postnatal. Dual-energy X-ray absorptiometry was used to quantify global bone mineral content, density and body composition. Peripheral quantitative computed tomography was utilised to determine trabecular and cortical content, density, circumferences and strength. Control rats exhibited expected reductions in trabecular and cortical content, density and bone strength from embryonic Day 20 to postnatal Day 1 (P<0.05). These skeletal alterations were absent in Restricted rats. By postnatal Day 7, bone parameters in Control and Restricted rats were not different from non-pregnant rats, indicating restoration of maternal bone. The lack of bone loss in mothers suffering uteroplacental insufficiency suggests that calcium transfer to pups would be impaired. This reduction in calcium availability is a likely contributor to the programming of poor adult bone health in growth-restricted offspring.


Decreased expression level and DNA-binding activity of specificity protein 1 via cyclooxygenase-2 inhibition antagonizes radiation resistance, cell migration and invasion in radiation-resistant lung cancer cells.
Radiation is able to inhibit tumor growth, promote tumor cell apoptosis and prolong patient survival. However, radiation resistance remains a major impediment to radiotherapy. Local and metastatic recurrences following radiation are still large impediments to overall survival. Although cyclooxygenase-2 (COX-2) inhibitors may induce radiation sensitivity in cancer cells, the underlying mechanisms are not fully understood. The present study demonstrated high potential for cell proliferation, migration and invasion in radiation-resistant lung cancer cell lines. The present study observed the overexpression of specificity protein 1 (Sp1) in these cells, and the overexpression of Sp1 induced upregulation of matrix metalloproteinase (MMP)-2, MMP-9, B cell lymphoma-2, in addition to a high potential for radiation resistance, migration and invasion in these cells. The present study revealed that the COX-2 selective inhibitor, celecoxib, enhanced radiation sensitivity and inhibited migration and invasion in these cells by inhibiting the expression and DNA-binding activity of Sp1. Furthermore, celecoxib downregulated Sp1 by inhibiting c-Jun N-terminal kinase (JNK). Taken together, the present study demonstrated that Sp1 overexpression in radiation-resistant cancer cells and COX-2 inhibitors enhanced radiation sensitivity and inhibited the migration and invasion of cancer cells, at least partially, via inactivation of the JNK/Sp1 signaling pathway and a decrease in Sp1 DNA-binding activity.


Challenges of Recruitment and Retention in Rural Areas.
There have long been rural health care workforce shortages; however, the urgency to find real solutions has increased with the changing health care landscape. The evidence makes a compelling case to be intentional in the candidates we support and to align educational resources across multiple systems. Programs need to continually evolve, utilizing workforce data, best practices, and new technological advances. This leads the Office of Rural Health (ORH) to secure funding for therapists practicing in integrated settings and to expand loan repayment to general surgeons and providers creating access through telehealth. While access is ORH's core mission, North Carolina's rural health plan reframed the discussion around creating healthy rural communities. This will require further refinement of the critical workforce definition, and it brings to the forefront the fact that a variety of new partnerships will be key to achieving the objective of healthy rural communities.


Parallel DNA circuits by autocatalytic strand displacement and nanopore readout.
DNA nanotechnology provides a unique opportunity for molecular computation, with strand displacement reactions enabling controllable reorganization of nanostructures. Additional DNA strand exchange strategies with high selectivity for input will enable novel complex systems including biosensing applications. Herein, we propose an autocatalytic strand displacement (ACSD) circuit: initiated by DNA breathing and accelerated by a seesaw catalytic reaction, ACSD ensures that only the correct base sequence starts the catalytic cycle. Analogous to an electronic circuit with a variable resistor, two ACSD reactions with different rates are connected in parallel to mimic a parallel circuit containing branches with different resistances. Finally, we introduce a multiplexed nanopore sensing platform to report the output results of a parallel path selection system at the single-molecule level. By combining the ACSD strategy with fast and sensitive single-molecule nanopore readout, a new generation of DNA-based computing tools is established.


Hydroxyethyl starch 130/0.4 (6%) and succinylated gelatine (4%) interfere with refractometry in dogs with haemorrhagic shock.
To determine if low molecular weight synthetic colloid fluids administered to dogs interfere with refractometric estimates of total plasma protein (TPPr) and urine osmolality (UOsm). Experimental study. Eighteen healthy Greyhound dogs. Anaesthetized Greyhounds subjected to haemorrhage for 60 minutes were given 80 mL kg-1 of Plasma-Lyte 148 (CRYST), or 20 mL kg-1 of hydroxyethyl starch 130/0.4 (HES) or succinylated gelatine (GELO) (n = 6 per group) intravenously over 20 minutes. Refractometric (TPPr) and biuret total plasma protein (TPPb) were measured before haemorrhage (Baseline), at end of shock (Shock), immediately (T20), then 40 minutes (T60), 100 minutes (T120) and 160 minutes (T180) after fluid administration. Urine specific gravity (USG) and UOsm were measured at all time points except T20. Estimated UOsm (eUOsm) was calculated from USG. Bias and limits of agreement (LOA) for TPPr versus TPPb, and eUOsm versus UOsm were calculated at each time point. For dogs given CRYST and GELO, median TPPr and TPPb decreased in parallel, with a small consistent TPP bias (CRYST range of bias, 0.38-0.67 g dL-1; GELO range of bias, 0.42-0.58 g dL-1). Dogs given HES showed divergence between median TPPr and TPPb after T20, with a peak bias at T20 of 1.62 g dL-1 (LOA 1.29-1.95). Dogs given HES and GELO had markedly increased USG [HES peak median USG at T180 of 1.119 (Q1-Q3 1.103-1.122); GELO peak median USG at T120 of 1.114 (Q1-Q3 1.082-1.119)], with large increases in bias between eUOsm and UOsm [HES peak bias at T60 of 2995 mOsm kg-1 (LOA 2032-3958 mOsm kg-1); GELO peak bias at T120 of 2465 mOsm kg-1 (LOA 940-3990 mOsm kg-1)]. Administration of HES and GELO to dogs with haemorrhagic shock interferes with refractometric measurements for at least 3 hours after administration.


Tracking neonicotinoids following their use as cotton seed treatments.
Neonicotinoids are a leading class of insecticides on the global market, accounting for nearly 25%. They are widely used in both agricultural and residential settings. Causing neuron failure by irreversibly binding to the insect nicotinic acetylcholine receptor, neonicotinoids offer broad spectrum efficacy against a variety of pests. However, because they are non-selective with regard to insect species, there has been some concern with neonicotinoid use over threats to pollinators such as honeybees, and potential indirect effects to migratory waterfowl as a result of invertebrate prey population depletion. In order to study occurrence and fate of neonicotinoids (thiamethoxam and imidacloprid), we analyzed cotton leaves on plants grown from neonicotinoid-treated seeds and corresponding soil samples between cotton rows. Neonicotinoid concentration data from cotton leaves appears to be consistent with the claim that seed treatments protect plants for 3-4 weeks; by 30 days post-planting, neonicotinoid concentrations fell, in general, to 200 ng/g or lower. This represents about a 10-fold decrease from plant concentrations at approximately 2 weeks post-planting. It was found that neonicotinoids used as seed treatments remained present in the soil for months post planting and could be available for runoff. To that end, 21 playa wetlands were sampled; 10 had at least one quantifiable neonicotinoid present, three of which were classified as grassland or rangeland playas, two were urban, and the remaining five were cropland playas. In several instances, neonicotinoid concentrations in playas exceeded EPA chronic benchmarks for aquatic invertebrates.


Direct cAMP signaling through G-protein-coupled receptors mediates growth cone attraction induced by pituitary adenylate cyclase-activating polypeptide.
Developing axons are guided to their appropriate targets by environmental cues through the activation of specific receptors and intracellular signaling pathways. Here we report that gradients of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide widely expressed in the developing nervous system, induce marked attraction of Xenopus growth cones in vitro. PACAP exerted its chemoattractive effects through PAC1, a PACAP-selective G-protein-coupled receptor (GPRC) expressed at the growth cone. Furthermore, the attraction depended on localized cAMP signaling because it was completely blocked either by global elevation of intracellular cAMP levels using forskolin or by inhibition of protein kinase A using specific inhibitors. Moreover, local direct elevation of intracellular cAMP by focal photolysis of caged cAMP compounds was sufficient to induce growth cone attraction. On the other hand, blockade of Ca2+, phospholipase C, or phosphatidyl inositol-3 kinase signaling pathways did not affect PACAP-induced growth cone attraction. Finally, PACAP-induced attraction also involved the Rho family of small GTPases and required local protein synthesis. Taken together, our results establish cAMP signaling as an independent pathway capable of mediating growth cone attraction induced by a physiologically relevant peptide acting through GPCRs. Such a direct cAMP pathway could potentially operate in other guidance systems for the accurate wiring of the nervous system.


Development and evaluation of a decision aid for women eligible for organized breast cancer screening according to international standards: A multi-method study.
and purpose: In France, women lack information to make a shared decision to start breast cancer screening. Decision aids are useful to facilitate this discussion, yet few meet international standards. The objective of this project was to build, validate and measure the quality of a decision aid for organized breast screening in France, in line with international standards, intended for both women and healthcare professionals. This mixed-methods study was conducted between January 2017 and June 2022. The prototype was developed from a qualitative study, systematic review and targeted literature review and alpha tested during two Delphi rounds. Readability was evaluated with the Flesch score and content with International Patient Decision Aid Standards Instrument (IPSASi). An online decision aid, accessible at www.Discutons-mammo.fr, written in French was developed. The content included eligibility, information about breast screening the advantages and disadvantages of screening, patient preferences and a patient-based discussion guide using text, infographics, and videos. The Flesch readability test score was 65.4 and the IPDASi construct quality score was 176 out of 188. This decision aid complies with IPDASi standards and could help women eligible for breast screening in France make a shared decision with a specialized healthcare professional about whether or not to participate in organized breast screening.


Trends in bacterial wound isolates and antimicrobial susceptibility in a pediatric burn hospital.
The purpose of this retrospective study was to collate data dealing with organisms cultured from the burn patients and evaluate trends in antimicrobial susceptibility. All cultures collected from each acute admission patient between 2004 and 2011 in the 30-bed pediatric burn hospital were evaluated for their annual frequency and antimicrobial susceptibility. Duplicate cultures were excluded. Staphylococcus aureus was isolated most frequently (25% of total isolates; range, 69-408 isolates/yr), followed by Pseudomonas aeruginosa (13%; range, 40-202 isolates/yr), coagulase-negative staphylococci (9%; range, 2-188 isolates/yr), Enterobacter cloacae (8%; range, 22-128 isolates/yr), and Escherichia coli (6%; range, 19-91 isolates/yr). This rank order remained relatively consistent during the period of study. The emergence of methicillin-resistant S. aureus increased from 20% in 2004 to about 45% in 2009 to 2011. Susceptibility to vancomycin was still 100%. In comparing periods 2004 to 2007 and 2008 to 2011, P. aeruginosa showed increased susceptibility to cefepime (from 76% to 84%) and the aminoglycosides (from 68% to 81%), whereas susceptibility to piperacillin-tazobactam remained high (from 91% to 93%). E. cloacae demonstrated 90 to 100% susceptibility to aminoglycosides, cefepime, and imipenem. E. coli showed an increased rate of resistance to ceftazidime but was still susceptible to imipenem and amikacin. S. aureus and P. aeruginosa continue to be the most prevalent organisms cultured from our pediatric burn population. Almost half of the staphylococcal isolates were methicillin-resistant S. aureus. Despite widespread use of piperacillin-tazobactam, P. aeruginosa susceptibility remained high. Several classes of antimicrobials continued to demonstrate good to excellent activity against the majority of organisms cultured from the burn patients.


Physiologic imaging of the brain.
Advances in imaging hardware for positron emission tomography and single-photon emission CT, coupled with a wide variety of radiopharmaceutical agents, have allowed these techniques to be used in the evaluation of neoplasm, stroke, epilepsy, and dementia. Cerebral perfusion agents continue to be the mainstay of single-photon emission CT imaging but, in addition to the evaluation of ischemia, it has seen an increasing role in the study of dementia, neuropsychiatric disorders, and seizures. Positron emission tomography scanning has had similar applications but it is playing a greater part in the evaluation of neoplasms, including primary gliomas and pituitary adenomas. Stable-xenon CT has shown value in the study of ischemia associated with meningitis, sickle cell disease, chronic subdural hematomas, and cerebral arteriovenous malformations. MR diffusion imaging shows promise in the evaluation of white matter pathology and some tumors.


Clustering of MS spectra for improved protein identification rate and screening for protein variants and modifications by MALDI-MS/MS.
It is an established fact that allelic variation and post-translational modifications create different variants of proteins, which are observed as isoelectric and size subspecies in two-dimensional gel based proteomics. Here we explore the stromal proteome of spinach and Arabidopsis chloroplast and show that clustering of mass spectra is a useful tool for investigating such variants and detecting modified peptides with amino acid substitutions or post-translational modifications. This study employs data mining by hierarchical clustering of MALDI-MS spectra, using the web version of the SPECLUST program (http://bioinfo.thep.lu.se/speclust.html). The tool can also be used to remove peaks of contaminating proteins and to improve protein identification, especially for species without a fully sequenced genome. Mutually exclusive peptide peaks within a cluster provide a good starting point for MS/MS investigation of modified peptides, here exemplified by the identification of an A to E substitution that accounts for the isoelectric heterogeneity in protein isoforms.


Respiratory microbiome profiles differ by recent hospitalization and nursing home residence in patients on mechanical ventilation.
Healthcare-associated pneumonia (HCAP) is a heterogeneous disease. We redefined nursing-home- and hospital-associated infections (NHAI) group by revising existing HCAP risk factors. The NHAI group comprised nursing home residents with a poor functional status, or recent (past 90 days) hospitalization or recent (past 180 days) antibiotic therapy. Our aim was to determine whether respiratory microbiota profiles are related to newly defined NHAI group in critically ill patients on mechanical ventilation. The 180 endotracheal aspirates (ETAs) from 60 mechanically ventilated ICU patients (NHAI group, n = 24; non-NHAI group, n = 36) were prospectively collected on days 1, 3 and 7 in a university hospital. The bacterial community profiles of the ETAs were explored by 16S rRNA gene sequencing. A phylogenetic-tree-based microbiome association test (TMAT), generalized linear mixed models (GLMMs), the Wilcoxon test and the reference frame method were used to analyze the association between microbiome abundance and disease phenotype. The relative abundance of the genus Corynebacterium was significantly higher in the pneumonia than in the non-pneumonia group. The microbiome analysis revealed significantly lower α-diversity in the NHAI group than in the non-NHAI group. In the analysis of β-diversity, the structure of the microbiome also differed significantly between the two groups (weighted UniFrac distance, Adonis, p < 0.001). The abundance of Corynebacterium was significantly higher, and the relative abundances of Granulicatella, Staphylococcus, Streptococcus and Veillonella were significantly lower, in the NHAI group than in the non-NHAI group. The microbiota signature of the ETAs distinguished between patients with and without risk factors for NHAI. The lung microbiome may serve as a therapeutic target for NHAI group.


Visual Attentional Training Improves Reading Capabilities in Children with Dyslexia: An Eye Tracker Study During a Reading Task.
Dyslexia is a specific disorder in reading abilities. The aim of this study was to explore whether a short visual attentional training could improve reading capabilities in children with reading disorders by changing their oculomotor characteristics. Two groups (G1 and G2) of 25 children with reading disabilities and who are matched in IQ (intelligence quotient), sex, and age participated in the study. The allocation of a subject to a specific group (G1 = experimental group; G2 = control group) was generated in an unpredictable random sequence. The reading task was recorded twice for G1, i.e., before (T1) and after (T2) 10 min of visual attentional training. Training consisted of oculomotor tasks (saccades and pursuits movements) and searching tasks (three different exercises). For G2, the two reading tasks at T1 and T2 were done at an interval of 10 min instead. We found that at T1, oculomotor performances during reading were statistically similar for both groups of children with reading disabilities (G1 and G2). At T2, the group G1 only improved oculomotor capabilities significantly during reading; in particular, children read faster, and their fixation time was shortest. We conclude that short visual attentional training could improve the cortical mechanisms responsible for attention and reading capabilities. Further studies on a larger number of dyslexic children will be necessary in order to explore the effects of different training types on the visual attentional span given its important role on the orienting and focusing visuospatial attention and on the oculomotor performance in children with dyslexia.


Unique genetic variation at a species' rear edge is under threat from global climate change.
Global climate change is having a significant effect on the distributions of a wide variety of species, causing both range shifts and population extinctions. To date, however, no consensus has emerged on how these processes will affect the range-wide genetic diversity of impacted species. It has been suggested that species that recolonized from low-latitude refugia might harbour high levels of genetic variation in rear-edge populations, and that loss of these populations could cause a disproportionately large reduction in overall genetic diversity in such taxa. In the present study, we have examined the distribution of genetic diversity across the range of the seaweed Chondrus crispus, a species that has exhibited a northward shift in its southern limit in Europe over the last 40 years. Analysis of 19 populations from both sides of the North Atlantic using mitochondrial single nucleotide polymorphisms (SNPs), sequence data from two single-copy nuclear regions and allelic variation at eight microsatellite loci revealed unique genetic variation for all marker classes in the rear-edge populations in Iberia, but not in the rear-edge populations in North America. Palaeodistribution modelling and statistical testing of alternative phylogeographic scenarios indicate that the unique genetic diversity in Iberian populations is a result not only of persistence in the region during the last glacial maximum, but also because this refugium did not contribute substantially to the recolonization of Europe after the retreat of the ice. Consequently, loss of these rear-edge populations as a result of ongoing climate change will have a major effect on the overall genetic diversity of the species, particularly in Europe, and this could compromise the adaptive potential of the species as a whole in the face of future global warming.


Cognitive effects of intravenous hydrocortisone in subjects with PTSD and healthy control subjects.
On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.


A specialist, second-tier response to out-of-hospital cardiac arrest: setting up TOPCAT2.
Out-of-hospital cardiac arrest (OHCA) is the most common, immediately life-threatening, medical emergency faced by ambulance crews. Survival from OHCA is largely dependent on quality of prehospital resuscitation. Non-technical skills, including resuscitation team leadership, communication and clinical decision-making are important in providing high quality prehospital resuscitation. We describe a pilot study (TOPCAT2, TC2) to establish a second tier, expert paramedic response to OHCA in Edinburgh, Scotland. Eight paramedics were selected to undergo advanced training in resuscitation and non-technical skills. Simulation and video feedback was used during training. The designated TC2 paramedic manned a regular ambulance service response car and attended emergency calls in the usual manner. Emergency medical dispatch centre dispatchers were instructed to call the TC2 paramedic directly on receipt of a possible OHCA call. Call and dispatch timings, quality of cardiopulmonary resuscitation and return-of-spontaneous circulation were all measured prospectively. Establishing a specialist, second-tier paramedic response was feasible. There was no overall impact on ambulance response times. From the first 40 activations, the TC2 paramedic was activated in a median of 3.2 min (IQR 1.6-5.8) and on-scene in a median of 10.8 min (8.0-17.9). Bimonthly team debrief, case review and training sessions were successfully established. OHCA attended by TC2 showed an additional trend towards improved outcome with a rate of return of spontaneous circulation of 22.5%, compared with a national average of 16%. Establishing a specialist, second-tier response to OHCA is feasible, without impacting on overall ambulance response times. Improving non-technical skills, including prehospital resuscitation team leadership, has the potential to save lives and further research on the impact of the TOPCAT2 pilot programme is warranted.


Multiple trans QTL and one cis-regulatory deletion are associated with the differential expression of cone opsins in African cichlids.
Dissecting the genetic basis of phenotypic diversity is one of the fundamental goals in evolutionary biology. Despite growing evidence for gene expression divergence being responsible for the evolution of complex traits, knowledge about the proximate genetic causes underlying these traits is still limited. African cichlids have diverse visual systems, with different species expressing different combinations of seven cone opsin genes. Using opsin expression variation in African cichlids as a model for gene expression evolution, this study aims to investigate the genetic architecture of opsin expression divergence in this group. Results from a genome-wide linkage mapping on the F2 progeny of an intergeneric cross, between two species with differential opsin expression show that opsins in Lake Malawi cichlids are controlled by multiple quantitative trait loci (QTLs). Most of these QTLs are located in trans to the opsins except for one cis-QTL for SWS1 on LG17. A closer look at this major QTL revealed the presence of a 691 bp deletion in the promoter of the SWS1 opsin (located 751 bp upstream of the start site) that is associated with a decrease in its expression. Phylogenetic footprinting indicates that the region spanning the deletion harbors a microRNA miR-729 and a conserved non-coding element (CNE) that also occurs in zebrafish and other teleosts. This suggests that the deletion might contain ancestrally preserved regulators that have been tuned for SWS1 gene expression in Lake Malawi. While this deletion is not common, it does occur in several other species within the lake. Differential expression of cichlid opsins is associated with multiple overlapping QTL, with all but one in trans to the opsins they regulate. The one cis-acting factor is a deletion in the promoter of the SWS1 opsin, suggesting that ancestral polymorphic deletions may contribute to cichlid's visual diversity. In addition to expanding our understanding of the molecular landscape of opsin expression in African cichlids, this study sheds light on the molecular mechanisms underlying phenotypic variation in natural populations.


Reoperations after the ross procedure in adults: towards autograft-sparing/Ross reversal.
The risk of reoperation and loss of a second native valve is a major drawback of the Ross operation. The study aim was to examine the indications, pathologies, procedures, and outcomes for reoperation after the Ross procedure, emphasizing the potential for autograft salvage. Between 1994 and 2009, a total of 60 reoperations was performed on 55 patients who previously had undergone the Ross procedure. Attention was focused on 49 patients with first-time reoperation for autograft or allograft-related problems (37 males, 12 females; mean age 49 +/- 14 years). At the original operation, 23% of patients had a history of endocarditis, 14% a previous valve replacement, and 61% a bicuspid aortic valve. The original implant technique was full root in 88% of cases, inclusion root in 2%, or subcoronary implant in 9%. Autograft and aortic indications (n = 38) included root and ascending aorta dilatation (53%), structural valve cusp deterioration (32%), endocarditis (11%), and technical failure (5%). Regurgitation was moderate to severe in 97% of cases. Pulmonary indications (n = 21) were allograft degeneration (71%), endocarditis (10%), and Ross reversal (19%). The autograft and aorta reoperation procedures (n = 38) included ascending aorta replacement (n = 2), David reimplantation (n = 1), valve repair (n = 2), valve replacement (n = 13), and root replacement (n = 22). Pulmonary valve replacements (n = 21) were with pulmonary allograft in 12 cases and autograft (Ross reversal) in nine. Twelve of the pulmonary valve replacement group, including the Ross reversals, were combined aortic and pulmonary. During the last 13 reoperations, only two autografts were lost, both of which were potentially salvageable. No intraoperative adverse events or postoperative deaths occurred, and minimal morbidity was observed. During the follow up period there was one death, while two patients required reoperation (one for endocarditis and one non-valve-related). Reoperation at up to 12 years after a Ross procedure was most commonly required for autograft failure, and less often for allograft degeneration. Of reassurance to prospective Ross patient was the finding that reoperation can be performed safely, and that the autograft can be salvaged either by repair and valve-sparing reimplantation in the aortic position, or by Ross reversal.


Epidemiological, clinical and viral determinants of the increased prevalence of high-risk human papillomavirus (HPV) infections in elderly women.
Population-based studies have reported a second peak of human papillomavirus (HPV) prevalence among women > 55 years, but reasons for this U-shaped HPV prevalence curve are poorly understood. To analyse determinants of high-risk HPV (HR-HPV) infections among postmenopausal women. A cohort of 3,187 women was stratified into three age categories: i) youngest age group < 25 years (n = 1.103); ii) women between 26-55 years (n = 2.004), and iii) women > 55 years (n = 80), analysed for epidemiological, clinical and virological determinants of their HR-HPV infections. Real-time PCR was used for HPV genotyping, analysis of viral loads for HPV16, 18/45, 31, 33/52/58, 35 and 39, and load of integrated HPV16. Age-standardised prevalence of HR-HPV infections showed a second peak among women > 55 years, with a perfect U-shaped curve (R2 = 0.966). The factors explaining this increased HR-HPV prevalence among older women include: i) cohort effect, ii) higher viral loads for HR-HPV types with cubic model curve (R2 = 0.714) for HPV 16, iii) distinct shift (p = 0.0001) from multiple-type infections to single HR-HPV types, iv) transition from episomal to integrated HPV16 (p = 0.009), v) higher load of integrated HPV16 (p = 0.009), and, vi) higher proportion of incident infections, higher rate of viral persistence, and lower rate of HR-HPV clearance. These data suggest that in women who fail to eradicate their HR-HPV infection until menopause, selection of integrated viral clone has taken place, driving the process towards progressing disease. Consequent to this, most of the HR-HPV infections in women > 55 years were associated with high-grade CIN or invasive carcinoma.


SCCRO promotes glioma formation and malignant progression in mice.
Originally identified as an oncogene activated by amplification in squamous cell carcinomas, several lines of evidence now suggest that squamous cell carcinoma-related oncogene (SCCRO; aka DCUN1D1) may play a role in the pathogenesis of a wide range of human cancers including gliomas. SCCRO's oncogenic function is substantiated by its ectopic expression, resulting in transformation of cells in culture and xenograft formation in nude mice. The aim of this study was to assess the in vivo oncogenicity of SCCRO in a murine model. Ubiquitous expression of SCCRO resulted in early embryonic lethality. Because SCCRO overexpression was detected in human gliomas, its in vivo oncogenic activity was assessed in an established murine glioma model. Conditional expression of SCCRO using a replication-competent ASLV long terminal repeat with splice acceptor/nestin-(tumor virus-A) tv-a model system was not sufficient to induce tumor formation in a wild-type genetic background, but tumors formed with increasing frequency and decreasing latency in facilitated background containing Ink4a deletion alone or in combination with PTEN loss. Ectopic expression of SCCRO in glial progenitor cells resulted in lower-grade gliomas in Ink4a(-/-) mice, whereas its expression in Ink4a(-/-)/PTEN(-/-) background produced high-grade glioblastoma-like lesions that were indistinguishable from human tumors. Expression of SCCRO with platelet-derived growth factor-beta (PDGF-beta) resulted in an increased proportion of mice forming glioblastoma-like tumors compared with those induced by PDGF-beta alone. This work substantiates SCCRO's function as an oncogene by showing its ability to facilitate malignant transformation and carcinogenic progression in vivo and supports a role for SCCRO in the pathogenesis of gliomas and other human cancers.


Seat pressure distribution.
The field of seat pressure distribution has grown more and more important in the last five decades. Compared to the early phases of development, when only a description in principle was the goal, the quantitative differentiation of force induction and furthermore the evaluation of different supporting systems by these methods have gained importance over the years. Recent developments in the ergonomic field assign increasing importance to the seat pressure distribution measurement, because now the effects of the seat design on the human body are not viewed monolinearly, but the interaction of the body and the seat is also taken into consideration in order to assess functional consequences for the person using the seat and to give guidelines for producing adequate products for the human bodysphere.


Comparing Long-term Mortality After Carotid Endarterectomy vs Carotid Stenting Using a Novel Instrumental Variable Method for Risk Adjustment in Observational Time-to-Event Data.
Choosing between competing treatment options is difficult for patients and clinicians when results from randomized and observational studies are discordant. Observational real-world studies yield more generalizable evidence for decision making than randomized clinical trials, but unmeasured confounding, especially in time-to-event analyses, can limit validity. To compare long-term survival after carotid endarterectomy (CEA) and carotid artery stenting (CAS) in real-world practice using a novel instrumental variable method designed for time-to-event outcomes, and to compare the results with traditional risk-adjustment models used in observational research for survival analyses. A multicenter cohort study was performed. The Vascular Quality Initiative, an observational quality improvement registry, was used to compare long-term mortality after CEA vs CAS. The study included 86 017 patients who underwent CEA (n = 73 312) or CAS (n = 12 705) between January 1, 2003, and December 31, 2016. Patients were followed up for long-term mortality assessment by linking the registry data to Medicare claims. Medicare claims data were available through September 31, 2015. Procedure type (CEA vs CAS). The hazard ratios (HRs) of all-cause mortality using unadjusted, adjusted, propensity-matched, and instrumental variable methods were examined. The instrumental variable was the proportion of CEA among the total carotid procedures (endarterectomy and stenting) performed at each hospital in the 12 months before each patient's index operation and therefore varies over the study period. Participants who underwent CEA had a mean (SD) age of 70.3 (9.4) years compared with 69.1 (10.4) years for CAS, and most were men (44 191 [60.4%] for CEA and 8117 [63.9%] for CAS). The observed 5-year mortality was 12.8% (95% CI, 12.5%-13.2%) for CEA and 17.0% (95% CI, 16.0%-18.1%) for CAS. The unadjusted HR of mortality for CEA vs CAS was 0.67 (95% CI, 0.64-0.71), and Cox-adjusted and propensity-matched HRs were similar (0.69; 95% CI, 0.65-0.74 and 0.71; 95% CI, 0.65-0.77, respectively). These findings are comparable with published observational studies of CEA vs CAS. However, the association between CEA and mortality was more modest when estimated by instrumental variable analysis (HR, 0.83; 95% CI, 0.70-0.98), a finding similar to data reported in randomized clinical trials. The study found a survival advantage associated with CEA over CAS in unadjusted and Cox-adjusted analyses. However, this finding was more modest when using an instrumental variable method designed for time-to-event outcomes for risk adjustment. The instrumental variable-based results were more similar to findings from randomized clinical trials, suggesting this method may provide less biased estimates of time-dependent outcomes in observational analyses.


Advanced data analysis in inertial confinement fusion and high energy density physics.
Bayesian analysis enables flexible and rigorous definition of statistical model assumptions with well-characterized propagation of uncertainties and resulting inferences for single-shot, repeated, or even cross-platform data. This approach has a strong history of application to a variety of problems in physical sciences ranging from inference of particle mass from multi-source high-energy particle data to analysis of black-hole characteristics from gravitational wave observations. The recent adoption of Bayesian statistics for analysis and design of high-energy density physics (HEDP) and inertial confinement fusion (ICF) experiments has provided invaluable gains in expert understanding and experiment performance. In this Review, we discuss the basic theory and practical application of the Bayesian statistics framework. We highlight a variety of studies from the HEDP and ICF literature, demonstrating the power of this technique. Due to the computational complexity of multi-physics models needed to analyze HEDP and ICF experiments, Bayesian inference is often not computationally tractable. Two sections are devoted to a review of statistical approximations, efficient inference algorithms, and data-driven methods, such as deep-learning and dimensionality reduction, which play a significant role in enabling use of the Bayesian framework. We provide additional discussion of various applications of Bayesian and machine learning methods that appear to be sparse in the HEDP and ICF literature constituting possible next steps for the community. We conclude by highlighting community needs, the resolution of which will improve trust in data-driven methods that have proven critical for accelerating the design and discovery cycle in many application areas.


Naturally acquired IgM antibody response to the C-terminal region of the merozoite surface protein 1 of Plasmodium vivax in Korea: use for serodiagnosis of vivax malaria.
The antibody levels against the C-terminal region of the merozoite surface protein 1 of Plasmodium vivax (PvMSP1c) were measured in 276 patients with P. vivax malaria (patient group), 320 malaria-naïve healthy individuals (control group 1), and 70 malaria-naïve individuals with various disorders (control group 2) using the immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA) and the direct sandwich ELISA. To evaluate the antibody response during relapse, 5 relapsed patients were tested using the IgM capture ELISA. The IgM antibodies were negative in 99.7% of control group 1 and in 100% of control group 2; they were positive in 90.6% of the patient group. The total antibody levels were positive in 88.4% of the patient group with the direct sandwich ELISA. The sera from the second malaria episode, i.e., relapsed patients, were 100% positive on the IgM capture ELISA. The results of this study suggest that the IgM capture ELISA may be a useful diagnostic method for P. vivax malaria for both primary infection and relapse.


The mechanism and physiological function of macroautophagy.
With regard to cell biology, one area of focus that has shifted back and forth over the years has been the relative emphasis on catabolic versus anabolic processes: the breakdown of glucose, the synthesis of DNA, the oxidation of pyruvate, the biogenesis of membranes, protein degradation, and protein synthesis. Historically, the majority of studies concerned with degradation dealt with the production of energy; however, the analysis of the ubiquitin-proteasome system revealed the importance of protein degradation for controlling various aspects of cell physiology. The ubiquitin-proteasome system is limited primarily to targeting individual proteins for destruction, but cells also have to deal with larger structures that are damaged, potentially toxic or superfluous, and these substrates, including entire organelles, are the purview of autophagy. As a general definition, autophagy encompasses a range of processes in which the cell degrades parts of itself within the lysosome (or the analogous organelle, the vacuole, in yeast and plants), followed by the release and reuse of the breakdown products. Thus, autophagy is in part a mechanism for cellular recycling, but such a definition belies the importance of the different autophagic processes in cell and organismal function and homeostasis. Indeed, defects in autophagy are associated with many human diseases and metabolic disorders. Here, we provide a brief overview of the mechanism of autophagy and some of the physiological roles in which this process is involved.


Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity.
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 microg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.


Genomic ancestry and ethnoracial self-classification based on 5,871 community-dwelling Brazilians (The Epigen Initiative).
Brazil never had segregation laws defining membership of an ethnoracial group. Thus, the composition of the Brazilian population is mixed, and its ethnoracial classification is complex. Previous studies showed conflicting results on the correlation between genome ancestry and ethnoracial classification in Brazilians. We used 370,539 Single Nucleotide Polymorphisms to quantify this correlation in 5,851 community-dwelling individuals in the South (Pelotas), Southeast (Bambui) and Northeast (Salvador) Brazil. European ancestry was predominant in Pelotas and Bambui (median = 85.3% and 83.8%, respectively). African ancestry was highest in Salvador (median = 50.5%). The strength of the association between the phenotype and median proportion of African ancestry varied largely across populations, with pseudo R(2) values of 0.50 in Pelotas, 0.22 in Bambui and 0.13 in Salvador. The continuous proportion of African genomic ancestry showed a significant S-shape positive association with self-reported Blacks in the three sites, and the reverse trend was found for self reported Whites, with most consistent classifications in the extremes of the high and low proportion of African ancestry. In self-classified Mixed individuals, the predicted probability of having African ancestry was bell-shaped. Our results support the view that ethnoracial self-classification is affected by both genome ancestry and non-biological factors.


Effect of seed sludge microbial community and activity on the performance of anaerobic reactors during the start-up period.
In this study, two laboratory-scale anaerobic batch reactors started up with different inoculum sludges and fed with the same synthetic wastewater were monitored in terms of performance and microbial community shift by denaturant gradient gel electrophoresis fingerprinting and subsequent cloning, sequencing analysis in order to reveal importance of initial quality of inoculum sludge for operation of anaerobic reactors. For this purpose, two different seed sludge were evaluated. In Reactor1 seeded with a sludge having less diverse microbial community (19 operational taxonomic unit (OTU's) for Bacterial and 8 OTU's for Archaeal community, respectively) and a methanogenic activity of 150 ml CH(4) g TVS(-1) day(-1), a chemical oxygen demand (COD) removal efficiency of 78.8 ± 4.17% was obtained at a substrate to microorganism (S/X) ratio of 0.38. On the other hand, Reactor2, seeded with a sludge having a much more diverse microbial community (24 OTU's for Bacterial and 9 OTU's for Archaeal communities, respectively) and a methanogenic activity, 450 ml CH(4) g TVS(-1) day(-1), operated in the same conditions showed a better start-up performance; a COD removal efficiency of over 98% at a S/X ratio of 0.53. Sequence analysis of Seed2 revealed the presence of diverse fermentative and syntrophic bacteria, whereas excised bands of Seed1 related to fermentative and sulfate/metal-reducing bacteria. This study revealed that a higher degree of bacterial diversity, especially the presence of syntrophic bacteria besides the abundance of key species such as methanogenic Archaea may play an important role in the performance of anaerobic reactors during the start-up period.


Prelabor rupture of the membranes at term: expectant management at home or in hospital? The TermPROM Study Group.
To determine whether adverse effects of expectant management for premature rupture of membranes (PROM) at term and patient satisfaction were greater if women were managed at home rather than in a hospital. We undertook a secondary analysis of data from the International TermPROM Study for women managed expectantly at home or in a hospital. Using multiple logistic regression analyses, we determined the effect of home and hospital management and controlled for differences in baseline characteristics, in measures of maternal and neonatal infections and rates of cesarean. Six hundred fifty-three women (39.1%) were managed at home, and 1017 (60.9%) in a hospital. Management at home, compared with in a hospital, increased risk of nulliparas needing antibiotics before delivery (odds ratio [OR] 1.52 95% confidence interval [CI] 1.04, 2.24, P =.03), those not colonized with group B streptococcus having cesareans (OR 1.48 95% CI 1.03, 2. 14, P =.04), and neonatal infections (OR 1.97 95% CI 1.00, 3.90, P =. 05). More multiparas managed at home said they would participate in the study again (OR 1.80 95% CI 1.27, 2.54, P <.001). Expectant management at home, rather than in a hospital, might increase the likelihood of some adverse outcomes.


Increase of eicosapentaenoic acid in thraustochytrids through thraustochytrid ubiquitin promoter-driven expression of a fatty acid {delta}5 desaturase gene.
Thraustochytrids, marine protists known to accumulate polyunsaturated fatty acids (PUFAs) in lipid droplets, are considered an alternative to fish oils as a source of PUFAs. The major fatty acids produced in thraustochytrids are palmitic acid (C(16:0)), n - 6 docosapentaenoic acid (DPA) (C(22:5)(n) (- 6)), and docosahexaenoic acid (DHA) (C(22:6)(n) (- 3)), with eicosapentaenoic acid (EPA) (C(20:5)(n) (- 3)) and arachidonic acid (AA) (C(20:4)(n) (- 6)) as minor constituents. We attempted here to alter the fatty acid composition of thraustochytrids through the expression of a fatty acid Δ5 desaturase gene driven by the thraustochytrid ubiquitin promoter. The gene was functionally expressed in Aurantiochytrium limacinum mh0186, increasing the amount of EPA converted from eicosatetraenoic acid (ETA) (C(20:4)(n) (- 3)) by the Δ5 desaturase. The levels of EPA and AA were also increased by 4.6- and 13.2-fold in the transgenic thraustochytrids compared to levels in the mock transfectants when ETA and dihomo-γ-linolenic acid (DGLA) (C(20:3)(n) (- 6)) were added to the culture at 0.1 mM. Interestingly, the amount of EPA in the transgenic thraustochytrids increased in proportion to the amount of ETA added to the culture up to 0.4 mM. The rates of conversion and accumulation of EPA were much higher in the thraustochytrids than in baker's yeasts when the desaturase gene was expressed with the respective promoters. This report describes for the first time the finding that an increase of EPA could be accomplished by introducing the Δ5 desaturase gene into thraustochytrids and indicates that molecular breeding of thraustochytrids is a promising strategy for generating beneficial PUFAs.


Improved flare and remission pattern in rheumatoid arthritis over recent decades: a population-based study.
To assess trends in the occurrence of flares and remission in RA over recent decades. A retrospective medical records review of each clinical visit was performed in a population-based cohort of patients with RA (age ⩾30 years; 1987 ACR criteria met in 1988-2007) to estimate flare and remission status. RA flare was defined as any worsening of RA activity leading to an initiation, change or increase of therapy (OMERACT 9). The primary definition for remission required the absence of RA disease activity (i.e. tender joint count 0, swollen joint count 0 and ESR ⩽10 mm/h) (OMERACT 7). All subjects were followed until death, migration or 1 July 2012. The study included 650 RA patients (mean age 55.8 years; 69% female) with a mean follow up of 10.3 years. Patients were flaring at 2887 (17%) visits. There was a significant decline in the RA flare rate across disease duration (P < 0.001), predominantly in the first 5 years after diagnosis of RA. Patients diagnosed with RA in more recent years experienced fewer flares during first few years of RA (P < 0.001). There was no difference between the sexes in trends of flare rates over time (P = 0.42) Current smokers had higher flare rates than non-smokers (P = 0.047) and former smokers were not different from non-smokers (P = 0.87). Patients diagnosed in more recent years have lower flare rates than those diagnosed in prior decades. Flare rates declined fastest in the first 5 years of disease and tended to be stable thereafter. Current smoking was associated with an adverse flare profile.


Gaining insight into tablet capping tendency from compaction simulation.
Capping or lamination is an unsolved common problem in tablet manufacturing. Knowledge gaps remain despite an enormous amount of effort made in the past to better understand the tablet capping/lamination phenomenon. Using acetaminophen - containing formulations, we examined the potential use of a compaction simulator as a material-sparing tool to predict capping occurrence under commercial tableting conditions. Systematical analyses of the in-die compaction data led to insight on the potential mechanism of tablet capping/lamination. In general, capping strongly correlates with high in-die elastic recovery, high Poisson's ratio, low tensile strength, and radial die-wall pressure. Such insight can be used to guide the formulation design of high quality tablet products that are free from capping problems for challenging active pharmaceutical ingredients.


Sinus node dysfunction in pediatric and young adult patients: treatment by implantation of a permanent pacemaker in 39 cases.
To examine the clinical course of sinus node dysfunction that necessitates permanent pacing in the pediatric and young adult populations, we studied the records of the 39 patients 40 years of age or younger (mean age, 23 years) who underwent implantation of a permanent pacemaker for treatment of this disorder at our medical center between 1960 and 1983. The tachycardia-bradycardia syndrome was the most common rhythm disturbance, and syncope was the most frequent initial symptom. All symptomatic patients noted resolution of symptoms after pacemaker implantation. Twenty-five of the 39 patients (64%) had associated cardiovascular disease, most commonly transposition of the great arteries. In each of the 11 patients with this anomaly, sinus node dysfunction developed after a surgical procedure for correction of the defect. Of the total patient population, 20 patients (51%) had previously undergone a cardiac operation. The mean interval between pacemaker implantation and the previous operation was 105 months. After a mean follow-up of 50.5 months, the patients with no obvious underlying heart disease have done well. Each of the eight patients who have died had underlying cardiovascular disease. None of the deaths was thought to be pacemaker related. Sinus node dysfunction should be considered in the differential diagnosis of young patients with syncope or dizziness, especially if they have undergone a reparative cardiac surgical procedure. If symptomatic sinus node dysfunction is confirmed, permanent pacing is an effective therapeutic modality. In the absence of associated heart disease, the prognosis seems to be excellent.


Project TENDR.
: Chemicals are ubiquitous in the food we eat, the water we drink, the air we breathe, and the products we use at work and in our personal lives. Toxic chemicals increase the risk of cognitive, behavioral, and neurodevelopmental disorders throughout the life span. The Toxic Substances Control Act of 1976 was intended to allow for the collection of data on and regulation of these chemicals but has been criticized for its significant limitations in protecting the public's health. In recognition of the scientific evidence demonstrating the connection between toxic environmental chemicals and neurodevelopmental disorders, Project TENDR (Targeting Environmental Neuro-Developmental Risks)-a collaborative initiative of scientists, health professionals, and children's health advocates-produced a call to action last July with the aim of reducing exposure to chemicals and pollutants that contribute to the development of these disorders.


Nutrition support pharmacist board certification process.
Specialization is the logical outcome of the maturation of the profession of pharmacy, although its acceptance has been controversial. Specialization also meets a need created by the increasing complexity of the medical management of disease. Although the skills of the generalist pharmacist are still much in demand, the specialist pharmacist has the skills and knowledge to meet more in depth, or more focused, patient care needs. The current specialties within pharmacy that are recognized by the Board of Pharmaceutical Specialties (BPS) are nuclear pharmacy, pharmacotherapy, and nutrition support pharmacy practice. Psychiatric pharmacy practice has also been approved by BPS as a specialty, however, the process for attaining certification has not yet been established. This article will describe the process by which pharmacists, whose practice is concentrated in nutrition support, may become recognized as Board Certified Nutrition Support Pharmacists (BCNSPs).


Uncertainties in IMRT dosimetry.
The purpose of this study is to investigate some characteristics of the beam delivery system and their effects on the dose distribution of intensity-modulated radiation therapy (IMRT) and the results of patient-specific IMRT quality assurance (QA). These characteristics include the accelerator source distribution and multileaf collimator (MLC) geometry. Monte Carlo dose calculations based on intensity maps that were built from the actual deliverable IMRT leaf sequences with and without considering the characteristics of the beam delivery system were performed in this study using in-house Monte Carlo software. The effect of the resolution of the intensity maps on the dose distribution was investigated first. The mean dose of the treatment target and the voxel doses in the high dose region of seven IMRT plans generated by different treatment planning systems for Varian 21EX and Siemens Primus linear accelerators were used for comparison and evaluation. The results show that a 0.2 x 0.2 mm2 or smaller pixel size is needed for the intensity maps for accurate IMRT dose calculation. The extrafocal source, MLC leaf thickness, leakage, tongue-and-groove structure, and the effective leaf offset can affect the mean dose by up to 1.5%, 4.5%, 5.6%, 5.3%, and 7.8%, respectively, when these factors are considered separately. They also cause significant uncertainties to the voxel dose with standard deviations up to 2.5%, 0.7%, 2.1%, 1.3%, and 5%, respectively. The overall effect on the mean dose is up to 8% and the standard deviation of the voxel dose uncertainty is up to 6.4% when all the effects are included. The maximum standard deviation is reduced to 4.6% if the voxel size of the dose calculation matrix is increased from 0.04 to 0.3 cm3 to make it comparable with the sensitive volume of the ionization chamber used for IMRT QA measurements. It can be concluded that the characteristics of the beam delivery system are the major contributors to the uncertainty of measurement-based IMRT QA because most of them are not fully considered in the currently available treatment planning systems.


[Recurrent hypoglycemia in the insulin autoimmune syndrome].
A 72-year-old man with recurrent hypoglycaemia was suspected of having an insulinoma. But several diagnostic methods (computed tomography; mesenteric and coeliac angiography; sella imaging) did not reveal any tumour. 72-hour hunger test did not precipitate any spontaneous hypoglycaemia. A falling insulin-glucose ratio spoke against an insulin-producing tumour. Reactive symptomatic hypoglycaemia occurred 4.5 hours after an oral glucose test. Measurement of insulin concentration demonstrated a slow but pronounced increase (3500 microU) over an already raised initial value (816 microU/ml), typical of prediabetic metabolic regulation. Demonstration of insulin autoantibodies confirmed the diagnosis of an insulin autoimmune syndrome, which has a good prognosis. The patient became free of symptoms on a regimen of frequent small, carbohydrate-poor but fat and bulk-rich meals. Hypoglycaemia recurred when the diet was not observed.